GENERIC NAME: clozapine BRAND NAME: Clozaril
DRUG CLASS AND MECHANISM: Clozapine is an anti-psychotic medication that works by blocking receptors in the brain for several neurotransmitters (chemicals that nerves use to communicate with each other) including dopamine type 4 receptors, serotonin type 2 receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors. Unlike traditional anti-psychotic agents, such as chlorpromazine (Thorazine) and haloperidol (Haldol) as well as the newer anti-psychotics, risperidone (Risperdal) and olanzapine (Zyprexa), clozapine only weakly blocks dopamine type 2 receptors. PRESCRIPTION: Yes GENERIC AVAILABLE: Yes PREPARATIONS: Tablets: 25 and100 mg. STORAGE: Tablets should be kept below 30°C (86 °F). PRESCRIBED FOR: Clozapine is use in the management of psychotic disorders including schizophrenia. Because of concern for the side effect of agranulocytosis (see side effects), clozapine should be reserved for patients who have failed to respond to other standard medications or who are at risk for recurring suicidal behavior. DOSING: Clozapine is given once, twice, or three times daily. The dose often is increased slowly until the optimal dose is found. The full effects of clozapine may not be seen until several weeks after treatment is begun. DRUG INTERACTIONS: Risperidone (Risperdal) may cause an increase in the amount of clozapine in the blood. This could lead to an increased risk of side effects from clozapine. PREGNANCY: There are no adequate studies of clozapine in pregnant women. Studies in animals suggest no important effects on the fetus. Clozapine can be used in pregnancy if the physician feels that it is necessary. NURSING MOTHERS: Animal studies suggest that clozapine is secreted in breast milk. Therefore, women taking clozapine should not nurse their infants. SIDE EFFECTS: Clozapine may cause a severe reduction in white blood cell count, a condition known as agranulocytosis, in approximately1 in 100 patients who take it for at least one year. White blood cells fight infections, and a severe reduction in white blood cells can result in severe infections. If not caught early, agranulocytosis can be fatal. Therefore, the white blood cell countshould bemeasured (with a blood test) prior to starting treatment and regularly (weekly) while patients receive this medication, and for 4 weeks after it is stopped. Among elderly patients with dementia-related psychosis, treatment with clozapine is associated with an increased risk of death for unclear reasons. Clozapine is not approved for use in dementia-related psychosis. Seizures have occurred in approximately 1 of every 20 to 30 persons receiving clozapine. Patients receiving higher doses seem to be at higher risk. Dizziness may occur in 1 of 5 persons taking clozapine. In some cases this may be due to orthostatic hypotension, a marked decrease in blood pressure that occurs when going from a lying or sitting position to a standing position. The drop in blood pressure may lead to loss of consciousness or even cardiac and respiratory arrest.This reaction is more common during the first few weeks of therapy while the dose is increasing, when drug is stopped briefly, or when patients are taking benzodiazepinessuch asdiazepam (Valium) or other anti-psychotic drugs. The most common side effect of clozapine is drowsiness. Other side effects include increased heart rate, increased salivation, headache, tremor, low blood pressure, and fever. Clozapine has anticholinergic effects that interfere with the function of smooth muscles. This can lead to blurred vision and difficulty urinating (when there isenlargement of
the prostate) due to effects on the muscles of the eye and bladder. Clozapine slows the intestine and leads to constipation in approximately 14% of patients. Paralysis of the intestinal muscles can lead to paralytic ileus, a conditionin which the intestine stops working.
( kloe' za peen) Clozaril PREGNANCY CATEGORY B Drug classes Therapeutic actions Indications Contraindications and cautions Available forms Dosages Adults Pediatric patients Pharmacokinetics Adverse effects Interactions Drug-drug Nursing considerations CLINICAL ALERT! Assessment Interventions Teaching points
Antipsychotic Dopaminergic blocking agent
Mechanism not fully understood: blocks dopamine receptors in the brain, depresses the RAS; anticholinergic, antihistaminic (H 1), and alpha-adrenergic blocking activity may contribute to some of its therapeutic (and adverse) actions. Clozapine produces fewer extrapyramidal effects than other antipsychotics.
• Management of severely ill schizophrenics who are unresponsive to standard antipsychotic drugs. • Reduction of the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
Contraindications and cautions
• Contraindicated with allergy to clozapine, myeloproliferative disorders, history of clozapine-induced agranulocytosis or severe granulocytopenia, severe CNS depression, comatose states, history of seizure disorders, lactation. • Use cautiously with CV disease, prostate enlargement, narrow-angle glaucoma, pregnancy.
Tablets—25, 100 mg
Initial: 25 mg PO daily or bid; then gradually increase with daily increments of 25–50 mg/day, if tolerated, to a dose of 300–450 mg/day by the end of second week. Adjust later dosage no more often than twice weekly in increments < 100 mg. Do not exceed 900 mg/day. Maintenance: Maintain at the lowest effective dose for remission of symptoms. Discontinuation: Gradual reduction over a 2-wk period is preferred. If abrupt discontinuation is required, carefully monitor patient for signs of acute psychotic symptoms. Reinitiation of treatment: Follow initial dosage guidelines, use extreme care; increased risk of severe adverse effects with re-exposure.
Safety and efficacy in patients < 16 yr not established.
• Increased therapeutic and toxic effects with cimetidine • Decreased therapeutic effect with phenytoin, mephenytoin, ethotoin
Nursing considerations CLINICAL ALERT!
Name confusion has occurred with Clozaril (clozapine) and Colazal (balsalazide); dangerous effects could occur. Use extreme caution.
• History: Allergy to clozapine, myeloproliferative disorders, history of clozapineinduced agranulocytosis or severe granulocytopenia, severe CNS depression, comatose states, history of seizure disorders, CV disease, prostate enlargement, narrow-angle glaucoma, lactation, pregnancy • Physical: T, weight; reflexes, orientation, intraocular pressure, ophthalmologic exam; P, BP, orthostatic BP, ECG; R, adventitious sounds; bowel sounds, normal output, liver evaluation; prostate palpation, normal urine output; CBC, urinalysis, liver and kidney function tests, EEG
• Use only when unresponsive to conventional antipsychotic drugs. • Obtain clozapine through the Clozaril Patient Management System. • Dispense only 1 wk supply at a time. • Monitor WBC carefully prior to first dose. • Weekly monitoring of WBC during treatment and for 4 wk thereafter. Dosage may be adjusted based on WBC count. • Monitor T. If fever occurs, rule out underlying infection, and consult physician for comfort measures. • Monitor elderly patients for dehydration. Institute remedial measures promptly; sedation and decreased thirst related to CNS effects can lead to dehydration. • Encourage voiding before taking drug to decrease anticholinergic effects of urinary retention. • Follow guidelines for discontinuation or reinstitution of the drug.
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Diagnosis Treatment Medications Psychotherap y Other Treatments Resources References Encyclopedia Schizophrenia Schizophrenia disorganize... Schizophrenia paranoid ty... More Features Printer-friendly version Schizophrenia Highlights Causes of Schizophrenia The causes of schizophrenia are unknown. Multiple factors may play a role such as genetics and brain chemistry. Risk Factors for Schizophrenia Risk factors for schizophrenia include: Age. Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood.
Gender. Schizophrenia affects both men and women, although males tend to develop it at a slightly younger age (teens and 20s) than females (20s and 30s). Family History. Schizophrenia often runs in families. Older paternal age is also being investigated as a risk factor for schizophrenia. Complications of Schizophrenia Schizophrenia can have a devastating impact on patients and their families. Patients with schizophrenia have increased risk for self-destructive behaviors and suicide. The antipsychotic drugs used to treat schizophrenia can have severe side effects, including increasing the risk of obesity and diabetes. Medications Schizophrenia is a chronic condition, which is usually treated with antipsychotic medication. There are two main classes of these drugs: Typical antipsychotics include haloperidol (Haldol), chlorpromazine (Thorazine), perphenazine (Trilafon), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), and fluphenazine (Prolixin). Side effects involving the nerves and muscle movement and coordination occur in up to 70% of patients. Typical antipsychotics are sometimes referred to as first-generation to distinguish them from newer second-generation atypical antipsychotics. Atypical antipsychotics include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and palperidone (Invega). These newer drugs may produce fewer unpleasant symptoms than the older antipsychotics but new research shows they pose a similar risk of adverse effects on the heart, which may include sudden death. In addition, recent research indicates that these drugs are no more effective than typical antipsychotics in treating some types of schizophrenia. Introduction Schizophrenia is a group of psychotic disorders that interfere with thinking and mental or emotional responsiveness. It is a disease of the brain. The term schizophrenia, which means "split mind," was first used in 1911 by Swiss psychiatrist Eugen Bleuler to categorize patients whose thought processes and emotional responses seemed disconnected. Despite its name, the condition does not cause a split personality.
Schizophrenia is a group of psychotic disorders characterized by disturbances in perception, behavior, and communication that last longer than 6 months. (This includes psychotic behavior.) A person with schizophrenia has deteriorated occupational, interpersonal, and self-supportive abilities. Schizophrenia is characterized by the following symptoms: Delusions Hallucinations Disordered thinking Emotional unresponsiveness Because symptoms of schizophrenia arise from various physical processes and respond differently to treatments, some doctors recommend classifying the disease based on the presence of the following symptom groups: Negative symptoms (including apathy and social withdrawal) Psychotic symptoms Disordered thinking Some psychiatrists group psychotic and disordered thinking into a single category called positive symptoms.
The disease is complicated by the fact that although a schizophrenic patient may have more than one symptom, the patient rarely has all of them. Symptoms also often go into remission. Causes No single cause can account for schizophrenia. Rather, it appears to be the result of multiple causes such as genetic factors, environmental and psychological assaults, and possible hormonal changes that alter the brain's chemistry. Abnormalities in Brain Structure, Circuitry, and Chemicals Brain scans using magnetic resonance imaging (MRI) have shown a number of abnormalities in the brain's structure associated with schizophrenia. Such problems can cause nerve damage and disconnections in the pathways that carry brain chemicals. Because these problems tend to show up on brain scans of people with chronic schizophrenia rather than newly diagnosed patients, some doctors believe they may be a result of the disease and its treatments rather than a cause. (Medications used for schizophrenia can also cause brain shrinkage over time.) Abnormal Brain Chemicals. Schizophrenia is associated with an unusual imbalance of neurotransmitters (chemical messengers between nerve cells) and other brain chemicals, such as dopamine overactivity, glutamate, reelin, and others. Whether any changes in these chemicals in the brain is a cause or a consequence of schizophrenia remains unclear. Abnormal Circuitry. Abnormalities in brain structure are also reflected in the disrupted connections between nerve cells that are observed in schizophrenia. Such miswiring could impair information processing and coordination of mental functions. For example, auditory hallucinations may be due to miswiring in the circuits that govern speech processing. Strong evidence suggests that schizophrenia involves decreased communication between the left and right sides of the brain. Genetic Factors Schizophrenia undoubtedly has a genetic component. The risk for inheriting schizophrenia is 10% in those who have one immediate family member with the disease and about 40% if the disease affects both parents or an identical twin. Family members of patients also appear to have higher risks for the specific symptoms (negative or positive) of the relative with schizophrenia. Researchers are seeking the specific genetic factors that may be responsible for schizophrenia in such cases. Current evidence suggests that there are a multitude of genetic abnormalities involved in schizophrenia, possibly originating from one or two changes in genetic expression. Scientists are beginning to discover the ways in
which specific genes affect particular brain functions and cause specific symptoms. Genes that have been studied include the neuregulin-1 gene, the OLIG2 gene, and the COMT gene. Heredity does not explain all cases of the disease. About 60% of people with schizophrenia have no close relatives with the illness. Infectious Factors The case for viruses as a cause of schizophrenia rests mainly on circumstantial evidence, such as living in crowded conditions. The risk is higher for people who are born in cities than in the country. The longer one lives in the city, the higher the risk. The following are some studies suggesting an association: Winter and Spring Births. The risk for schizophrenia worldwide is 5 - 8% higher for those born during winter and spring, when colds and viruses are more prevalent. Large Families. The risk for schizophrenia is also greater in large families in which there are short intervals between siblings (2 or fewer years). Such observations suggest that exposure to infection early in infancy may help set the stage for later development of the disease. Pregnant Mother's Exposure to Viruses. The mother's exposure to viral infections such as rubella, measles, chicken pox, or others while the infant is in the womb has also been associated with a higher risk for schizophrenia in her child. Researchers are trying to identify specific viruses that may be responsible for some cases. Of particular interest is research finding evidence of a virus that belongs to the HERV-W retrovirus family in 30% of people with acute schizophrenia. Some research has found an association between some cases of schizophrenia and toxoplasmosis, a parasite carried by cats and other domestic animals. Several studies suggest that patients with schizophrenia have an increased prevalence of antibodies to toxoplasmosis. Toxoplasmosis can lie dormant in the nervous system and migrate to the brain over many years. Psychologic Factors Although parental influence is no longer believed to play a major role in the development of schizophrenia, it would be irresponsible to ignore outside pressures and influences that may exacerbate or trigger symptoms. The prefrontal lobes of the brain, the brain areas often thought to lead to this disease, are extremely responsive to environmental stress. Given the fact that schizophrenic symptoms naturally elicit negative responses from the patient's circle of family and acquaintances, negative feedback may intensify deficits in a vulnerable brain and perhaps even trigger and exacerbate existing symptoms.
Risk Factors Schizophrenia is the most common psychotic condition. Age Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood. Schizophrenia in children is likely to be severe. Although the risk of schizophrenia declines with age, its incidence has been known to peak in those who are about 45 years old, and again in people who are in their mid-60s (mostly women). Late-onset schizophrenia that develops in the 40s is most likely to be the paranoid subtype with fewer negative symptoms or learning impairment. Such patients usually have functioned at a nearnormal level until structural deficits in the brain break down. Gender Although schizophrenia affects both men and women, there are some differences: Men tend to develop schizophrenia between the ages of 15 - 24. Paranoid schizophrenia may be more common in men, and symptoms tend to be more severe. The onset in women is usually slightly later, between ages 25 - 34, and the symptoms tend to be less severe. The earlier a girl starts menstruation, the longer she is protected against schizophrenia. Schizophrenia is more severe during a woman's menstrual cycle when estrogen levels are low. Such findings and other evidence suggest that estrogen may have nerve-protecting properties. For example, the higher the estrogen levels in female patients with schizophrenia, the better their mental functions. Intelligence People with schizophrenia span the full range of intelligence. In fact, one study reported that a higher than expected number of people who develop schizophrenia had been intellectually gifted children. Research suggests, however, that a decline in IQ scores during childhood may be a sign of potential psychotic symptoms in adults. Cultural and Geographic Factors No cultural or geographic group is immune from schizophrenia, although the course of the disease seems to be more severe in developed countries. However, the content of delusions may vary depending on a person's culture. According to one study, European patients were more apt to have delusions of poisoning or religious guilt while in Japan the delusions were most often related to being slandered. Socioeconomic Factors
Schizophrenia occurs twice as often in unmarried and divorced people as in married or widowed individuals. Furthermore, people with schizophrenia are eight times more likely to be in the lowest socioeconomic groups. However, these findings are likely to be a result of schizophrenia rather than a cause. Nevertheless, low income and poverty increases the risk for delayed diagnosis and treatment, and such delays could lead to more severe disease in patients with fewer resources. Famine and Malnutrition Prenatal malnutrition may also play a role in the development of schizophrenia. Some studies have found that people who are born during times of famine are more than twice as likely to develop schizophrenia as those born during years of adequate food. The association between famine and schizophrenia illustrates how environmental and biologic factors are connected. For example, scientists think that malnourished mothers may not get enough folate in their diet. Folate is a micronutrient important for genetic processes. Folate deficiencies may cause genetic mutations in the developing fetus that can lead to schizophrenia. Other Factors Associated with Schizophrenia Being Left- or Mixed-Handed. The rate of left-handedness or mixed-handedness is significantly higher among patients with schizophrenia than the general population. This suggests that some neurologic pattern that may be responsible for each. (A large minority of the population is non-right handed, and very few of these people develop schizophrenia.) Obsessive-Compulsive Disorder. Obsessive compulsive disorder (OCD) affects a significant number of schizophrenic patients. OCD is an anxiety disorder marked by obsessions (recurrent or persistent mental images, thoughts, or ideas) that may result in compulsive behaviors, repetitive, rigid, and self-prescribed routines that are intended to prevent the manifestation of the obsession. Some doctors believe the behaviors exhibited in the disorder may actually be protective in people with schizophrenia in early stages. Behavioral and Motor Problems in Childhood. Children who later develop schizophrenia often suffer from the following certain problems, including excessive shyness or minor early physical and motor-control problems. Such problems are so common, however, that their presence without any other risk factors is no cause for concern. Fathers Age. According to some studies, the older a father is when a child is born, the greater the risk is for schizophrenia in his offspring, perhaps because of a greater chance of genetic mutations in the sperm that can be passed on. In one study, children of fathers who were 50 years old or more faced a three-fold risk for schizophrenia compared to children of fathers who were 25 or younger.
Epilepsy. A family history of epilepsy increases the chance for developing schizophrenia or similar psychosis. Scientists think that epilepsy and schizophrenia may share similar genetic or environmental factors. Complications Schizophrenia has a devastating effect on all aspects of human thought, emotion, and expression. Only about 20% of patients reach full recovery after a first episode, but new drugs are offering significant hope for improving quality of life. Medical Illnesses Studies have reported that people with severe mental illnesses suffer more from serious health problems than those without mental disorders, and they are less likely to receive medical help. Substance abuse is a significant factor in this higher risk. Research has suggested an increased risk of diabetes among people with schizophrenia. In addition, many new antipsychotic medications can elevate blood sugar levels. Patients taking atypical antipsychotics drugs -- such as clozapine, olanzapine, risperidone, aripiprazole, quetiapine fumarate, and ziprasidone -- should receive a baseline blood sugar level reading and be monitored for any increases in blood sugar levels. (See Diabetes Risk and Atypical Antipsychotics in Medications section.) Depression Depression is common later in adulthood. Although this mood disorder can certainly be a result of the negative social impact of schizophrenia, some doctors believe that depression is part of the disease process itself. Effect on Social Status Studies indicate that after 20 - 30 years, half of patients are able to care for themselves, work, and participate socially. Support services and appropriate housing improve this outcome. Unsurprisingly, the decline in status, including the inability to earn a living, is less steep when there are more financial resources and fewer emotional disorders at the outset of symptoms. Also, on average, the later the onset of the disease, the milder the social impact. The long-term effects on work and relationships, however, are usually severe and difficult to repair, even if symptoms improve. Effect on Intelligence In one study, about half of patients experienced some decline in IQ (10 points or more), but intelligence scores remained the same in the other half. Researchers
believe that a decline in IQ reflects early nerve damage but that it is not an inevitable consequence of the disease process. Suicide In spite of the sometimes frightening behavior, people with schizophrenia are no more likely to behave violently than are those in the general population. In fact, these patients are more apt to withdraw from others or to harm themselves. Suicide. Between 20 - 50% of patients with schizophrenia attempt suicide, and an estimated 9 - 13% commit suicide. The general risk for suicide is higher at certain times in the course of the disease: Within the first 5 years of onset of the disease During the first 6 months after hospitalization Following an acute psychotic episode The widespread use of antipsychotic drugs over the past decade does not appear to have had much effect on suicide rates. In fact, evidence suggests that the use of these drugs as a way of reducing hospitalization time is increasing the incidence of suicide. Depression, not delusions, appears to be the most important motive for suicide in these patients. Suicide risk is also associated with prior suicide attempts, drug abuse, agitation, poor treatment compliance, fear of mental deterioration, and personal loss. Self-Destructive Behaviors Smoking and Other Addictions. Most people with schizophrenia abuse nicotine, alcohol, and other substances. Substance abuse, in addition to its other adverse effects, increases non-compliance with antipsychotic drugs in the schizophrenic patient and may worsen symptoms. Smoking is of special interest. According to one study, up to 88% of schizophrenic patients are nicotine dependent. Biologic and genetic factors may be partially responsible for the addiction in this particular group. Nicotine helps reduce psychotic symptoms and impulsivity, perhaps by inhibiting the activity of a protein called monoamine oxidase B (MAO- B), which is linked to improved mood and possibly to nerve protection. Smoking for schizophrenics, then, may be a form of self-medication. Obesity and Diabetes. Obesity is very common in patients with schizophrenia. Factors that contribute to obesity and diabetes in these patients include unstable lifestyle, low social economic status, and side effects of any antipsychotic medications. Patients should be monitored closely for onset diabetes.
Effect on Family Members Family members suffer from grief, long-term guilt, and many emotional issues when faced with a schizophrenic loved one. If these patients commit suicide, the effects can be devastating. Lack of Social and Government Support In the 1970s, tens of thousands of patients were put on antipsychotic drugs and released from institutions into the community, a concept called deinstitutionalization. In spite of these attempts to reduce mental hospital costs, schizophrenia still accounts for 40% of all long-term hospitalization days. More than half of patients with schizophrenia require public assistance within a year of their reentry into the community. Symptoms Research indicates that symptoms in childhood strongly predict disease in adulthood. In one long-term study, over 40% of people with schizophrenia who developed the disease in young adulthood had reported psychotic symptoms by age 11. For children with a family history of schizophrenia, the following inherited traits may be warning signs: Deficits in working (short-term) and verbal memory Impairments in gross motor skills (the child's ability to control different parts of the body) Attention deficits A decline in verbal memory, IQ, and other mental functions Any signs of hallucinations or delusions must be differentiated from normal childhood fantasies. Most often, early warning signs go unnoticed, and schizophrenia usually becomes evident for the first time in late adolescence or early adulthood. Schizophrenia that starts in childhood or adolescence tends to be severe. It should be strongly noted that the traits discussed above, even combinations of them, can be present without schizophrenia. Negative Symptoms A person with schizophrenia may have the following negative symptoms: Lack of self confidence Lack of emotions
Colorless speaking tones Inappropriate reactions to events (such as laughing hysterically over a loss) A general loss of interest in life and the ability to experience pleasure Lack of responsiveness and poor sociability often appear in childhood as the first indications of schizophrenia. Certain imaging techniques suggest that these findings are based on biologic changes in specific parts of the brain. In many patients, however, negative symptoms do not appear until after positive symptoms develop. Negative symptoms tend to be more common than positive symptoms in older patients and typically persist after positive symptoms have been treated. Psychotic Symptoms Psychotic symptoms, particularly delusions and hallucinations, are the most widely recognized manifestations of schizophrenia. Hallucinations. A hallucination is the experience of seeing, hearing, tasting, smelling, or feeling something that doesn't really exist. Auditory hallucinations are false senses of sound such as hearing voices that go unheard by others. They are the most common psychotic symptoms, affecting about 70% of patients. Delusions. A delusion is a fixed, false belief. It can be bizarre (such as invisible aliens have entered the room through an electric socket) or nonbizarre (such as unwarranted jealousy or the paranoid belief in being persecuted or watched). Psychotic symptoms usually occur every now and then, alternating with periods of remission. They typically occur in men ages 17 - 30 and in women ages 20 - 40. Cognitive Impairment (Disordered Thinking) The symptoms of cognitive impairment and disordered thinking may occur before other symptoms of schizophrenia. They include: A lack of attention. Impaired information processing and an aberrant association between words and ideas. Sometimes this condition is so extreme that speech becomes incoherent and is referred to as "word salad." Patients may connect words because of similarity of sound, rather than by meaning, a condition known as "clang associations." Memory impairment. In keeping with other aspects of disordered thinking, memory impairment in schizophrenia is likely to involve the inability to connect an event with its source into a complete and whole memory. For instance, a patient may recall and even feel a familiarity with a specific event but be unable to remember where, when, or how it took place.
Backward masking dysfunction. This is a trait in which a distraction causes a person to forget a preceding event. It might be an important symptom and a marker of schizophrenia even in people with normal working memories. People with schizophrenia do poorly on mental tasks requiring conscious awareness, such as verbal fluency, short-term and working memory, and processing speed. However, they are no worse than the general population in underlying (implicit) learning, such as grammar skills, vocabulary, and spatial skills (such as map reading). Some experts believe that impaired verbal memory in schizophrenia is a consequence of depression and slowness, but not a result of the disease process. Other Symptoms People with schizophrenia may experience other symptoms, such as intolerance of heat (often associated with antipsychotic medications) and a reduced sense of smell. Symptoms of Progression to Full-Blown Schizophrenia The course of the disease varies from one patient to the next. Symptoms of psychosis can become gradually or suddenly evident. In up to a third of patients, the disease is unrelenting and progresses from the first episode onward. In others, schizophrenia follows a fluctuating course with psychotic flare-ups, followed by remissions. In one study, a third of patients experienced a complete remission of symptoms within 3 years after one or more episodes. Women are more likely to go into remission, possibly because of some protective effect of estrogen on the brain. Typically, patients develop considerable cognitive dysfunction (disordered thinking) within the first 4 - 5 years of the onset of psychotic symptoms. Some evidence indicates that the physical disease process in schizophrenia is progressive, as with Alzheimer's and Parkinson's disease. However, schizophrenia does not progress in the same way as those two diseases. Unlike Parkinson's and Alzheimer's, cognitive function usually eventually stabilizes. Psychosis, disorganized thought, and negative symptoms often improve over time, although, even in such cases, deficits in verbal memory usually persist. (Thought disorder often improves along with improvements in negative symptoms.) Diagnosis The doctor will use one or more verbal screening tests to help determine whether a patient's symptoms meet the criteria for schizophrenia. Because no single symptom
is specific to schizophrenia, a diagnosis may be made when one or more of the following conditions is present: If a patient has at least one active flare-up lasting a month or more. The flare-up consists of at least two characteristic symptoms (such as hallucinations, delusions, evidence of disorganized thinking, and emotional unresponsiveness with a flat speaking tone). If the patient has particularly bizarre delusions or hallucinations, even in the absence of other characteristic symptoms. If certain symptoms are present for at least 6 months, even in the absence of active flare-ups. Such symptoms include marked social withdrawal, peculiar behavior (talking to oneself, severe superstitiousness), vague and incoherent speech, or other indications of disturbed thinking. The patient's social and personal relationships would also have deteriorated since the onset of symptoms. Ruling Out Other Conditions The common hallmarks of schizophrenia are also symptoms that can occur in dozens of other psychologic and medical conditions, as well as with certain medications. Shared symptoms include delusions, hallucinations, disorganized and incoherent speech, a flat tone of voice, and bizarrely disorganized or catatonic behavior (such as lack of speech, muscular rigidity, and unresponsiveness). Among the conditions that may resemble schizophrenia are the following: Depression. Delusions that focus on a physical abnormality or disease that isn't real, known as somatic delusions, sometimes occur in people with depression. Bipolar Disorder. Paranoia and delusions of grandeur (the belief that one has a special power or mission) can occur in people with bipolar disorder during the manic phase. Sometimes it is difficult even for doctors to differentiate between these two disorders. Evidence suggests that they may share certain genetic factors that make some families vulnerable to either one. Schizophrenia-Like Psychoses. Several other conditions exhibit schizophrenia-like psychoses but do not meet the diagnostic criteria for schizophrenia. Such conditions may be variations of entirely different diseases and are classified as schizoaffective disorder, schizophreniform psychosis, and atypical and brief reactive schizophrenia. Alcohol and Drug Abuse. Either substance abuse itself or withdrawal from drugs or alcohol can trigger psychosis. Because of the high risk for substance abuse among people with schizophrenia, it is important that the health professional distinguish psychosis triggered by drugs or alcohol from a schizophrenic episode. Usually, the diagnosis is confirmed if the psychosis ends after withdrawal from drugs or alcohol, and returns if the patient returns to alcohol or substance abuse.
Medical Illnesses. Other causes of psychotic symptoms include cancer in the central nervous system, encephalitis, neurosyphilis, thyroid disorders, Alzheimer's disease, epilepsy, Huntington's disease, multiple sclerosis, stroke, Wilson's disease, some vitamin B deficiencies, and systemic lupus erythematosus. Medication Reactions. Many medications may induce psychosis as a side effect, and some can precipitate delusions and severe confusion. Such medication-induced symptoms are most often observed in elderly patients. Imaging Techniques Many brain imaging techniques can detect changes in the brain structure that relate to specific sets of symptoms in schizophrenia. These imaging techniques include magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). Such techniques are used as research tools. However, research continues in evaluating whether they may be useful for identifying candidates for early treatment among high-risk young people with early warnings signs of schizophrenia and brain damage. Treatment Schizophrenia is categorized as a brain disease, not a psychological disorder, and drug treatment is the primary therapy. Studies indicate, however, that an integrated approach better prevents relapses than routine care (medication, monitoring, and access to rehabilitation programs). Integrated Approach. An integrated approach, which may help to ease psychotic symptoms, may include: Motivational interviewing to encourage the patient's commitment to change Use of antipsychotic medications (generally atypical or novel antipsychotics) with monitoring Community-based rehabilitation and social skills training Family psychotherapy Cognitive-behavioral therapy to reduce delusions and hallucinations Treatment of schizophrenia has traditionally focused on decreasing patients negative symptoms. Today, an important shift is now taking place. Doctors are now emphasizing patients ability to function -- shop, eat, cook, clean, do laundry, and in some cases, work independently. Early Treatment. The earlier schizophrenia is detected and treated, the better the outcome. Patients who receive antipsychotic drugs and other treatments during their first episode are admitted to the hospital less often during the following 5
years and may require less time to control symptoms than those who do not seek help as quickly. In spite of strong evidence for the positive effects of early treatment, patients usually do not receive treatment until after 10 months of serious symptoms. Classes of Drugs Used for Schizophrenia Most drugs that treat schizophrenia work by blocking receptors of the neurotransmitter dopamine. Dopamine is thought to play a major role in psychotic symptoms. Although the drugs used to treat schizophrenia have important benefits, they may also cause side effects. The most disturbing and common side effects are those known as extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. The following drug classes are generally used for schizophrenia: Typical antipsychotics. Until recently, these drugs were the mainstay treatments for schizophrenia. They include haloperidol (Haldol), chlorpromazine (Thorazine), perphenazine (Trilafon), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), and fluphenazine (Prolixin). Side effects involving the nerves and muscle movement and coordination occur in up to 70% of patients. Typical antipsychotics are sometimes referred to as first-generation to distinguish them from newer second-generation atypical antipsychotics. Atypical antipsychotics. These newer drugs may be better tolerated than the older antipsychotics but new research contradicts the belief that they are safer for the heart. They include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and palperidone (Invega). Which Type of Drug to Choose. Doctors have debated whether newer atypical antipsychotics carry a treatment advantage over the older typical antipsychotics, which are much less expensive. Most practicing psychiatrists feel that atypical antipsychotics may work better than the older drugs. However, the additional benefits may be modest for most patients. Large, high-quality studies have compared newer and older drugs and generally found that newer atypical antipsychotics work no better than older typical antipsychotics such as haloperidol, at least for initial treatment of first-episode schizophrenia Similarly, for treatment of children and adolescents with schizophrenia, both atypical and typical antipsychotics appear to be equally effective, but atypical antipsychotics carry a higher risk for metabolic side effects. Side effect profiles between typical and atypical antipsychotics are different. Both groups cause extrapyramidal side effects, (including muscle stiffness, tremors, and abnormal movements), but the newer atypical drugs do not seem to cause them as
often. However, the atypical antipsychotics pose a higher risk for weight gain, which can lead to diabetes as well as heart disease. One problem with most of the studies that evaluate these medications is that often more than half the patients discontinue the drugs either because of side effects or because they do not feel the medications are helping them. In 2007, risperidone and aripiprazole became the first atypical antipsychotics approved for treatment of schizophrenia in adolescents (ages 13 - 17 years). Doctors caution that more research is needed to determine the long-term safety and efficacy of these drugs for pediatric patients. Treating an Acute or Initial Phase For the severe, active phase of schizophrenia, injections of an antipsychotic drug are typically given every few hours until the patient is calm. Anti-anxiety drugs are also often administered at the same time. Some of the newer atypical drugs, such as olanzapine or risperidone, may prove to be as effective as the older antipsychotics with significantly fewer severe side effects. In patients who are being treated for the first time, improvement in psychotic symptoms may be evident within 1 - 2 days of treatment, although the full benefit of the drug usually manifests over about 6 - 8 weeks. Thought disturbances tend to abate more gradually. Maintenance To reduce the risk of relapse, many doctors recommend that drugs be given daily for at least 1 year. Atypical drugs are increasingly being used as maintenance for those with new-onset psychosis, although the choice of the drug depends on many factors. Side effects and effectiveness vary from individual to individual. 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. The doctor must monitor the drug effects carefully. Keeping patients on maintenance therapy, however, is very difficult, and many patients stop their medication. Factors that may contribute to poor compliance include: Lower occupational status A history of alcohol or drugs abuse Delusions of persecution A history of stopping medications within the first 6 months after diagnosis Stopping Medications
Nearly all patients experience some relapse or worsening of symptoms within 2 years of stopping maintenance medication. Recognizing signs of relapse and starting medications immediately can help prevent rehospitalization for these patients. Supportive Drugs Antidepressants and anti-anxiety drugs may also play an important role in treating the patient with schizophrenia, particularly given the role of depression in the high rates of suicide among these patients. General Guidelines for Psychological Treatments Psychiatrists generally agree that current treatment should offer both medical and psychological treatment to the patient. Cognitive-behavioral approaches are showing promise. Support to the family or other caregiver is also important for the long-term improvement of people with schizophrenia. 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 antianxiety 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 antianxiety 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. Psychotherapy One-fifth to one-third of all patients with schizophrenia do not respond adequately to drug treatment. Many patients who have been successfully treated with medications experience the "awakenings" phenomena, which are painful reactions that are manifested as inner emotions and the recognition of real losses. The effects of the disease, in any case, are profoundly emotional. As a result, psychological therapies can be helpful for many patients. Cognitive-Behavioral and Other Psychosocial Therapies The use of cognitive-behavioral therapy is showing particular promise for improvement in both positive and negative symptoms in some patients, and the benefits may persist after treatment has stopped. This approach attempts to strengthen the patient's capacity for normal thinking, using mental exercises and self-observation. More evidence is showing that improving patients' ability to learn, remember, and pay attention allows them to better cope with ongoing positive symptoms and lead independent lives. Patients with schizophrenia are taught to critically analyze hallucinations and examine underlying beliefs in them. Family and Outside Support Structures Positive social interaction is extremely important for people with schizophrenia and may help reduce symptoms, including the number of delusional moments. Family Support. It is deeply painful for anyone to interact with a loved one whose behavior is determined by a mysterious internal mechanism that has gone awry. Given support and direction, however, families or other caregivers can be very helpful in a number of ways: They can encourage patients to comply with drug treatments and to recognize early signs of serious treatment side effects. They can be taught to recognize impending symptoms of relapse and help the patient avoid situations that might trigger them. (Symptoms for an impending relapse after remission may include feeling distant from family and friends, being increasingly bothered by persistent thoughts, and having an increased interest in religion.)
Unfortunately, the family's own mental health is often threatened. As a result, caretakers also need help. Numerous studies have shown that patients with schizophrenia do worse in families who are too emotional, hostile, critical, or even overly involved. The problem is an emotional loop: When affection and reason have failed to bring a loved one back to reality, overly critical or emotional family members typically react with anger and frustration. This generates anxiety and depression in patients. The subsequent expression of these emotions by the patient triggers yet more criticism or acting out. So the cycle continues. Eventually, out of despair and fear, the family may reject the patient completely. Studies indicate that once the patient receives appropriate treatment and support, the family's over-emotional state also recedes. Some studies have reported that when families receive help for themselves (group support or cognitive therapy) the relapse rates for the related patients are significantly lower than for patients whose families did not seek help. Still, only a small number of families of patients with schizophrenia receive the support and education needed not only for the patient but also for themselves. Community Treatment Programs. Community treatment programs, in which a team of professional caregivers provides treatment and support for patients in their homes, is highly beneficial and cost effective (compared to frequent hospitalization). At this time, however, only a small percentage of patients participate in such programs. Vocational Rehabilitation. Paid work may help the mental health of the patient. One study reported that after 1 year, 40% of workers with schizophrenia who were paid for their labor reported much improvement in all symptoms, and 50% reported much improvement in positive symptoms. Those who were not paid for their work did considerably less well. (The arts and crafts activities that are often used to enhance self-esteem in rehabilitation programs offer few real benefits to the patient.) Unfortunately, at this time, few patients with schizophrenia are in programs that help them find and keep jobs, and up to 90% of patients with severe mental problems are unemployed. Other Treatments Electroconvulsive therapy (ECT), often called shock treatment, has received bad press since it was introduced in the 1940s. However, refined techniques have revived its use, particularly for those with severe depression. Imaging studies have not found that current ECT techniques cause any damage to the brain's structure,
and some doctors feel it is safer than drug therapy. A recent review of many clinical trials indicated that ECT combined with antipsychotic medication can provide rapid improvements for patients who are suicidal or severely psychotic. The review found that the combined treatment worked better than antipsychotics alone for these patients. ECT treatments are usually given 2 - 3 times a week, for a total of 8 - 12 sessions. Transcranial Magnetic Stimulation Investigators are testing a procedure called slow repetitive transcranial magnetic stimulation (rTMS), which affects brain activity in the cerebral cortex. The procedure uses an electromagnet placed on the scalp to administer magnetic stimulation to the brains cerebral cortex. This region of the brain appears to be associated with auditory hallucinations. A review of 15 clinical trials indicated that rTMS may be an effective treatment for auditory hallucinations. Further research is underway.