• Delusions.
  
• Hallucinations.
  
• Disordered thinking.
  
• Emotional unresponsiveness.

Because symptoms of schizophrenia arise from various physical processes and respond differently to treatments, some experts 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 experts group psychotic and disordered thinking in a single category called positive symptoms.)

The disease is complicated by the fact that although a schizophrenic patient may have more than one symptom, he or she rarely has all of them. Symptoms also often go into remission. As the mechanisms in the brain that lead to schizophrenia are being discovered, researchers are attempting to define more accurate ways of describing the disease as it relates to the biologic processes that cause them.

Negative symptoms reflect the following states:

• Diminishment of the self.
  
• Lack of emotions.
  
• Colorless speaking tones.
  
• A general loss of interest in life and the ability to experience pleasure. (One study reported that patients were able to experience unpleasant odors in a normal way, but not pleasant ones.)
  
• Inappropriate affect (a condition in which the patient displays inappropriate reactions to an event (e.g., laughing hysterically over a loss).

Often certain negative symptoms (e.g., lack of responsiveness and poor sociability) 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, particularly delusions and hallucinations, are the most widely recognized manifestations of schizophrenia.

• Hallucinations. Hallucinations are the experiences of seeing, hearing, tasting, smelling, or feeling things that don't 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. One study even reported that schizophrenic patients who had been profoundly deaf since birth were able to describe convincing experiences of hearing voices.
  
• Delusions. Delusions are fixed, false beliefs. They can be bizarre (e.g., invisible aliens have entered the room through an electric socket) or nonbizarre (e.g., unwarranted jealousy, or the paranoid belief in being persecuted or watched).

After the initial event, psychotic symptoms usually occur episodically and are interspersed with periods of remission. They typically occur in men between the ages of 17 and 30 and in women between the ages of 20 and 40.

The symptoms of cognitive impairment and disordered thinking include the following and may occur before other symptoms of schizophrenia:

• 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. As an example of a test used to diagnose this trait, the patient is given an item to look at, such as four letters on a computer screen. The screen goes blank and another image called a masking stimulus appears (such as four broken letter fragments). The patient is then asked to type in the original letters. Both symptomatic and presymptomatic patients commonly have problems with this particular exercise.

In summary, 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 (e.g., 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.

People with schizophrenia may experience other symptoms, such as intolerance of heat (which is associated with antipsychotic medications) and a reduced sense of smell.

No single cause can account for all cases of schizophrenia. Rather, it appears to be the result of multiple hits from genetic factors, environmental and psychological assaults, and possible hormonal changes that alter the brain's chemistry and trigger this devastating disease.

Abnormalities of Brain Volume and Activity. Imaging techniques have revealed reduced volume and actual loss of tissue in the brains of people with schizophrenia. Of particular importance are volume losses and abnormal activity in the prefrontal cortex and the temporal lobes .

• Reductions in volume of the prefrontal cortex have been observed in many patients with schizophrenia. This area affects verbal memory, attention, reasoning, aggression, and meaningful speech. (Not all patients have the same deficits. For example, one study reported that patients with paranoid schizophrenia tend to have preserved left prefrontal volumes.)
  
• Overactivity in the specific parts of the frontal and the right temporal lobes has been associated with auditory hallucinations (e.g., hearing voices).
  
• Loss of volume in the temporal lobe affects the limbic areas (located deep in the brain), which contain the hypothalamus, amygdala, and hippocampus. Activity in this area is related to emotions and memory, and abnormalities are associated with positive symptoms, including delusions and hallucinations, and also with disordered thinking. Some evidence suggests that abnormalities here occur after the disease process has started or may only indicate a susceptibility to the disease.

Abnormal Brain Chemicals. Schizophrenia is associated with an unusual imbalance of neurotransmitters (chemical messengers between nerve cells) and other factors.

• Abnormalities in dopamine receptors. Imbalances in the neurotransmitter dopamine are important research targets in schizophrenia. Dopamine overactivity is now known to be closely linked to reduced prefrontal cortex activity. Over-activity, particularly the left side, is associated with psychotic symptoms and appears to be due to an increase in specific chemical receptors, particularly those called C1 and D1. (These receptors attract and lock dopamine.)
  
• Abnormalities in glutamate receptors. Glutamate, an amino acid known to affect dopamine and excite nerve activity, is also under scrutiny. For example, glutamate binds to N-methyl-D-aspartate (NMDA) receptors, which play a critical role in healthy nerve development and may be abnormal in schizophrenia. Abnormalities in NMDA and other molecules in the glutamate pathway appear to play significant roles in impairment of mental function and development of negative symptoms.
  
• 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.
  
• Loss of reelin. A protein called reelin, which is involved in the nerve cell architecture, is also being investigated. Studies have observed abnormally lower levels of reelin in the prefrontal cortex region of patients with both schizophrenia and bipolar psychosis, perhaps contributing to psychosis and to impaired information processing.

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 (i.e., negative or positive) of the relative with schizophrenia.

Researchers are seeking the specific genetic factors that may be responsible for structural brain abnormalities, including reduced brain size and enlarged ventricles, that have been observed in patients with schizophrenia and their families. For example an abnormal so- gene called COMT may make people susceptible to deficits in the prefrontal cortex of the brain, where schizophrenia develops.

It should be noted that heredity does not explain all cases of the disease, however. About 60% of people with schizophrenia have no close relatives with the illness.

Viruses. The case for viruses as a cause of this disease rests mainly on circumstantial evidence, such as living in crowded conditions. The following are some studies suggesting an association:

• Winter and Spring Births. The risk for schizophrenia worldwide is 5% to 8% higher for those born during winter and spring, when colds and viruses are more prevalent.
  
• 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.
  
• Large Families. The risk for schizophrenia is also greater in large families in which there are short intervals between siblings (two or fewer years). Such observations suggest that exposure to infectious agents 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.
  
• 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 retroviruses family in 30% of people with acute schizophrenia.
  
• Some researchers have found an association between some cases of schizophrenia and toxoplasmosis (a parasite carried by cats and other domestic animals), which can lie dormant in the nervous system and migrate to the brain over many years. Schizophrenia patients who are exposed to the parasite respond poorly to clozapine treatment. There is no evidence, however, that exposure to toxoplasmosis causes schizophrenia.

Many studies have reported an association between schizophrenia and problems surrounding birth, particularly those that cause oxygen deprivation, which could effect the nerve systems in the developing brain. Specific complications that have been associated with such a higher risk include the following:

• Prolonged labor.
  
• Bleeding during pregnancy.
  
• A short gestation period and low birth weight.

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, which are 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 sufferer's circle of family and acquaintances, it is safe to assume that negative feedback can intensify deficits in a vulnerable brain and perhaps even trigger and exacerbate existing symptoms. One study to support this indicated that early parental loss, either from death or separation, increases the risk for psychiatric disorders, including schizophrenia. In another interesting 2000 study, criticism by family members was significantly correlated with the onset of disorganized thinking in patients with impaired working memory. (This effect of criticism was not observed in patients with functioning working memories.)

Schizophrenia is the most common psychotic condition; it affects about 1% of the earth's population, including more than 2.7 million people in America.

Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood. Schizophrenia that is recognized in children is likely to be severe. Although the risk of schizophrenia declines with age, there is a lesser peak incidence at around 45 years and another, mostly in women, in the mid-60s. 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 near-normal level until structural deficits in the brain break down.

Genius is not spared; schizophrenia's victims 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 harbinger of psychotic symptoms in adults.

No cultural or geographic group is immune, although the course of the disease seems to be more severe in developed than in developing countries. Also, interestingly, the content of delusions may vary depending on a person's culture. According to one study, for example, 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.

The disease 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. These statistics are likely to reflect the alienating effects of this disease rather than any causal relationship or risk factor associated with poverty or a single life. Nevertheless, low income and poverty may increase the risk for exposure to biologic factors (e.g., infections or toxins) or social stressors that could trigger the illness in susceptible people.

Although schizophrenia affects both genders, there are some differences:

• Men tend to develop schizophrenia between the ages of 15 and 24. Paranoid schizophrenia, in particular, may be more common in men, and symptoms tend to be more severe.
  
• The onset in women is usually slightly later, between 25 and 34, and the symptoms tend to be less severe. The earlier a girl starts menstruation the longer she is protected against schizophrenia, offering evidence of estrogen's nerve-protecting properties. (The higher the estrogen levels in female patients with schizophrenia, the better their mental functions.)

Non-Right Handedness. The prevalence of mixed- and left-handedness is significantly higher in patients with schizophrenia than in the general population, suggesting 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.)

Abnormal Olfactory Bulbs. Studies are reporting impairment in the sense of smell in patients with schizophrenia. One study reported abnormally small olfactory bulbs in patients with schizophrenia. Olfactory bulbs are nerve centers in the brain that regulate the sense of smell.

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 experts 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.

Malnutrition in the Pregnant Mother. Malnutrition in the mother during the first trimester of pregnancy (less than 1,000 calories a day) has been associated with later schizophrenia in the child. Nutritional deficiencies during that time are believed to impair fetal brain growth.

Father's Age. According to one 2001 study, the older a father is when a child is born, the greater the child's risk is for schizophrenia, perhaps because of a greater chance of genetic mutations in the sperm that can be passed on. In the study, children whose fathers were 50 years old or more or faced a three-fold risk for schizophrenia compared to children whose fathers were 25 or younger.

Research indicates that symptoms in childhood strongly predict disease in adult. In one long-term study, over 40% of schizophrenics who developed the disease in young adulthood had reported psychotic symptoms at 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.
  
• Mixed-handedness (the use of different hands for different tasks), particularly in females.
  
• Eye tracking dysfunction. This genetic trait is strongly associated with schizophrenia and may reflect abnormalities in the frontal regions of the brain. (Some experts believe that this is such a powerful marker in patients with close relatives with schizophrenia that it can be used as a predictor. This trait can only be detected by a health professional using special equipment.)
  
• Hallucinations or delusions. (This does not include normal childhood fantasies and stories, in which the child is aware that they are inventions.)
  
• A decline in verbal memory, IQ, and other mental functions.

Some experts suggest that screening young high-risk individuals using brain imaging techniques possibly followed by treatment may help prevent nerve damage and improve the outcome for this difficult disease.

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.

The course of the disease varies from one patient to the next. Symptoms of psychosis can become evident either gradually or suddenly.

• 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, 31% experienced a complete remission of symptoms within three 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 four or five years of the onset of psychotic symptoms. There is some evidence that the physical disease process in schizophrenia is progressive, as with Alzheimer's and Parkinson's. However, schizophrenia does not progress in the same way as those two diseases. In one study, men with schizophrenia showed an annual decline of 3% in areas in the front of the brain compared to slightly less than 1% in men without schizophrenia. Unlike Parkinson's and Alzheimer's, however, eventually cognitive function usually 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 in concert with improvements in negative symptoms.)

Although there is no cure, new drugs are offering significant hope for improving the patient's life. Even with care and adequate treatment, however, people with schizophrenia suffer. The disease has a devastating effect on all aspects of human thought, emotion, and expression.

Depression is common later in adulthood. Although , such a mood disorder can certainly be a result of the negative social impact of schizophrenia, some experts believe that depression is part of the disease process itself.

Studies indicate that after 20 to 30 years, half of schizophrenic 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.

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. Experts believe that a decline in IQ reflects early nerve damage but that it is not an inevitable consequence of the disease process.

In spite of their 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% and 50% of patients with schizophrenia attempt suicide and an estimated 9% to 13% of schizophrenics succeed.

The general risk for suicide is higher at certain times in the course of the disease:

• Within the first five years of onset of the disease.
  
• During the first six 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 agents as a way of reducing hospitalization time is increasing the incidence of suicide. Hopelessness, not delusions, appears to be the most important motive for suicide in these patients. In one study of patients who had attempted suicide, the most frequent reason given for an attempt was depression, and the second was the loss of an intimate partner. Cognitive impairment, which reduces the patient's ability to hold jobs and function normally, also seems to be a major factor in suicidal motivation.

Smoking and Other Addictions. A large majority of 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 exacerbate symptoms.

Smoking is of special interest. According to a 2000 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 in schizophrenia, then, may be a form of self-medication.

Note: Although attempts to help schizophrenic patients quit smoking usually fail, those taking atypical medications have a better chance of quitting successfully than those taking typical medications. The use of bupropion and therapeutic administration of nicotine may also help. (For further information, see the Well-Connected report, Smoking).

A 2001 study reported that children of women with schizophrenia have a significantly higher risk for stillbirth or infant death. This is most likely due, however, to their higher risk for other factors that can contribute to infancy mortality rates, such as smoking, medications, or substance abuse.

In the 1970s, tens of thousands of patients were put on antipsychotic agents 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 requires public assistance within a year of their reentry into the community. And using drugs alone has done nothing to reduce the high suicide rates among this patient group.

The physician 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 less. The flare-up consists of at least two characteristic symptoms (e.g., 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 six 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.

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. In fact, sometimes it is difficult even for experts 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. There are a number of conditions that 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 at this time 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 also 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.

A number of brain imaging techniques are becoming useful in detecting changes in the brain structure that relate to specific sets of symptoms in schizophrenia. At this time such techniques are used only as research tools, although some experts believe they may be useful for identifying candidates for early treatment among high-risk young people with early warnings signs of schizophrenia and brain damage.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) has become a particularly valuable tool for revealing parts of the brain inaccessible to other scanning methods. MRI does not use radiation, and it can show the brain from a number of different perspectives.

Other Imaging Techniques. Other imaging techniques are single photon emission computed tomography (SPECT) and positron emission tomography (PET), which can provide information on blood flow and metabolism in the brain.

Research is ongoing to find simple tests that will detect schizophrenia accurately and early enough to initiate preventive measures. Some examples include the following:

• One investigative test uses computers to analyze brain scans and identify changes in blood flow indicative of schizophrenia, even before symptoms occur. It appears to be highly reliable, and more research is warranted.
  
• A blood test that detects genetic evidence of high levels of D3 dopamine receptor may prove to useful. People with schizophrenia have over three times the normal amount of this substance.
  
• Measurements of certain esters (phosphomonoesters and phosphodiesters) may detect high-risk individuals.

Integrated Approach. Schizophrenia is now officially categorized as a brain disease, not a psychologic disorder, and drug treatment is the primary therapy. Studies indicate, however, that an integrated approach is superior in preventing relapses compared to routine care (drugs plus monitoring and access to rehabilitation programs). In one study, this approach involved the following:

• Motivational interviewing to encourage the patients' commitment to change.
  
• Use of antipsychotic medications (generally atypical or novel antipsychotics) with monitoring.
  
• Community-based rehabilitation.
  
• Cognitive-behavioral therapy, which aims to reduce delusions and hallucinations.
  
• Family interventions.

In the study, relapse rates were 33% in the integrated group and 67% in the group who received routine care. Unfortunately, such treatment is expensive. Research shows that more than half of individuals with schizophrenia does not even receive routine care. Increased cost cutting in mental health services is making the situation worse. African Americans, in particular, are less likely to receive effective treatment.

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 hospitalized less frequently during the following five years and may require less time to control the symptoms than those who do not seek help as quickly. One study, in fact, found that when patients with very early signs of schizophrenia were given low-dose medication and therapy that they reduced their risk for full-blown schizophrenia by tenfold. In spite of strong evidence for the positive effects of early treatment, patients usually endure an average of 10 months of serious symptoms before they receive treatment.

Choosing Between Atypical and Standard Antipsychotic Agents. Experts are debating whether older antipsychotics or the new atypicals should be used at the onset of symptoms. The debate includes some of the following issues:

• The atypicals are considerably more expensive than the conventional antipsychotics.
  
• Studies are increasingly reporting more rapid action and fewer dropouts from side effects with the new atypicals compared to the older antipsychotics. Furthermore, a well-conducted 2002 study reported that risperidone, an atypical, was more effective for preventing relapse than the conventional antipsychotic haloperidol. .
  
• A study on the older drugs found a higher than normal risk for sudden death from a cardiac (heart-related) event. The newer atypicals were not compared in this study, however, and some of these pose a higher risk for weight gain, diabetes, and heart disease.
  
• There appears to be no difference between atypicals and conventional antipsychotics in their ability to prevent suicide. In fact, there is some evidence that the lower hospitalization rates coinciding with the use of any of these medication may actually be increasing the risk for suicide among patients.
  
• 2001 review of 52 trials reported that patients taking the conventional antipsychotics did worse overall than those on the atypicals. When the results were examined closely, however, patients who took low doses of the standard antipsychotics (haloperidol and chlorpromazine) did as well as those on the atypicals.
  
• experts recommend the following approach:
  
• Use older antipsychotics at low doses as first-line agents for most patients.
  
• If the patients either do not respond to the conventional antipsychotics or have severe extrapyramidal effects, they should switch to atypicals.

For the severe, active phase of schizophrenia, injections of an antipsychotic drug are typically given every few hours until the patient is calm. Antianxiety agents are also often administered at the same time. Injections of some of the newer atypical agents, such as olanzapine, may prove to be as effective as the older antipsychotics with significantly fewer severe side effects. (Of particular interest is a new oral solution of the atypical agent risperidone, which may prove to be a valuable alternative in the emergency room.) In any case, if possible, physicians prefer administering a drug orally or at least switching to an oral drug as soon as possible.

In patients who are being treated for the first time, improvement in psychotic symptoms may be evident within one or two days of treatment, although the full benefit of the drug usually becomes manifest over about six to eight weeks. Thought disturbances tend to abate more gradually.

To reduce the risk of relapse, many physicians recommend that drugs be given daily for at least one year. Atypical agents 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, and 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 drug effects must be monitored carefully by the physician.

Keeping patients on maintenance therapy, however, is very difficult and many patients stop their medicaton. Two 2000 studies suggested factors that might affect either positive or negative medication compliance. In one, patients least likely to adhere to their medication regimens had the following:

• Lower occupational status.
  
• A history of alcohol or drugs abuse.
  
• Delusions of persecution.
  
• A history of stopping their medications within the first six months after diagnosis.

In the other 2000 study, patients were more likely to take their medications if they perceived their illness as severe and believed that the drugs would prevent future hospitalizations. It should be noted that neither of these studies indicated whether the medications used were standard antipsychotics or atypical agents. Adding psychotherapy, such as cognitive therapy, to the regimen may help reduce this rate.

According to a 2001 study, nearly all patients experience some relapse or worsening of symptoms within two years of stopping maintenance medication. However, in the same study they were closely monitored and medications were reinstated early enough so that only 13% required hospitalization.

Antidepressants and antianxiety agents 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.

Experts 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.

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), ziprasidone (Zeldox), and others. They appear to have fewer side effects than clozapine. Not all are available in the US.

Atypical agents have the following benefits:

• They simultaneously affect both dopamine receptors and other neurotransmitters responsible for psychotic symptoms.
  
• Some may improve negative as well as positive symptoms.
  
• Some may even improve working memory and mental functioning.
  
• They may reduce depression, hostility, and even suicide risk.
  
• These drugs, particularly the newer atypicals, have fewer side effects than the typical neuroleptics.

• Nasal congestion or runny nose.
  
• Drooling.
  
• Dizziness.
  
• Headache.
  
• Drowsiness. (In some cases, drugs may also cause restlessness and insomnia, however.)
  
• 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:

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) have been used with success in people who have difficulty complying with a daily regimen of these agents.

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:

The most disturbing and common side effects are those known as extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. In fact, a 1999 analysis reported that fewer than 12% of patients faithfully took these drugs over the course of a year, predominantly because of such adverse effects. [ See Box Extrapyramidal Side Effects.]

• Sleepiness and lethargy commonly occur in the beginning of therapy, but they usually decrease over time. It should be noted that the drugs can also cause insomnia and agitation.
  
• Gastrointestinal side effects (nausea, vomiting, diarrhea, constipation, heartburn).
  
• Dry mouth and blurred vision.
  
• Allergic reactions.
  
• Sexual dysfunction resulting from treatments 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 occur. Without prompt and expert treatment, this condition can be fatal in 20% of those who develop it.
  
• Hyperprolactinemia (high levels of the hormone prolactin) is common with 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.
  
• 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.

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 antianxiety 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.

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. The agents being investigated include:

• Tandospirone, a serotonin-agonist, which has been shown in Japanese studies to improve memory function in schizophrenic patients.
  
• Agents used for Alzheimer's patients, such as rivastigmine, are being tested for patients with schizophrenia to see if they have any benefits on memory, attention, and planning skills.
  
• Ampakines are agents that target specific glutamate receptors and may help reduce severity when used in combination with antipsychotic or atypical agent.

• B6. O ne very small 2001 study suggested that vitamin B6 (pyridoxine) therapy may help to alleviate depression in some schizophrenic patients. Further research is needed.

Between one-fifth and one-third of all patients with schizophrenia do not respond adequately to drug treatment. And, 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.

The use of cognitive-behavioral method 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. Patients with schizophrenia are taught to critically analyze hallucinations and examine underlying beliefs in them.

In a 2000 study, for example, patients underwent the following process:

• In order to think analytically about the origins and the nature of their auditory hallucinations they kept a diary of the nature of the voices and the times they were heard.
  
• They were then taught ways of coping with the voices.
  
• Patients also learned to think objectively about the source of their delusions and to find the links between thoughts that jumped from topic to topic.
  
• After the patients gained some mastery over positive symptoms, the therapist worked on negative symptoms.
  
• The patients received an average of 19 individual sessions over nine months. At a follow-up period of nine months, patients continued to improve. (A comparison group of patients who received so-called befriending therapy, which involved empathy and non-directed support, also improved during treatment, but did not get better after treatment stopped.) Another interesting behavioral approach used memory exercises to correct verbal deficits.
  
• should be noted that not all psychosocial interactions are helpful and some can even endanger the patient. For example, brief education intervention that is not extensive or therapeutic enough to lead to behavioral change may increase suicidal thoughts.

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 and they need help almost as much as the patient does. Numerous studies have shown that schizophrenic patients 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. And, two studies reported that when families received help for themselves (group support or cognitive therapy) the relapse rates for the related patients were significantly lower than for patients whose families did not seek help. For example, when families received cognitive therapy, the patient relapse rate was 37% versus 72% in the group without family support. Still, fewer than 10% of families of patients with schizophrenia receive the support and education needed not only for the patient but also for themselves. [ See Where Else Can Someone Get Help For Schizophrenia?, below.]

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 between 2% and 10% of patients now participate in such programs.

Vocational Rehabilitation. Paid work is very important in the health of the patient. One study reported that after one 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, less than a quarter of patients with schizophrenia are in programs that assist them in finding and keeping jobs, and up to 90% of patients with severe mental problems are unemployed.

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 physicians feel it is safer than drug therapy. A major 2000 analysis reported that ECT may provide some short-term relief, but it does not appear to be equal in effectiveness to drug therapies. In spite of 50 years of use, however, research on ECT and schizophrenia is limited. In one 2000 Japanese study, for example, nearly 60% of patients with schizophrenia went into remission after treatment with ECT. The US, however, may limit the output charge to the extent that it may not be as effective. (Higher currents may increase the risk for seizures.)

Some research suggests that auditory hallucinations may be due to inappropriate activation of the brain circuitry responsible for speech processing. With this in mind, some investigators are testing magnetic stimulation of the scalp in the area above and behind the left ear (which corresponds to the speech processing region). In one early study, between 60% and 70% of patients receiving this therapy experienced significant reductions in hearing voices by 50% or more. Further research is underway. Other attempts at magnetic stimulation have not been successful.

Review Date: March 2002

This Report Reviewed by:

Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

Well-Connected reports are written and updated by experienced medical writers and reviewed and edited by the in-house editors and a board of physicians who have faculty positions at Harvard Medical School and Massachusetts General Hospital. Neither Harvard Medical School nor Massachusetts General Hospital, as institutions, review or endorse their content. The reports are distinguished from other information sources available to patients and health care consumers by their quality, detail of information, and currency. These reports are not intended as a substitute for medical professional help or advice but are to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. The reports may not be copied without the express permission of the publisher.

Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School; Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center

John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts General Hospital

Edwin Huang, MD, Gynecology, Harvard Medical School; Physician, Massachusetts General Hospital

Daniel Heller, MD, Pediatrics, Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital

Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital