Schizophrenia(精神分裂症)
Schizophrenia is a mental disorder that makes it difficult to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses, and to behave normally in social situations.
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.
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.
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 anti-anxiety 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 anti-anxiety 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 brain’s 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.
Visualizing Schizophrenia
By IRENE WIELAWSKI
Paul Thompson, Ph.D.
Paul Thompson is professor of neurology at the University of California, Los Angeles, and leads the research group at the school’s Laboratory of Neuro Imaging. He uses imaging technology to map disease processes involving the human brain, carried out in collaboration with the National Institutes of Health and more than 40 laboratories around the world. A goal is to create disease-specific atlases of the brain that can aid in the diagnosis, treatment and possible prevention of illnesses like schizophrenia.
Q. Your team has found evidence of significant and progressive brain damage in people with schizophrenia. What areas of the brain are affected, and how does this account for symptoms?
A. The damage in schizophrenia appears specific to two basic areas: the parietal cortex and the frontal lobe.
The parietal cortex is located just above the temple area by the ears; it’s the part of the brain that makes sense of what we hear, see, taste or touch — essentially, our sensory experience. We know about differences in function between a normal parietal cortex and a damaged one from people who have suffered brain trauma. They can’t make sense of what something is. They may be given an apple or an orange, and they can see it and touch it, but they can’t name it or understand its purpose.
The frontal lobe helps us organize our lives, go to work, analyze information and make decisions. This area of the brain is where teenagers have the most developmental changes — a process of pruning excess cells and streamlining brain function until it reaches its adult form around age 25. This reshaping process seems to go profoundly awry in young people with schizophrenia. Instead of healthy pruning, you see massive loss of brain tissue. Because the frontal cortex is also the part of the brain that prevents you from doing things that are rash, a result of this damage is that people with schizophrenia may behave in a bizarre way; they may shout in public or react in an exaggerated way to minor upsets. Ten percent of schizophrenia patients die by suicide.
Q. What causes the damage, and over what period of time does it take place?
A. Mapping this timeline was one of the things we wanted to accomplish through our imaging studies of young people with schizophrenia. From images taken at regular intervals of literally hundreds of patients and control subjects, we created an aggregate image of the disease process — basically, time-lapse movies of what happens when and at what rate. In the movies, you see this traveling wave of tissue loss, starting with the parietal cortex and then relentlessly sweeping forward into the frontal lobe. We’ve calculated the tissue loss at over 5 percent a year, which is comparable to Alzheimer’s disease — brain cells are actually dying as a result of schizophrenia.
Q. Clinically, there’s great variation in schizophrenia patients. Some are able to hold jobs and sustain relationships while others are severely disabled. How does this variation show up in the brain?
A. It appears that the amount of tissue loss depends upon the age at which you develop the illness. If it comes on in your early teens, up to 25 percent of your brain tissue can be lost over a period of about five years. That is very severe — comparable to Alzheimer’s in the degree of damage, but different in that schizophrenia does not attack every area of the brain.
If you develop schizophrenia later, with your first psychotic episode in your latter 20s, brain tissue loss appears to be no more than 1 percent a year. Because it is a much slower process, the opportunities to intervene with drugs are greater. In brain scans of people who developed schizophrenia later and have lived with the illness for a long time, we see maybe only 10 percent to 15 percent of tissue loss over all.
Q. For centuries, mental illness could be described only by its external symptoms, with causal theories that ranged far outside the boundaries of science, including devil-possession and witchcraft. How did scientists come to see schizophrenia as a brain-damaging disease?
A. The earliest sign of structural differences in the brains of people with schizophrenia came in the 1970s. Eve Johnstone, a scientist in Scotland, used 3-D X-ray and found that the fluid-filled spaces in the brain, called ventricles, were abnormally large in people with schizophrenia. There was huge controversy when she reported it. A lot of people didn’t believe it, partly because you couldn’t see the pathology on autopsy the way you can with neurologic diseases like Alzheimer’s, where the amyloid plaques so toxic to brain cells are clearly visible. It led to a huge flurry among scientists to identify which parts of the brain are damaged in schizophrenia, why you don’t see pathology on autopsy when you can see it on imaging, and so on.
The next big step was having the tool of M.R.I. in the mid-1980s, which greatly aided these investigations. But because no two brains are exactly alike structurally, it’s difficult to identify a subtle disease process or make a diagnosis simply with one image — as you can with a single X-ray of a broken leg. It required a lot of mathematics, a lot of computer science and really a lot of ingenuity to figure out what were the collective differences between people with healthy brains and people with schizophrenia. We needed to establish scientifically consistent patterns of difference.
Q. How did you achieve this?
A. Judith Rapoport at the N.I.H. proposed imaging the brains of children with schizophrenia every two years in order to assemble a scan database to see if there were changes over time. Similar studies were under way in Scotland. Basically, by the year 2000, we had hundreds and hundreds of scans from schizophrenia patients and from controls, collected every two years over six years.
What we then did was to merge them into a time-lapse movie of brain changes in people with schizophrenia. It’s comparable to what you would get from time-lapse photography of the weather in your backyard if you took a photo every hour. You would see clouds moving around and wind and maybe some rain, but if you were simply standing outside you wouldn’t necessarily focus on these changes or notice how they came about. By using mathematics, we were able to string these images into a movie; the random variations go away if you have enough scans.
Q. Were the movies surprising?
A. We were absolutely staggered by the amount of tissue loss in the subjects with schizophrenia compared to controls. We had expected, of course, to see some loss of tissue, because we already knew from earlier findings that there were excessive fluid-filled spaces in the brains of people with schizophrenia, which suggests tissue loss. But the degree of loss that we saw in our scans was shocking.
We were also surprised to find that this destruction has a shifting pattern. Most neurological illnesses affect one part of the brain. If you have epilepsy, for example, typically the seizures have a focus. But it is quite different in schizophrenia. You have this progressively spreading wave of grey matter loss — brain cells that can never be replaced.
The first sign of schizophrenia is usually a psychotic break, with hallucinations and sensory distortions. The patient may think someone is talking to them who is not really there, for example. Our brain scans in this very early stage of illness showed structural changes in the parietal cortex — damage that would be consistent with these psychotic symptoms.
But then the tissue loss progressed to the frontal lobe, which controls our ability to regulate behavior and make sense of sensory perceptions. These images support a theory of schizophrenia that there’s some trigger that causes the normal pruning of brain cells that goes on throughout the teenage years to be accelerated, leaving the patient with insufficient brain tissue to function normally.
Q. These movies are quite stark in their depiction of schizophrenia’s impact on brain tissue, yet you refer only to “theories” of how and why.
A. That’s absolutely correct. Schizophrenia is so horrendously complicated from a scientific point of view that everything one says has to be qualified. This is true for all the mental illnesses. There’s simply no agreed-upon physical marker in the brain for what causes them. There are various theories, but even the most basic information is a matter of debate.
This makes mental illness very tricky to treat, in contrast to many neurological illnesses. In Alzheimer’s disease and epilepsy, for example, we know exactly what is happening in the brain. We may not be able to prevent it in all cases, but we know what the structural and functional change is, which greatly helps us to develop treatments to intervene somehow in the disease process and stop or lessen the damage. In mental illness, we’re not so far along.
Q. What cause-and-effect theories are scientists pursuing?
A. There are three basic theories, all of which rest on a genetic base, since schizophrenia runs in families. We’ve already discussed one — that some unknown trigger causes exaggerated pruning of brain cells, leaving the patient with insufficient tissue to function normally.
The second theory has to do with inadequate myelin coating. Myelin is a taffy-like substance that insulates your brain cells and enables communication among them — as much as 100 times faster than if the cells had no myelin. We know that some of the drugs that are effective in treating schizophrenia promote myelin growth. So if you put the drug findings together with the cell damage findings, it makes sense that even with drastic loss of brain tissue, improved myelin growth could ameliorate symptoms.
The third theory has to do with chemical imbalance, specifically excessive amounts of the brain chemical dopamine. Some schizophrenia cases are environmentally triggered; there may be a genetic predisposition, but the activating trigger is external — stress, possibly, or trauma or, in a significant number of cases, drug abuse. Schizophrenia-like symptoms have been observed in people who use methamphetamine, and we know the effect of this drug is to stimulate the release of a huge amount of dopamine into the brain. At the same time, we know that some medicines for schizophrenia act to limit dopamine. This makes a very powerful case for schizophrenia being caused by dopamine imbalance.
Q. Even if the specific mechanism of schizophrenia remains elusive, how can better knowledge of its impact on brain structure contribute to treatment?
A. With any illness, it is extremely important to know if it is progressing. If you are a patient or the doctor treating a patient, you need information on the degree of change not only in clinical symptoms — how the patient feels, say — but also with regard to what’s going on inside the body. In cancer, for example, we can measure tumor size to know if the chemotherapy is working. This is just as important for mental illnesses.
There are many questions which better knowledge of brain changes could help answer. How far along is the disease? Is a particular medication effective in slowing or preventing progression — actually saving brain tissue? If so, when is the best time to start a patient on this medication? Is the maximum effect achieved in the first year, or should they continue taking it, bearing in mind that many of the drugs have side effects? And for people with a family history who are worried about developing schizophrenia, can you reassure them that their brain is O.K.? All of these questions require a means to see into the brain, understand the difference between normal and damaged structures, and measure progression in the context of treatment.
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.
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.
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 anti-anxiety 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 anti-anxiety 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 brain’s 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.
Visualizing Schizophrenia
By IRENE WIELAWSKI
Paul Thompson, Ph.D.
Paul Thompson is professor of neurology at the University of California, Los Angeles, and leads the research group at the school’s Laboratory of Neuro Imaging. He uses imaging technology to map disease processes involving the human brain, carried out in collaboration with the National Institutes of Health and more than 40 laboratories around the world. A goal is to create disease-specific atlases of the brain that can aid in the diagnosis, treatment and possible prevention of illnesses like schizophrenia.
Q. Your team has found evidence of significant and progressive brain damage in people with schizophrenia. What areas of the brain are affected, and how does this account for symptoms?
A. The damage in schizophrenia appears specific to two basic areas: the parietal cortex and the frontal lobe.
The parietal cortex is located just above the temple area by the ears; it’s the part of the brain that makes sense of what we hear, see, taste or touch — essentially, our sensory experience. We know about differences in function between a normal parietal cortex and a damaged one from people who have suffered brain trauma. They can’t make sense of what something is. They may be given an apple or an orange, and they can see it and touch it, but they can’t name it or understand its purpose.
The frontal lobe helps us organize our lives, go to work, analyze information and make decisions. This area of the brain is where teenagers have the most developmental changes — a process of pruning excess cells and streamlining brain function until it reaches its adult form around age 25. This reshaping process seems to go profoundly awry in young people with schizophrenia. Instead of healthy pruning, you see massive loss of brain tissue. Because the frontal cortex is also the part of the brain that prevents you from doing things that are rash, a result of this damage is that people with schizophrenia may behave in a bizarre way; they may shout in public or react in an exaggerated way to minor upsets. Ten percent of schizophrenia patients die by suicide.
Q. What causes the damage, and over what period of time does it take place?
A. Mapping this timeline was one of the things we wanted to accomplish through our imaging studies of young people with schizophrenia. From images taken at regular intervals of literally hundreds of patients and control subjects, we created an aggregate image of the disease process — basically, time-lapse movies of what happens when and at what rate. In the movies, you see this traveling wave of tissue loss, starting with the parietal cortex and then relentlessly sweeping forward into the frontal lobe. We’ve calculated the tissue loss at over 5 percent a year, which is comparable to Alzheimer’s disease — brain cells are actually dying as a result of schizophrenia.
Q. Clinically, there’s great variation in schizophrenia patients. Some are able to hold jobs and sustain relationships while others are severely disabled. How does this variation show up in the brain?
A. It appears that the amount of tissue loss depends upon the age at which you develop the illness. If it comes on in your early teens, up to 25 percent of your brain tissue can be lost over a period of about five years. That is very severe — comparable to Alzheimer’s in the degree of damage, but different in that schizophrenia does not attack every area of the brain.
If you develop schizophrenia later, with your first psychotic episode in your latter 20s, brain tissue loss appears to be no more than 1 percent a year. Because it is a much slower process, the opportunities to intervene with drugs are greater. In brain scans of people who developed schizophrenia later and have lived with the illness for a long time, we see maybe only 10 percent to 15 percent of tissue loss over all.
Q. For centuries, mental illness could be described only by its external symptoms, with causal theories that ranged far outside the boundaries of science, including devil-possession and witchcraft. How did scientists come to see schizophrenia as a brain-damaging disease?
A. The earliest sign of structural differences in the brains of people with schizophrenia came in the 1970s. Eve Johnstone, a scientist in Scotland, used 3-D X-ray and found that the fluid-filled spaces in the brain, called ventricles, were abnormally large in people with schizophrenia. There was huge controversy when she reported it. A lot of people didn’t believe it, partly because you couldn’t see the pathology on autopsy the way you can with neurologic diseases like Alzheimer’s, where the amyloid plaques so toxic to brain cells are clearly visible. It led to a huge flurry among scientists to identify which parts of the brain are damaged in schizophrenia, why you don’t see pathology on autopsy when you can see it on imaging, and so on.
The next big step was having the tool of M.R.I. in the mid-1980s, which greatly aided these investigations. But because no two brains are exactly alike structurally, it’s difficult to identify a subtle disease process or make a diagnosis simply with one image — as you can with a single X-ray of a broken leg. It required a lot of mathematics, a lot of computer science and really a lot of ingenuity to figure out what were the collective differences between people with healthy brains and people with schizophrenia. We needed to establish scientifically consistent patterns of difference.
Q. How did you achieve this?
A. Judith Rapoport at the N.I.H. proposed imaging the brains of children with schizophrenia every two years in order to assemble a scan database to see if there were changes over time. Similar studies were under way in Scotland. Basically, by the year 2000, we had hundreds and hundreds of scans from schizophrenia patients and from controls, collected every two years over six years.
What we then did was to merge them into a time-lapse movie of brain changes in people with schizophrenia. It’s comparable to what you would get from time-lapse photography of the weather in your backyard if you took a photo every hour. You would see clouds moving around and wind and maybe some rain, but if you were simply standing outside you wouldn’t necessarily focus on these changes or notice how they came about. By using mathematics, we were able to string these images into a movie; the random variations go away if you have enough scans.
Q. Were the movies surprising?
A. We were absolutely staggered by the amount of tissue loss in the subjects with schizophrenia compared to controls. We had expected, of course, to see some loss of tissue, because we already knew from earlier findings that there were excessive fluid-filled spaces in the brains of people with schizophrenia, which suggests tissue loss. But the degree of loss that we saw in our scans was shocking.
We were also surprised to find that this destruction has a shifting pattern. Most neurological illnesses affect one part of the brain. If you have epilepsy, for example, typically the seizures have a focus. But it is quite different in schizophrenia. You have this progressively spreading wave of grey matter loss — brain cells that can never be replaced.
The first sign of schizophrenia is usually a psychotic break, with hallucinations and sensory distortions. The patient may think someone is talking to them who is not really there, for example. Our brain scans in this very early stage of illness showed structural changes in the parietal cortex — damage that would be consistent with these psychotic symptoms.
But then the tissue loss progressed to the frontal lobe, which controls our ability to regulate behavior and make sense of sensory perceptions. These images support a theory of schizophrenia that there’s some trigger that causes the normal pruning of brain cells that goes on throughout the teenage years to be accelerated, leaving the patient with insufficient brain tissue to function normally.
Q. These movies are quite stark in their depiction of schizophrenia’s impact on brain tissue, yet you refer only to “theories” of how and why.
A. That’s absolutely correct. Schizophrenia is so horrendously complicated from a scientific point of view that everything one says has to be qualified. This is true for all the mental illnesses. There’s simply no agreed-upon physical marker in the brain for what causes them. There are various theories, but even the most basic information is a matter of debate.
This makes mental illness very tricky to treat, in contrast to many neurological illnesses. In Alzheimer’s disease and epilepsy, for example, we know exactly what is happening in the brain. We may not be able to prevent it in all cases, but we know what the structural and functional change is, which greatly helps us to develop treatments to intervene somehow in the disease process and stop or lessen the damage. In mental illness, we’re not so far along.
Q. What cause-and-effect theories are scientists pursuing?
A. There are three basic theories, all of which rest on a genetic base, since schizophrenia runs in families. We’ve already discussed one — that some unknown trigger causes exaggerated pruning of brain cells, leaving the patient with insufficient tissue to function normally.
The second theory has to do with inadequate myelin coating. Myelin is a taffy-like substance that insulates your brain cells and enables communication among them — as much as 100 times faster than if the cells had no myelin. We know that some of the drugs that are effective in treating schizophrenia promote myelin growth. So if you put the drug findings together with the cell damage findings, it makes sense that even with drastic loss of brain tissue, improved myelin growth could ameliorate symptoms.
The third theory has to do with chemical imbalance, specifically excessive amounts of the brain chemical dopamine. Some schizophrenia cases are environmentally triggered; there may be a genetic predisposition, but the activating trigger is external — stress, possibly, or trauma or, in a significant number of cases, drug abuse. Schizophrenia-like symptoms have been observed in people who use methamphetamine, and we know the effect of this drug is to stimulate the release of a huge amount of dopamine into the brain. At the same time, we know that some medicines for schizophrenia act to limit dopamine. This makes a very powerful case for schizophrenia being caused by dopamine imbalance.
Q. Even if the specific mechanism of schizophrenia remains elusive, how can better knowledge of its impact on brain structure contribute to treatment?
A. With any illness, it is extremely important to know if it is progressing. If you are a patient or the doctor treating a patient, you need information on the degree of change not only in clinical symptoms — how the patient feels, say — but also with regard to what’s going on inside the body. In cancer, for example, we can measure tumor size to know if the chemotherapy is working. This is just as important for mental illnesses.
There are many questions which better knowledge of brain changes could help answer. How far along is the disease? Is a particular medication effective in slowing or preventing progression — actually saving brain tissue? If so, when is the best time to start a patient on this medication? Is the maximum effect achieved in the first year, or should they continue taking it, bearing in mind that many of the drugs have side effects? And for people with a family history who are worried about developing schizophrenia, can you reassure them that their brain is O.K.? All of these questions require a means to see into the brain, understand the difference between normal and damaged structures, and measure progression in the context of treatment.
