# Understanding Schizophrenia: Causes, Risk Factors, Treatment



## David Baxter PhD (Jan 8, 2008)

Understanding Schizophrenia: Causes and Risk Factors
SchizophreniaConnection.com 
December 26, 2006

Schizophrenia is a group of psychotic disorders that interfere with thinking and responsiveness. It is a disease of the brain, just like Alzheimer's and Parkinson's diseases. The term schizophrenia, which means "split mind," was first used in 1911 by Swiss psychiatrist Eugen Bleuler to categorize patients whose thought processes and emotional responses seemed disconnected. Despite its name, the condition does not cause a split personality.

Schizophrenia is a group of psychotic disorders characterized by disturbances in perception, behavior, and communication that last longer than 6 months. (This includes psychotic behavior.) A person with schizophrenia has deteriorated occupational, interpersonal, and self-supportive abilities.

Schizophrenia is characterized by the following symptoms:


Delusions 
Hallucinations 
Disordered thinking 
Emotional unresponsiveness
Because symptoms of schizophrenia arise from various physical processes and respond differently to treatments, some experts recommend classifying the disease based on the presence of the following symptom groups:


Negative symptoms (including apathy and social withdrawal) 
Psychotic symptoms 
Disordered thinking
Some experts group psychotic and disordered thinking into a single category called positive symptoms.

The disease is complicated by the fact that although a schizophrenic patient may have more than one symptom, he or she rarely has all of them. Symptoms also often go into remission.

*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. One study reported that schizophrenic patients who had been profoundly deaf since birth were able to describe convincing experiences of hearing voices. Patients describe the voices as occurring all about them and that they are impossible to filter out or ignore. 
_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 with periods of remission. They typically occur in men between the ages of 17 - 30 and in women between the ages of 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. One test to diagnose this trait uses four letters on a computer screen. The screen goes blank, and another image, called a masking stimulus, appears (such as four broken letter fragments). After viewing the images, the patient is asked to type in the original letters. Both symptomatic and presymptomatic patients commonly have problems with this particular exercise.
In summary, people with schizophrenia do poorly on mental tasks requiring conscious awareness such as verbal fluency, short-term and working memory, and processing speed. However, they are no worse than the general population in underlying (implicit) learning such as grammar skills, vocabulary, and spatial skills (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.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Causes*
No single cause can account for schizophrenia. Rather, it appears to be the result of multiple "hits" from genetic factors, environmental and psychological assaults, and possible hormonal changes that alter the brain's chemistry.

*Abnormalities in Brain Structure, Circuitry, and Chemicals*
Brain scans using magnetic resonance imaging (MRI) have shown that there are a number of abnormalities in the brain's structure associated with schizophrenia. Such abnormalities can cause nerve damage and disconnections in the pathways that carry brain chemicals.

_Abnormal Brain Activity and Volume._ Imaging techniques have revealed abnormal brain activity and shrinkage (reduced volume) in the brains of people with schizophrenia. Of particular importance are those in the prefrontal cortex, which contains the white matter of the brain, and the temporal lobes, which contain the limbic system.


The limbic system of the brain is a group of structures that control emotions and behavior. This system (in particular, the hippocampus and amygdala) is involved in the formation of long-term memory, and is closely associated with the olfactory structures, which play a role in the sense of smell.


Gray matter in the brain and spinal cord is called substantia grisea. Gray matter is made up of cell bodies. White matter, also called substantia alba, is composed of nerve fibers.


Shrinkage of the prefrontal cortex has been seen in many patients with schizophrenia. This can damage nerve cells and impair the connections that are required for verbal memory, attention, decision-making, reasoning, aggression, and meaningful speech. Impairment in the left side of the cortex is also associated with auditory hallucinations (hearing voices). Not all patients have this deficit. 
Shrinkage in the limbic areas of the brain is associated with problems finding words. The limbic areas of the brain contain the hypothalamus (controls physiological functions), amygdala (responsible for arousal and emotional states), and hippocampus (the part of the brain that makes memories). A number of studies have specifically noted smaller left hippocampi in people with schizophrenia. Activity in the limbic area in general is related to emotions and memory, and abnormalities there are also associated with positive symptoms, including delusions, hallucinations, and disordered thinking. 
Because such abnormalities tend to show up on brain scans of people with chronic schizophrenia rather then in newly diagnosed patients, some experts 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.) There is now strong evidence to suggest that small hippocampi combined with environmental conditions (such as low oxygen levels at the time of childbirth) are important contributory factors in many cases of schizophrenia.
_Abnormal Brain Chemicals_. Schizophrenia is associated with an unusual imbalance of neurotransmitters (chemical messengers between nerve cells) and other factors.


_Dopamine_. Dopamine overactivity, particularly on the left side of the prefrontal cortex, is now known to be closely linked to psychotic symptoms and appears to be due to an increase in specific chemical receptors, particularly those called C1 and D1. (These receptors attract and lock dopamine.) Scientists think that the COMT gene on chromosome 22 may play a role in regulating dopamine levels. Defects in this gene may be involved in some cases of childhood schizophrenia. 
_Glutamate_. Glutamate, an amino acid known to affect dopamine and excite nerve activity, is also under investigation. For example, glutamate binds to N-methyl-D-aspartate (NMDA) receptors, which play a critical role in healthy nerve development and may be abnormal in schizophrenia. Abnormalities in NMDA and other molecules in the glutamate pathway appear to play significant roles in impairment of mental function and development of negative symptoms. Calcineurin, a protein that regulates the NMDA receptor, plays a role in cognition and is now recognized as a marker of risk for schizophrenia. 
_Reelin_. Studies have observed abnormally low levels of the protein reelin in the prefrontal cortex region of patients with both schizophrenia and bipolar psychosis. This may contribute to psychosis and to impaired information processing.
_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.

Scientists have identified the neuregulin-1 gene as a major candidate gene for schizophrenia risk. This gene is involved with growth of the glial cells in the brain, memory, and motor neuron functioning, all of which are abnormal in schizophrenia. Researchers at the U.S. National Institute of Mental Health have also identified the metabotropic glutamate receptor GRM3 as another prime gene candidate for schizophrenia. GRM3 regulates glutamate transmission.

Myelin, the fatty substance that coats nerve fibers and is important for brain function, may also be linked to the development of schizophrenia. Myelin is formed by central nervous cells called oligodendrocytes. In 2006, researchers suggested that OLIG2, a gene that regulates oligodendrocytes, may be an important genetic cause of schizophrenia. Patients with schizophrenia often have insufficient levels of oligodendrocytes.

Other research targets are genes that affect brain structure. For example, mutations in the COMT gene may make people susceptible to deficits in the prefrontal cortex of the brain, where schizophrenia develops. In addition to COMT and neuregulin-1, other genes and genetic regions implicated in schizophrenia include dysbindin, G72, RGS4, PPP3CC, DISC1, PDE4B, CAPON, and others.

It should be noted that 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 researchers have found an association between some cases of schizophrenia and toxoplasmosis,a parasite carried by cats and other domestic animals. Toxoplasmosis can lie dormant in the nervous system and migrate to the brain over many years. Patients with schizophrenia who are exposed to the parasite respond poorly to clozapine treatment. There is no evidence, however, that exposure to toxoplasmosis causes schizophrenia.

*Loss of Oxygen around the Time of Birth*
Many studies have reported an association between schizophrenia and problems surrounding birth, particularly those that cause oxygen deprivation, which could affect the nerve growth or structure in the developing brain. Specific complications that have been associated with such a higher risk include:


Prolonged labor 
Bleeding during pregnancy 
A short gestation period and low birth weight
*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, which are the brain areas often thought to lead to this disease, are extremely responsive to environmental stress. Given the fact that schizophrenic symptoms naturally elicit negative responses from the patient's circle of family and acquaintances, it is safe to assume that negative feedback can intensify deficits in a vulnerable brain and perhaps even trigger and exacerbate existing symptoms.

One study indicated that early parental loss, either from death or separation, increases the risk for psychiatric disorders, including schizophrenia. In another interesting 2000 study, criticism by family members was significantly correlated with the onset of disorganized thinking in patients with impaired working memory. (This effect of criticism was not observed in patients with functioning working memories.)


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Risk Factors*

Schizophrenia is the most common psychotic condition.

*Age*
Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood. Schizophrenia that is recognized in children is likely to be severe. Although the risk of schizophrenia declines with age, its incidence has been known to peak in those who are about 45 years old, and again in people who are in their mid-60s (mostly women). Late-onset schizophrenia that develops in the 40s is most likely to be the paranoid subtype with fewer negative symptoms or learning impairment. Such patients usually have functioned at a near-normal level until structural deficits in the brain break down.

*Gender*
Although schizophrenia affects both men and women, there are some differences:


Men tend to develop schizophrenia between the ages of 15 - 24. Paranoid schizophrenia may be more common in men, and symptoms tend to be more severe. 
The onset in women is usually slightly later, between ages 25 - 34, and the symptoms tend to be less severe. The earlier a girl starts menstruation, the longer she is protected against schizophrenia. Schizophrenia is more severe during a woman's menstrual cycle when estrogen levels are low. Such findings and other evidence suggest that estrogen may have nerve-protecting properties. For example, the higher the estrogen levels in female patients with schizophrenia, the better their mental functions.
*Intelligence*
People with schizophrenia span the full range of intelligence. In fact, one study reported that a higher than expected number of people who develop schizophrenia had been intellectually gifted children. Research suggests, however, that a decline in IQ scores during childhood may be a sign of potential psychotic symptoms in adults.

*Cultural and Geographic Factors*
No cultural or geographic group is immune from schizophrenia, although the course of the disease seems to be more severe in developed countries. However, the content of delusions may vary depending on a person's culture. According to one study, European patients were more apt to have delusions of poisoning or religious guilt while in Japan the delusions were most often related to being slandered.

*Socioeconomic Factors*
Schizophrenia occurs twice as often in unmarried and divorced people as in married or widowed individuals. Furthermore, people with schizophrenia are eight times more likely to be in the lowest socioeconomic groups. According to a 2001 study, however, these findings are likely to be a result of schizophrenia rather than a cause. Nevertheless, low income and poverty increases the risk for delayed diagnosis and treatment, and such delays could lead to more severe disease in patients with fewer resources. Poverty may also increase exposure to biologic factors (such as infections or toxins) or social stressors that could trigger the illness in susceptible people.

*Famine and Malnutrition*
Prenatal malnutrition may also play a role in the development of schizophrenia. A 2005 study found that people who were born during times of famine were more than twice as likely to develop schizophrenia as those born during years of adequate food. The association between famine and schizophrenia illustrates how environmental and biologic factors are connected. Scientists think that malnourished mothers may not get enough folate in their diet. Folate is a micronutrient important for genetic processes. Folate deficiencies may cause genetic mutations in the developing fetus that can lead to schizophrenia.

*Other Factors Associated with Schizophrenia*
_Being Left- or Mixed-Handed_. The rate of left-handedness or mixed-handedness is significantly higher among patients with schizophrenia than the general population. This suggests that some neurologic pattern that may be responsible for each. (A large minority of the population is non-right handed and very few of these people develop schizophrenia.)

_Abnormal Olfactory Bulbs_. Studies suggest a problem in the sense of smell among patients with schizophrenia. One study reported abnormally small olfactory bulbs in patients with schizophrenia. Olfactory bulbs are nerve centers in the brain that regulate the sense of smell.

_Obsessive-Compulsive Disorder_. Obsessive compulsive disorder (OCD) affects a significant number of schizophrenic patients. OCD is an anxiety disorder marked by obsessions (recurrent or persistent mental images, thoughts, or ideas) that may result in compulsive behaviors, repetitive, rigid, and self-prescribed routines that are intended to prevent the manifestation of the obsession. Some experts believe the behaviors exhibited in the disorder may actually be protective in people with schizophrenia in early stages.

_Behavioral and Motor Problems in Childhood_. Children who later develop schizophrenia often suffer from the following certain problems, including excessive shyness or minor early physical and motor-control problems. Such problems are so common, however, that their presence without any other risk factors is no cause for concern.

_Father?s Age_. According to some studies, the older a father is when a child is born, the greater the risk is for schizophrenia in his offspring, perhaps because of a greater chance of genetic mutations in the sperm that can be passed on. In one study, children of fathers who were 50 years old or more or faced a three-fold risk for schizophrenia compared to children of fathers who were 25 or younger.

_Epilepsy_. A family history of epilepsy increases the chance for developing schizophrenia or schizophrenia-like psychosis. Scientists think that epilepsy and schizophrenia may share similar genetic or environmental factors.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*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 
Mixed-handedness (the use of different hands for different tasks), particularly in females 
Hallucinations or delusions 
A decline in verbal memory, IQ, and other mental functions
The hallucinations or delusions did not include normal childhood fantasies.

Some experts suggest that screening using brain imaging techniques (possibly followed by treatment) may help prevent nerve damage and improve outcome.

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.

*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, 31% 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. There is some evidence that the physical disease process in schizophrenia is progressive, as with Alzheimer's and Parkinson's. However, schizophrenia does not progress in the same way as those two diseases. 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.)


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Complications*
Schizophrenia has a devastating effect on all aspects of human thought, emotion, and expression. Only about 20% of patients reach full recovery after a first episode, but new drugs are offering significant hope for improving quality of life.

*Medical Illnesses*
Studies in 2002 reported that people with severe mental illnesses suffer more from serious health problems than those without mental disorders and they are less likely to receive medical help. Substance abuse is a significant factor in this higher risk.

Research has suggested an increased risk of diabetes among people with schizophrenia. In addition, many new antipsychotic medications can elevate blood sugar levels. Patients taking atypical antipsychotics drugs such as clozapine, olanzapine, risperidone, aripiprazole, quetiapine fumarate, and ziprasidone should receive a baseline blood sugar level reading and be monitored for any increases in blood sugar levels. 

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

*Effect on Social Status*
Studies indicate that after 20 - 30 years, half of patients are able to care for themselves, work, and participate socially. Support services and appropriate housing improve this outcome. Unsurprisingly, the decline in status, including the inability to earn a living, is less steep when there are more financial resources and fewer emotional disorders at the outset of symptoms. Also, on average, the later the onset of the disease, the milder the social impact. The long-term effects on work and relationships, however, are usually severe and difficult to repair, even if symptoms improve.

*Effect on Intelligence*
In one study, about half of patients experienced some decline in IQ (10 points or more), but intelligence scores remained the same in the other half. Experts believe that a decline in IQ reflects early nerve damage but that it is not an inevitable consequence of the disease process.

*Suicide and Self-Destructive Behaviors*
In spite of the sometimes frightening behavior, people with schizophrenia are no more likely to behave violently than are those in the general population. In fact, these patients are more apt to withdraw from others or to harm themselves.

_Suicide_. Between 20 - 50% of patients with schizophrenia attempt suicide, and an estimated 9 - 13% commit suicide.

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


Within the first 5 years of onset of the disease 
During the first 6 months after hospitalization 
Following an acute psychotic episode
The widespread use of antipsychotic drugs over the past decade does not appear to have had much effect on suicide rates. In fact, evidence suggests that the use of these drugs as a way of reducing hospitalization time is increasing the incidence of suicide. Hopelessness, not delusions, appears to be the most important motive for suicide in these patients. In one study of patients who had attempted suicide, the most frequent reason given for an attempt was depression, and the second was the loss of an intimate partner. Cognitive impairment, which reduces the patient's ability to hold jobs and function normally, also seems to be a major factor in suicidal motivation.

_Smoking and Other Addictions_. Most people with schizophrenia abuse nicotine, alcohol, and other substances. Substance abuse, in addition to its other adverse effects, increases non-compliance with antipsychotic drugs in the schizophrenic patient and may exacerbate symptoms.

_Smoking is of special interest_. According to a 2000 study, up to 88% of schizophrenic patients are nicotine dependent. Biologic and genetic factors may be partially responsible for the addiction in this particular group. Nicotine helps reduce psychotic symptoms and impulsivity, perhaps by inhibiting the activity of a protein called monoamine oxidase B (MAO- B), which is linked to improved mood and possibly to nerve protection. Smoking for schizophrenics, then, may be a form of self-medication.

Although attempts to help schizophrenic patients quit smoking usually fail, those taking atypical medications may have a better chance of quitting successfully than those taking typical medications. The use of bupropion and therapeutic administration of nicotine may also help.

*Effect on Family Members*
Family members suffer from grief, long-term guilt, and many emotional issues when faced with a schizophrenic loved one. If such patients commit suicide, which is not uncommon, the effects can be devastating.

*Lack of Social and Government Support*
In the 1970s, tens of thousands of patients were put on antipsychotic drugs and released from institutions into the community, a concept called deinstitutionalization. In spite of these attempts to reduce mental hospital costs, schizophrenia still accounts for 40% of all long-term hospitalization days. More than half of patients with schizophrenia require public assistance within a year of their reentry into the community.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*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 less. 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.
*Possible Markers of Schizophrenia*
Experts are investigating tests of specific phenomenon that might suggest a higher risk for the presence of schizophrenia.


_Eye Tracking Dysfunction_. A dysfunction in eye tracking is a genetic trait that is strongly associated with schizophrenia and may reflect abnormalities in the frontal regions of the brain. (Some experts believe that this is such a powerful marker in patients with close relatives with schizophrenia that it can be used as a predictor. This trait can only be detected by a health professional using special equipment.) 
_Impaired Prepulse Inhibition_. Prepulse inhibition (PPI) is a phenomenon in which a weak stimulus (such as a low sound) that occurs before a strong stimulus (such as a loud sound) reduces the startle response to it. PPI is impaired in schizophrenia.
*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. In fact, sometimes it is difficult even for experts to differentiate between these two disorders. Evidence suggests that they may share certain genetic factors that make some families vulnerable to either one. 
_Schizophrenia-Like Psychoses_. There are a number of conditions that exhibit schizophrenia-like psychoses but do not meet the diagnostic criteria for schizophrenia. Such conditions may be variations of entirely different diseases and are classified at this time as schizoaffective disorder, schizophreniform psychosis, and atypical and brief reactive schizophrenia. 
_Alcohol and Drug Abuse_. Either substance abuse itself or withdrawal from drugs or alcohol can also trigger psychosis. Because of the high risk for substance abuse among people with schizophrenia, it is important that the health professional distinguish psychosis triggered by drugs or alcohol from a schizophrenic episode. Usually, the diagnosis is confirmed if the psychosis ends after withdrawal from drugs or alcohol, and returns if the patient returns to alcohol or substance abuse. 
_Medical Illnesses_. Other causes of psychotic symptoms include cancer in the central nervous system, encephalitis, neurosyphilis, thyroid disorders, Alzheimer's disease, epilepsy, Huntington's disease, multiple sclerosis, stroke, Wilson's disease, some vitamin B deficiencies, and systemic lupus erythematosus. 
_Medication Reactions_. Many medications may induce psychosis as a side effect, and some can precipitate delusions and severe confusion. Such medication-induced symptoms are most often observed in elderly patients.
*Imaging Techniques*
A number of brain imaging techniques are becoming useful in detecting changes in the brain structure that relate to specific sets of symptoms in schizophrenia. At this time such techniques are used only as research tools, although some experts believe they may be useful for identifying candidates for early treatment among high-risk young people with early warnings signs of schizophrenia and brain damage.

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

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

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


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


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*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 may include:


Motivational interviewing to encourage the patients? 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 
A 2005 study found that an integrated approach significantly reduced psychotic symptoms. These improvements lasted for several years after treatment.

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.

_Cognitive Remediation Therapy_. Cognitive remediation therapy teaches patients specific strategies for enhancing their attention, memory, and ability to learn. More and 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. Cognitive remediation therapy should be part of an integrated treatment approach that includes medication, family support, cognitive-behavioral therapy, and community-based rehabilitation.

_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 the 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.

Researchers are trying to determine if intensive early treatment with a second-generation antipsychotic (also known as an atypical drug) can prevent progression in people who are at very high risk for a first psychotic episode. In one study, risperidone delayed psychosis by 6 months, but did not prevent its occurrence. Even a delay in progression to full-blown schizophrenia, however, warrants further research.

*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:

_Antipsychotic or neuroleptic drugs_. Until recently, these have been the mainstay treatments for schizophrenia. Such drugs 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. 
_Second generation antipsychotics, also called atypicals_. These drugs may be better tolerated than the older antipsychotics and have significantly fewer severe side effects. They include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon). 
_Third generation antipsychotics_. Aripiprazole (Abilify, Abilitat) is the first ?third-generation? antipsychotic medication is approved for adults with schizophrenia. It is a selective dopamine receptor blocker. That means it does not block other receptors. Such an effect may reduce the risk for severe side effects.
_Which Type of Drug to Choose_. Experts have debated whether older antipsychotics or the new atypicals should be used to treat schizophrenia symptoms. The debate includes some of the following issues:


Atypicals are considerably more expensive than the conventional antipsychotics. 
Atypicals may work better than the older drugs, but the additional benefits may be modest for most patients. 
Older drugs may cause more neurological problems, including muscle stiffness and tremors. They may also increase the risk for sudden death from a cardiac (heart-related) event. However, many of the newer atypicals pose a higher risk for weight gain, which can lead to diabetes as well as heart disease.
A landmark 2005 study published in the _New England Journal of Medicine _compared the older antipsychotic drug perphenazine with four newer ones: Olanzapine, quetiapine, risperidone, and ziprasidone. This study was extremely important because it was the first large clinical trial to evaluate whether atypical antipsychotics really do work better than standard antipsychotics.

The study found little difference between the old and new drugs. They all worked fairly well in controlling schizophrenia symptoms. However, nearly three-quarters of the patients stopped taking their assigned drug before the end of the 18-month trial and switched to another drug. Fewer patients stopped taking olanzapine, even though it caused more weight gain (an average of 2 pounds per month) than the other drugs. Other side effects increase the risk of diabetes and heart disease.

Similarly, several 2006 studies suggested that second-generation antipsychotics are no more effective than first-generation antipsychotic drugs. Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) also indicated that older antipsychotic drugs such as perphenazine are far less expensive than the newer atypicals.

Doctors are also increasingly prescribing second-generation antipsychotics to children and adolescents, even though these drugs are approved only for adults. Experts warn 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 becomes manifested 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, and some trial and error adjustments may be necessary when prescribing dosage amounts so that the benefits of treatment outweigh the side effects of the therapy. The doctor must monitor the drug effects carefully.

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


Lower occupational status 
A history of alcohol or drugs abuse 
Delusions of persecution 
A history of stopping their medications within the first 6 months after diagnosis
In the other 2000 study, patients were more likely to take their medications if they perceived their illness as severe and believed that the drugs would prevent future hospitalizations. It should be noted that neither of these studies indicated whether the medications used were standard antipsychotics or atypical drugs. Adding psychotherapy, such as cognitive therapy, to the regimen may help reduce this rate.

*Stopping Medications*
According to a 2001 study, nearly all patients experience some relapse or worsening of symptoms within 2 years of stopping maintenance medication. However, in the same study they were closely monitored and medications were reinstated early enough so that only 13% required hospitalization.

*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*
Experts generally agree that current treatment should offer both medical and psychological treatment to the patient. Cognitive-behavioral approaches are showing promise. Support to the family or other caregiver is also important for the long-term improvement of people with schizophrenia.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Medications*
Six atypical antipsychotic drugs are currently approved in the United States:


Clozapine (Clozaril) 
Risperidone (Risperdal) 
Olanzapine (Zyprexa) 
Quetiapine (Seroquel) 
Aripiprazole (Abilify) 
Ziprasidone (Geodon)
Clozapine was the first atypical drug approved. The other five appear to have fewer side effects than clozapine. In general, it may take up to 6 months before an atypical drug has an effect. Most of these drugs come in pill form, but some may come in liquid form or as an injection.

The atypical antipsychotics zotepine (Zoleptil) and amisulpride (Solian) are not approved for use in the United States.

_Benefits of Atypical Antipsychotics_ 

They simultaneously affect both dopamine receptors and other neurotransmitters responsible for psychotic symptoms. 
They improve negative as well as positive symptoms. 
Some may even improve working memory and mental functioning. 
They may reduce depression and hostility. 
They may reduce the risk for suicide. (Clozapine is specifically approved for the prevention of suicide and may be more effective than other drugs in this important area.) 
These drugs, particularly the newer atypicals, have fewer extrapyramidal side effects than the typical neuroleptics.
These drugs do 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. For example, in one 2002 study, clozapine and olanzapine were more effective than risperidone, but the differences were modest. However, clozapine and olanzapine may have some heart risks that are not as great as other atypicals. Zisprasidone may produce less movement disorders and less weight gain than risperidone.

Studies to date do not report much effect on information processing and concentration, and high doses can dull the mind to the same extent as the older drugs. A 2005 study did indicate that olanzapine prevents loss of gray matter in the brain, unlike the older typical antipsychotic haloperidol. Loss of gray matter has been linked to social, cognitive, and emotional deficits. This study suggests that atypical antipsychotics may halt the brain deterioration that is part of the schizophrenia disease process. More research is needed.

*Comparing Atypical Drugs*


Drug|Comparative Studies on Effectiveness|Comparative Studies on Adverse Effects
Clozapine (Clozaril)|Superior to risperidone for severe, chronic schizophrenia. Superior to olanzapine in reducing the risk for suicide. May be slightly better than others for improving negative symptoms.|Agranulocytosis (1.3% risk). Potentially life-threatening reduction in white blood cells. Occurs within 3 months of taking clozapine. Higher risk in older women. Unlikely to develop after 6 months. Can be reversed if clozapine is withdrawn at once. Reports of inflammation of the heart, which in rare cases can be fatal. Highest risk for weight gain of all atypicals. Along with olanzapine has higher risk for diabetes and elevated triglycerides than other atypicals.
Risperidone (Risperdal)|Not as effective as clozapine or olanzapine for chronic, severe schizophrenia, but differences are modest. More and longer hospitalizations compared to olanzapine. Monthly injection is available that may cause less symptom fluctuation than the oral form.|Less risk for weight gain and unhealthy cholesterol levels than clozapine and olanzapine. (There is still some risk for weight gain, however. In one study 12% gained weight.) Causes more sexual dysfunction than olanzapine and quetiapine.
Olanzapine (Zyprexa)|Greater improvement in positive, negative, depressive, and cognitive symptoms than quetiapine or risperidone.|Higher risk for unhealthy cholesterol levels, weight gain (27% in one study) and diabetes than other atypicals (except for clozapine).
Quetiapine (Seroquel)|Similar to older antipsychotics in treating positive and negative symptoms. May improve mental performance. May have benefits for elderly patients.|Can cause weight gain, but not as much as clozapine or olanzapine. Also appears to be free of extrapyramidal side effects and increases in prolactin.
Ziprasidone (Geodon)|May improve negative as well as positive symptoms. May also reduce anxiety.|Appears to have no significant risk for weight gain, high cholesterol levels, or diabetes. May, however, have some adverse effect on heart rate compared to other atypicals. Causes less movement disorders and less effect on prolactin levels than risperidone.
Aripiprazole (Abilify, Abilitat)|Improves positive and negative symptoms.|May have less risk for extrapyramidal and other side effects.
_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 
Seizures 
Heat stroke 
Sudden drop in blood pressure (hypotension) 
A drop in white blood cell count (neutropenia) and neutrophils (agranulocytosis). Patients should have their white blood count and absolute neutrophil count regularly monitored if they take clozapine. 
Extrapyramidal side effects (See box: Extrapyramidal symptoms) 
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.
Warning: Because of an increase in death rates for elderly patients with dementia, the FDA has advised that atypicals not be used to treat behavioral disorders in this population. Atypicals are not approved for this indication, but are frequently prescribed on an ?off-label? basis.

*Diabetes Risk and Atypical Antipsychotics*
In 2003, the FDA requested that the strongest warning be added to the product labels of all atypical antipsychotics. This so-called ?black box? warning advises that these drugs can increase the risk of high blood sugar (hyperglycemia) and diabetes. The 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 (or Neuroleptic) Drugs*
The standard neuroleptic drug used for schizophrenia is haloperidol (Haldol). Others include:


Chlorpromazine (Thorazine) 
Perphenazine (Trilafon) 
Thioridazine (Mellaril) 
Mesoridazine (Serentil) 
Trifluoperazine (Stelazine) 
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 Neuroleptics_. Neuroleptics can have adverse side effects related to many organs and systems in the body. The very name neuroleptic comes from the neurological side effects that these drugs cause, which can be very severe. 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 that patient's 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 the following:


Ondansetron (Zofran), an anti-nausea medication, is now under investigation for treating tardive dyskinesia. 
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 have no beneficial effect on tardive dyskinesia, however. Some of these drugs may also be helpful in managing negative symptoms of schizophrenia. The use of these drugs, however, adds to the cost, complicates management, and they have their own, sometimes serious, side effects. Most experts recommend them only for patients who cannot be monitored regularly and for those who 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. It should be noted that withdrawal from anticholinergics can cause depression that can exacerbate schizophrenia. 
Benzodiazepines may also alleviate these symptoms. 
Small studies have suggested that certain alternative drugs, including vitamin B6 and melatonin, may help reduce 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, less than half of all patients are given these medications.

_Anti-Anxiety Drugs_. Benzodiazepines are drugs normally used to treat anxiety. They also have some modest effect on psychotic symptoms. They may be useful in the early stages of a psychotic relapse for preventing a full attack. They also are sometimes used to treat the restlessness and agitation that can occur with the use of neuroleptics. Severe side effects, including respiratory arrest, very low blood pressure, and loss of consciousness, have been reported in a few people taking anti-anxiety medication and clozapine but there is no evidence yet of a clear danger associated with the use of these two drugs. In any case, prolonged use of anti-anxiety drugs is generally not recommended in schizophrenia. Withdrawal from these drugs should be achieved gradually.

_Lithium_. Lithium, ordinarily used for bipolar disorder, is useful for some schizophrenic patients. It appears to help those with fewer negative symptoms and without a family history of schizophrenia. However, there are no reliable criteria to predict who will benefit.

_Antiepileptic Drugs_. Drugs ordinarily prescribed for epilepsy, such as carbamazepine (Tegretol), gabapentin (Neurontin), lamotrigine (Lamictal), or others, are occasionally used in combination with neuroleptics or atypical drugs for patients who do not respond to standard drugs.

_Omega-3 Fatty Acids_. Studies suggest that omega-3 fatty acids found in fish oils have been associated with improvement in patients with schizophrenia. Docosahexaenoic acid and eicosapentaneoic acid (EPA) are the important compounds in these fatty acids. EPA is particularly promising. In a 2002 study, patients taking EPA in addition to their usual medicine reported improvements in treatment-related dyskinesia (involuntary movements) and in schizophrenia symptoms as well.

_Stimulants and Other Drugs to Promote Wakefulness_. The drugs used for schizophrenia can cause severe and persistent sleepiness. This is a difficult side effect to treat because stimulants may trigger psychosis. Modafinil (Provigil), a drug used for narcolepsy, is being investigated because it has different activities and experts hope it might be safer. Unfortunately, a 2002 case report suggested that this drug, too, may pose a risk for triggering psychosis.

_Estrogen Replacement in Women_. Estrogen may be nerve-protective. Some investigators are studying whether estrogen therapy will improve symptoms. In a 2002 study, women who wore an estrogen patch plus their regular medication experienced improved symptoms compared to those who had a dummy patch.

_Drugs Used to Reduce Weight Gain and Prevent Diabetes_. A number of drugs, such as orlistat and metformin, are under investigation to prevent weight gain and diabetes, which are serious side effects of some of the atypical drugs.

_Drugs Used for Alzheimer's Disease_. Drugs used for Alzheimer's patients, such as rivastigmine or donepezil, are also being tested for patients with schizophrenia to see if they have any benefits on memory, attention, and planning skills and for reducing medication side effects. To date, studies have reported few or no benefits.

*Investigational Therapies for Improving Cognitive Function*
Experts are investigating drugs to be used along with antipsychotics or atypicals for improving mental function. Developing such drugs would be an important advance in this disease, particularly as some research suggests that cognitive disturbances play a major role in suicide motivation.

For example, ampakines are drugs that target specific glutamate receptors and some early evidence suggests that they may improve symptoms when used as add-ons to antipsychotic or atypical drugs.

Other investigators are studying the effects of glycine, a common amino acid, which stimulates receptors in the brain that are impaired in schizophrenia. In small studies, large doses of glycine resulted in a small improvement in negative symptoms in some patients. Researchers, however, are more interested in drugs called glycine transport inhibitors, which would elevate glycine levels in the brain, and would therefore have a more potent effect. (Glycine itself is available in health stores, but such products are unlikely to have much effect.)

*Herbs and Supplements*
Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

The following are special concerns for people taking natural remedies for schizophrenia:


Gingko biloba can increase the risk for bleeding and interact with anti-clotting medications when used at high doses. Commercial gingko preparations have also been reported to contain colchicine, which can be harmful to pregnant women and people with kidney or liver problems.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Therapy*
Between one-fifth and 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 and 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. Patients with schizophrenia are taught to critically analyze hallucinations and examine underlying beliefs in them.

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


In order to think analytically about the origins and the nature of their auditory hallucinations they kept a diary of the nature of the voices and the times they were heard. 
They were then taught ways of coping with the voices. 
Patients also learned to think objectively about the source of their delusions and to find the links between thoughts that jumped from topic to topic. 
After the patients gained some mastery over positive symptoms, the therapist worked on negative symptoms. 
The patients received an average of 19 individual sessions over 9 months. At a follow-up period of 9 months, patients continued to improve. (A comparison group of patients who received so-called befriending therapy, which involved empathy and non-directed support, also improved during treatment, but did not get better after treatment stopped.) Another interesting behavioral approach used memory exercises to correct verbal deficits.
In another 2002 study, training in social and interpersonal skills using behavioral methods resulted in improvement in functioning, relationships, and overall adjustment.

Not all psychosocial interactions are helpful and some can even endanger the patient. For example, brief education intervention that is not extensive or therapeutic enough to lead to behavioral change may increase suicidal thoughts.

*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 and they need help almost as much as the patient. 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. And, two studies reported that when families received help for themselves (group support or cognitive therapy) the relapse rates for the related patients were significantly lower than for patients whose families did not seek help. For example, when families received cognitive therapy, the patient relapse rate was 37% versus 72% in the group without family support. Still, fewer than 10% of families of patients with schizophrenia receive the support and education needed not only for the patient but also for themselves.

_Community Treatment Programs_. Community treatment programs, in which a team of professional caregivers provides treatment and support for patients in their homes, is highly beneficial and cost effective (compared to frequent hospitalization). At this time, however, only between 2 - 10% of patients now participate in such programs.

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

*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 2005 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.

_Magnetic Stimulation_. Investigators are testing a procedure called transcranial magnetic stimulation (rTMS), which reduces brain activity. The procedure administers magnetic stimulation to the scalp in the area above and behind the left ear (which corresponds to the areas in the brain associated with auditory hallucinations). Some early studies report reduced hallucinations in 52 - 70% of patients receiving this therapy. Further research is underway.


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## David Baxter PhD (Jan 8, 2008)

*Re: Understanding Schizophrenia: Causes and Risk Factors*

*Resources*


NIMH  Home -- National Institute of Mental Health 
Welcome to SAMHSA's National Mental Health Information Center (inner template) -- National Mental Health Information Center 
NAMI: National Alliance on Mental Illness-The Nation's Voice on Mental Illness-Formerly National Alliance for the Mentally Ill -- National Alliance on Mental Illness 
Mental Health America: Welcome -- Mental Health America 
http://www.narsad.org -- National Alliance for Research on Schizophrenia and Depression 
American Psychiatric Association -- American Psychiatric Association 
American Academy of Child & Adolescent Psychiatry -- American Academy of Child and Adolescent Psychiatry 
Schizophrenia and Mental Illness -- World Fellowship for Schizophrenia and Allied Disorders 
http://www.schizophrenia.com -- Information resources and research news

*References*
Georgieva L, Moskvina V, Peirce T, Norton N, Bray NJ, Jones L, et al. Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12469-74.

Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct;63(10):1079-87.

McClellan JM, Susser E, King MC. Maternal famine, de novo mutations, and schizophrenia. JAMA. 2006 Aug 2;296(5):582-4.

Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry. 2006 Jun;63(6):679-85.

Rosenheck RA, Leslie DL, Sindelar J, Miller EA, Lin H, Stroup TS, et al. Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry. 2006 Dec;163(12):2080-9.

Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005 Oct 19;294(15):1934-43.


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## David Baxter PhD (Jan 8, 2008)

To download the complete article in Adobe Acrobat format, see attached file.


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## forgetmenot (Feb 21, 2009)

Thanks for all this info on schizophrenia.  My family certainly has alot of components that could have been cause of 4 out of 8 children having it.   It scares me that I may up to age 60 develop it I am 50 now.   I dont' drink I don't use any medications at all and I try so hard to keep my mind active learning.   Being educated is my pill.

Thanks Mary


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