The Effects of Schizophrenia on the Brain

Adina Cazaban
Schizophrenia is a severe mental illness that affects one to two percent of people worldwide. The disorder can develop as early as the age of five, though it is very rare at such an early age. (3)) Most men become ill between the ages of ! and "# whereas most women become ill between the ages of "# and 3$. %ven though there are differences in the age of development between the se&es, men and women are e'ually at ris( for schizophrenia. ()) There is of yet no definitive answer as to what causes the disorder. *t is believed to be a combination of factors including genetic ma(e+up, pre+natal viruses, and early brain damage which cause neurotransmitter problems in the brain. (3) These problems cause the symptoms of schizophrenia, which include hallucinations, delusions, disordered thin(ing, and unusual speech or behavior. ,o -cure- has yet been discovered, although many different methods have been tried. %ven in these modern times, only one in five affected people fully recovers. ()) The most common treatment is the administration of antipsychotic drugs. .ther treatments that were previously used, and are occasionally still given are electro+convulsive therapy, which runs a small amount of electric current through the brain and causes seizures, and large doses of /itamin 0. (3) 1ue to neurological studies of the brain, antipsychotic drugs have become the most widely used treatments. These studies show that there are widespread abnormalities in the structural connectivity of the brains of affected people. (") *t was noticed that in brains affected with schizophrenia, far more neurotransmitters are released between neurons, which is what causes the symptoms. 2t first, researchers thought that the problem was solely caused by e&cesses of dopamine in the brain. 3owever, newer studies indicate that the neurotransmitter serotonin also plays a role in causing the symptoms. This was discovered when tests indicated that many patients better results with medications that affect the serotonin as well as the dopamine transmissions in the brain. (!) ,ew test and machines also enabled researchers to study the structure of schizophrenic brains using Magnetic 4esonance *magery (M4*) and Magnetic 4esonance Spectroscopy (M4S). The different lobes of affected brains were e&amined and compared to those of normal brains, showing several structural differences. The most common finding was the enlargement of the lateral ventricles, which are the fluid+filled sacs that surround the brain. The other differences, however, are not nearly as universal, though they are significant. There is some evidence that the volume of the brain is reduced and that the cerebral corte& is smaller. (") Tests showed that blood flow was lower in frontal regions in afflicted people when compared to non+afflicted people. This condition has become (nown as hypofrontality. .ther studies illustrate that people with schizophrenia often show reduced activation in frontal regions of the brain during tas(s (nown to normally activate them. ( ) %ven though many tests show that the frontal lobe function performance is impaired and although there is evidence of reduced volume of some frontal lobe regions, no consistent pattern of structural degradation has yet been found. (")

There is, however, a great deal of evidence that shows that the temporal lobe structures in schizophrenic patients are smaller. Some studies have found the hippocampus and amygdala to be reduced in volume. 2lso, components of the limbic system, which is involved in the control of mood and emotion, and regions of the Superior Temporal 5yrus (ST5), which is a large contributor in language function, have been notably smaller. The 3eschl6s 5yrus (which contains the primary auditory corte&), and the 7lanum Temporale are diminished. The severity of symptoms such as auditory hallucinations has been found to be dependent upon the sizes of these language areas. (") 2nother area of the brain that has been found to be severely affected is the prefrontal corte&. The prefrontal corte& is associated with memory, which would e&plain the disordered thought processes found in schizophrenics. Test done on humans and animals in which the prefrontal corte& has been damaged showed similar cognitive problems as those seen in schizophrenic patients. The prefrontal corte& has one of the highest concentrations of nerve fibers with the neurotransmitter dopamine and scientists have learned that the relatively new antipsychotic drug, which increases the amount of dopamine released in the prefrontal corte&, often improves cognitive symptoms. They also found that the prefrontal corte& contains a high concentration of dopamine receptors that interact with glutamate receptors to enable neurons to form memories. This means that dopamine receptors may be especially important for reducing cognitive symptoms. (#) 8hile these drugs do help control the symptoms of schizophrenia, they do not get rid of the disorder. *t is becoming clearer ever day, 9ust what damage schizophrenia is doing to the brain, but researchers are nowhere near to finding all of the answers. 1ifferent researchers are still arguing over the conclusiveness of the data that does e&ist. .ther scientists are trying to discover the cause of schizophrenia. *s it caused by various genes, by a virus, or from trauma: This too is still a mystery. The only thing that is truly (nown is that the disorder is debilitating and that it affects nearly every portion of the brain. .bviously, much more research still needs to be done to help those who suffer from it.

Schizophrenia
Highlights
Causes of Schizophrenia The causes of schizophrenia are un(nown. Multiple factors may play a role such as genetics and brain chemistry. Risk Factors for Schizophrenia 4is( factors for schizophrenia include;

Age. Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood. Gender. Schizophrenia affects both men and women, although males tend to develop it at a slightly younger age (teens and 20s) than females (20s and 30s). Family History. Schizophrenia often runs in families. investigated as a ris! factor for schizophrenia. lder paternal age is also being

Complications of Schizophrenia Schizophrenia can have a devastating impact on patients and their families. 7atients with schizophrenia have increased ris( for self+destructive behaviors and suicide. The antipsychotic drugs used to treat schizophrenia can have severe side effects, including increasing the ris( of obesity and diabetes. Medications Schizophrenia is a chronic condition, which is usually treated with antipsychotic medication. There are two main classes of these drugs;

"ypical antipsychotics include haloperidol (#aldol), chlorpromazine ("horazine), perphenazine ("rilafon), thioridazine ($ellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), and fluphenazine (%roli&in). Side effects involving the nerves and muscle movement and coordination occur in up to '0( of patients. "ypical antipsychotics are sometimes referred to as first)generation to distinguish them from newer second) generation atypical antipsychotics. *typical antipsychotics include clozapine (+lozaril), risperidone (,isperdal), olanzapine (-ypre&a), .uetiapine (Sero.uel), ziprasidone (/eodon), aripiprazole (*bilify), and palperidone (0nvega). "hese newer drugs may produce fewer unpleasant symptoms than the older antipsychotics but new research shows they pose a similar ris! of adverse effects on the heart, which may include sudden death. 0n addition, recent research indicates that these drugs are no more effective than typical antipsychotics in treating some types of schizophrenia.

ntroduction
Schizophrenia is a group of psychotic disorders that interfere with thin(ing and mental or emotional responsiveness. *t is a disease of the brain. The term schizophrenia, which means -split mind,- was first used in < by Swiss psychiatrist %ugen 0leuler to categorize patients whose thought processes and emotional responses seemed disconnected. 1espite 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 1 months. ("his includes psychotic behavior.) * person with schizophrenia has deteriorated occupational, interpersonal, and self)supportive abilities.

Schizophrenia is characterized by the following symptoms;

2elusions #allucinations 2isordered thin!ing 3motional unresponsiveness

0ecause symptoms of schizophrenia arise from various physical processes and respond differently to treatments, some doctors recommend classifying the disease based on the presence of the following symptom groups;

4egative symptoms (including apathy and social withdrawal) %sychotic symptoms 2isordered thin!ing

Some psychiatrists group psychotic and disordered thin(ing into a single category called positive symptoms. The disease is complicated by the fact that although a schizophrenic patient may have more than one symptom, the patient rarely has all of them. Symptoms also often go into remission.

Causes
,o single cause can account for schizophrenia. 4ather, it appears to be the result of multiple causes such as genetic factors, environmental and psychological assaults, and possible hormonal changes that alter the brain6s chemistry.

Abnormalities in Brain Structure, Circuitry, and Chemicals

0rain scans using magnetic resonance imaging (M4*) have shown a number of abnormalities in the brain6s structure associated with schizophrenia. Such problems can cause nerve damage and disconnections in the pathways that carry brain chemicals. 0ecause 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 shrin(age 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. 8hether any changes in these chemicals in the brain is a cause or a conse'uence of schizophrenia remains unclear. Abnormal Circuitry. 2bnormalities 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. =or e&ample, 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 ris( for inheriting schizophrenia is $> in those who have one immediate family member with the disease and about )$> if the disease affects both parents or an identical twin. =amily members of patients also appear to have higher ris(s for the specific symptoms (negative or positive) of the relative with schizophrenia. 4esearchers are see(ing the specific genetic factors that may be responsible for schizophrenia in such cases. ?urrent evidence suggests that there are a multitude of genetic abnormalities involved in schizophrenia, possibly originating from one or two changes in genetic e&pression. Scientists are beginning to discover the ways in which specific genes affect particular brain functions and cause specific symptoms. 5enes that have been studied include the neuregulin+ gene, the .@*5" gene, and the ?.MT gene. 3eredity does not e&plain all cases of the disease. 2bout !$> 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 ris( is higher for people who are born in cities than in the country. The longer one lives in the city, the higher the ris(. The following are some studies suggesting an association;

5inter and Spring 6irths. "he ris! for schizophrenia worldwide is 7 ) 8( higher for those born during winter and spring, when colds and viruses are more prevalent. 9arge :amilies. "he ris! for schizophrenia is also greater in large families in which there are short intervals between siblings (2 or fewer years). Such observations suggest that e&posure to infection early in infancy may help set the stage for later development of the disease. %regnant $other;s 3&posure to <iruses. "he mother's e&posure to viral infections such as rubella, measles, chic!en po&, or others while the infant is in the womb has also been associated with a higher ris! for schizophrenia in her child. ,esearchers are trying to identify specific viruses that may be responsible for some cases. f particular interest is research finding evidence of a virus that belongs to the #3,<)5 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 to&oplasmosis. To&oplasmosis can lie dormant in the nervous system and migrate to the brain over many years.
Psychologic Factors

2lthough parental influence is no longer believed to play a ma9or role in the development of schizophrenia, it would be irresponsible to ignore outside pressures and influences that may e&acerbate or trigger symptoms. The prefrontal lobes of the brain, the brain areas often thought to lead to this disease, are e&tremely responsive to environmental stress. 5iven the fact that schizophrenic symptoms naturally elicit negative responses from the patient6s circle of family and ac'uaintances, negative feedbac( may intensify deficits in a vulnerable brain and perhaps even trigger and e&acerbate e&isting symptoms.

Risk Factors
Schizophrenia is the most common psychotic condition.
Age

Schizophrenia can occur at any age, but it tends to first develop (or at least become evident) between adolescence and young adulthood. Schizophrenia in children is li(ely to be severe. 2lthough the ris( of schizophrenia declines with age, its incidence has been (nown to pea( in those who are about )# years old, and again in people who are in their mid+!$s (mostly women). @ate+onset schizophrenia that develops in the )$s is most li(ely 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 brea( down.
Gender

2lthough schizophrenia affects both men and women, there are some differences;

$en tend to develop schizophrenia between the ages of =7 ) 2>. %aranoid schizophrenia may be more common in men, and symptoms tend to be more severe. "he onset in women is usually slightly later, between ages 27 ) 3>, and the symptoms tend to be less severe. "he 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. :or e&ample, the higher the estrogen levels in female patients with schizophrenia, the better their mental functions.

Intelligence

7eople with schizophrenia span the full range of intelligence. *n fact, one study reported that a higher than e&pected number of people who develop schizophrenia had been intellectually gifted children. 4esearch suggests, however, that a decline in *A scores during childhood may be a sign of potential psychotic symptoms in adults.
Cultural and Geographic Factors

,o cultural or geographic group is immune from schizophrenia, although the course of the disease seems to be more severe in developed countries. 3owever, the content of delusions may vary depending on a person6s culture. 2ccording to one study, %uropean patients were more apt to have delusions of poisoning or religious guilt while in Bapan 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. =urthermore, people with schizophrenia are eight times more li(ely to be in the lowest socioeconomic groups. 3owever, these findings are li(ely to be a result of schizophrenia rather than a cause. ,evertheless, low income and poverty increases the ris( for delayed diagnosis and treatment, and such delays could lead to more severe disease in patients with fewer resources.
Famine and Malnutrition

7renatal malnutrition may also play a role in the development of schizophrenia. Some studies have found that people who are born during times of famine are more than twice as li(ely to develop schizophrenia as those born during years of ade'uate food. The association between famine and schizophrenia illustrates how environmental and biologic factors are connected. =or e&ample, scientists thin( that malnourished mothers may not get enough folate in their diet. =olate is a micronutrient important for genetic processes. =olate deficiencies may cause genetic mutations in the developing fetus that can lead to schizophrenia.
Other Factors Associated ith Schi!ophrenia

Being Left- or Mixed-Handed. The rate of left+handedness or mi&ed+handedness is significantly higher among patients with schizophrenia than the general population. This suggests that some

neurologic pattern that may be responsible for each. (2 large minority of the population is non+ right handed, and very few of these people develop schizophrenia.) bsessive-Compulsive !isorder. .bsessive compulsive disorder (.?1) affects a significant number of schizophrenic patients. .?1 is an an&iety disorder mar(ed by obsessions (recurrent or persistent mental images, thoughts, or ideas) that may result in compulsive behaviors, repetitive, rigid, and self+prescribed routines that are intended to prevent the manifestation of the obsession. Some doctors believe the behaviors e&hibited in the disorder may actually be protective in people with schizophrenia in early stages. Behavioral and Motor "roblems in Childhood. ?hildren who later develop schizophrenia often suffer from the following certain problems, including e&cessive shyness or minor early physical and motor+control problems. Such problems are so common, however, that their presence without any other ris( factors is no cause for concern. #athers Age. 2ccording to some studies, the older a father is when a child is born, the greater the ris( is for schizophrenia in his offspring, perhaps because of a greater chance of genetic mutations in the sperm that can be passed on. *n one study, children of fathers who were #$ years old or more faced a three+fold ris( for schizophrenia compared to children of fathers who were "# or younger. $pilepsy. 2 family history of epilepsy increases the chance for developing schizophrenia or similar psychosis. Scientists thin( that epilepsy and schizophrenia may share similar genetic or environmental factors.

Complications
Schizophrenia has a devastating effect on all aspects of human thought, emotion, and e&pression. .nly about "$> of patients reach full recovery after a first episode, but new drugs are offering significant hope for improving 'uality of life.
Medical Illnesses

Studies have reported that people with severe mental illnesses suffer more from serious health problems than those without mental disorders, and they are less li(ely to receive medical help. Substance abuse is a significant factor in this higher ris(. 4esearch has suggested an increased ris( of diabetes among people with schizophrenia. *n addition, many new antipsychotic medications can elevate blood sugar levels. 7atients ta(ing atypical antipsychotics drugs ++ such as clozapine, olanzapine, risperidone, aripiprazole, 'uetiapine fumarate, and ziprasidone ++ should receive a baseline blood sugar level reading and be monitored for any increases in blood sugar levels. (See !iabetes %is& and Atypical Antipsychotics in Medications section.)

"epression

1epression is common later in adulthood. 2lthough this mood disorder can certainly be a result of the negative social impact of schizophrenia, some doctors believe that depression is part of the disease process itself.
#ffect on Social Status

Studies indicate that after "$ + 3$ years, half of patients are able to care for themselves, wor(, and participate socially. Support services and appropriate housing improve this outcome. Cnsurprisingly, 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. 2lso, on average, the later the onset of the disease, the milder the social impact. The long+term effects on wor( and relationships, however, are usually severe and difficult to repair, even if symptoms improve.
#ffect on Intelligence

*n one study, about half of patients e&perienced some decline in *A ( $ points or more), but intelligence scores remained the same in the other half. 4esearchers believe that a decline in *A reflects early nerve damage but that it is not an inevitable conse'uence of the disease process.
Suicide

*n spite of the sometimes frightening behavior, people with schizophrenia are no more li(ely to behave violently than are those in the general population. *n fact, these patients are more apt to withdraw from others or to harm themselves. 'uicide. 0etween "$ + #$> of patients with schizophrenia attempt suicide, and an estimated < + 3> commit suicide. The general ris( for suicide is higher at certain times in the course of the disease;

5ithin the first 7 years of onset of the disease 2uring the first 1 months after hospitalization :ollowing 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. *n fact, evidence suggests that the use of these drugs as a way of reducing hospitalization time is increasing the incidence of suicide. 1epression, not delusions, appears to be the most important motive for suicide in these patients. Suicide ris( is also associated with prior suicide attempts, drug abuse, agitation, poor treatment compliance, fear of mental deterioration, and personal loss.

Self$"estructi%e Beha%iors

'mo&ing and ther Addictions. Most people with schizophrenia abuse nicotine, alcohol, and other substances. Substance abuse, in addition to its other adverse effects, increases non+ compliance with antipsychotic drugs in the schizophrenic patient and may worsen symptoms. Smo(ing is of special interest. 2ccording to one study, up to DD> of schizophrenic patients are nicotine dependent. 0iologic and genetic factors may be partially responsible for the addiction in this particular group. ,icotine helps reduce psychotic symptoms and impulsivity, perhaps by inhibiting the activity of a protein called monoamine o&idase 0 (M2.+ 0), which is lin(ed to improved mood and possibly to nerve protection. Smo(ing for schizophrenics, then, may be a form of self+medication. besity and !iabetes. .besity is very common in patients with schizophrenia. =actors that contribute to obesity and diabetes in these patients include unstable lifestyle, low social economic status, and side effects of any antipsychotic medications. 7atients should be monitored closely for onset diabetes.
#ffect on Family Members

=amily members suffer from grief, long+term guilt, and many emotional issues when faced with a schizophrenic loved one. *f these patients commit suicide, the effects can be devastating.
&ac' of Social and Go%ernment Support

*n the <E$s, tens of thousands of patients were put on antipsychotic drugs and released from institutions into the community, a concept called deinstitutionalization. *n spite of these attempts to reduce mental hospital costs, schizophrenia still accounts for )$> of all long+term hospitalization days. More than half of patients with schizophrenia re'uire public assistance within a year of their reentry into the community.

S!mptoms
4esearch indicates that symptoms in childhood strongly predict disease in adulthood. *n one long+term study, over )$> of people with schizophrenia who developed the disease in young adulthood had reported psychotic symptoms by age . =or children with a family history of schizophrenia, the following inherited traits may be warning signs;

2eficits in wor!ing (short)term) and verbal memory 0mpairments in gross motor s!ills (the child;s ability to control different parts of the body) *ttention deficits * decline in verbal memory, 0?, and other mental functions

2ny 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. *t should be strongly noted that the traits discussed above, even combinations of them, can be present without schizophrenia.
(egati%e Symptoms

2 person with schizophrenia may have the following negative symptoms;

9ac! of self confidence 9ac! of emotions +olorless spea!ing tones 0nappropriate reactions to events (such as laughing hysterically over a loss) * general loss of interest in life and the ability to e&perience pleasure

@ac( of responsiveness and poor sociability often appear in childhood as the first indications of schizophrenia. ?ertain imaging techni'ues suggest that these findings are based on biologic changes in specific parts of the brain. *n many patients, however, negative symptoms do not appear until after positive symptoms develop. ,egative symptoms tend to be more common than positive symptoms in older patients and typically persist after positive symptoms have been treated.
Psychotic Symptoms

7sychotic symptoms, particularly delusions and hallucinations, are the most widely recognized manifestations of schizophrenia.

Hallucinations. * hallucination is the e&perience of seeing, hearing, tasting, smelling, or feeling something that doesn;t really e&ist. *uditory hallucinations are false senses of sound such as hearing voices that go unheard by others. "hey are the most common psychotic symptoms, affecting about '0( of patients. Delusions. * delusion is a fi&ed, false belief. 0t can be bizarre (such as invisible aliens have entered the room through an electric soc!et) or nonbizarre (such as unwarranted @ealousy or the paranoid belief in being persecuted or watched).

7sychotic symptoms usually occur every now and then, alternating with periods of remission. They typically occur in men ages E + 3$ and in women ages "$ + )$.
Cogniti%e Impairment )"isordered *hin'ing+

The symptoms of cognitive impairment and disordered thin(ing may occur before other symptoms of schizophrenia. They include;

* lac! of attention.

0mpaired information processing and an aberrant association between words and ideas. Sometimes this condition is so e&treme that speech becomes incoherent and is referred to as Aword salad.A %atients may connect words because of similarity of sound, rather than by meaning, a condition !nown as Aclang associations.A $emory impairment. 0n !eeping with other aspects of disordered thin!ing, memory impairment in schizophrenia is li!ely to involve the inability to connect an event with its source into a complete and whole memory. :or instance, a patient may recall and even feel a familiarity with a specific event but be unable to remember where, when, or how it too! place. 6ac!ward mas!ing dysfunction. "his is a trait in which a distraction causes a person to forget a preceding event. 0t might be an important symptom and a mar!er of schizophrenia even in people with normal wor!ing memories.

7eople with schizophrenia do poorly on mental tas(s re'uiring conscious awareness, such as verbal fluency, short+term and wor(ing memory, and processing speed. 3owever, they are no worse than the general population in underlying (implicit) learning, such as grammar s(ills, vocabulary, and spatial s(ills (such as map reading). Some e&perts believe that impaired verbal memory in schizophrenia is a conse'uence of depression and slowness, but not a result of the disease process.
Other Symptoms

7eople with schizophrenia may e&perience other symptoms, such as intolerance of heat (often associated with antipsychotic medications) and a reduced sense of smell.
Symptoms of Progression to Full$Blo n Schi!ophrenia

The course of the disease varies from one patient to the ne&t. Symptoms of psychosis can become gradually or suddenly evident.

0n up to a third of patients, the disease is unrelenting and progresses from the first episode onward. 0n others, schizophrenia follows a fluctuating course with psychotic flare)ups, followed by remissions. 0n one study, a third of patients e&perienced a complete remission of symptoms within 3 years after one or more episodes. 5omen are more li!ely to go into remission, possibly because of some protective effect of estrogen on the brain.

Typically, patients develop considerable cognitive dysfunction (disordered thin(ing) within the first ) + # years of the onset of psychotic symptoms. Some evidence indicates that the physical disease process in schizophrenia is progressive, as with 2lzheimer6s and 7ar(inson6s disease. 3owever, schizophrenia does not progress in the same way as those two diseases. Cnli(e 7ar(inson6s and 2lzheimer6s, cognitive function usually eventually stabilizes. 7sychosis, 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.)

"iagnosis
The doctor will use one or more verbal screening tests to help determine whether a patient6s symptoms meet the criteria for schizophrenia. 0ecause no single symptom is specific to schizophrenia, a diagnosis may be made when one or more of the following conditions is present;

0f a patient has at least one active flare)up lasting a month or more. "he flare)up consists of at least two characteristic symptoms (such as hallucinations, delusions, evidence of disorganized thin!ing, and emotional unresponsiveness with a flat spea!ing tone). 0f the patient has particularly bizarre delusions or hallucinations, even in the absence of other characteristic symptoms. 0f certain symptoms are present for at least 1 months, even in the absence of active flare)ups. Such symptoms include mar!ed social withdrawal, peculiar behavior (tal!ing to oneself, severe superstitiousness), vague and incoherent speech, or other indications of disturbed thin!ing. "he patient;s social and personal relationships would also have deteriorated since the onset of symptoms.

,uling Out Other Conditions

The common hallmar(s 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 lac( of speech, muscular rigidity, and unresponsiveness). 2mong the conditions that may resemble schizophrenia are the following;

Depression. 2elusions that focus on a physical abnormality or disease that isn;t real, !nown as somatic delusions, sometimes occur in people with depression. Bipolar Disorder. %aranoia 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. 3vidence suggests that they may share certain genetic factors that ma!e some families vulnerable to either one. Schizophrenia-Li e !sychoses. Several other conditions e&hibit schizophrenia)li!e 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. 3ither substance abuse itself or withdrawal from drugs or alcohol can trigger psychosis. 6ecause of the high ris! 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. Bsually, 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.

"edical #llnesses. ther causes of psychotic symptoms include cancer in the central nervous system, encephalitis, neurosyphilis, thyroid disorders, *lzheimer;s disease, epilepsy, #untington;s disease, multiple sclerosis, stro!e, 5ilson;s disease, some vitamin 6 deficiencies, and systemic lupus erythematosus. "edication $eactions. $any 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 *echni-ues

Many brain imaging techni'ues can detect changes in the brain structure that relate to specific sets of symptoms in schizophrenia. These imaging techni'ues include magnetic resonance imaging (M4*), single photon emission computed tomography (S7%?T), and positron emission tomography (7%T). Such techni'ues are used as research tools. 3owever, research continues in evaluating whether they may be useful for identifying candidates for early treatment among high+ris( 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). (ntegrated Approach. 2n integrated approach, which may help to ease psychotic symptoms, may include;

$otivational interviewing to encourage the patient;s commitment to change Bse of antipsychotic medications (generally atypical or novel antipsychotics) with monitoring +ommunity)based rehabilitation and social s!ills training :amily psychotherapy +ognitive)behavioral therapy to reduce delusions and hallucinations

Treatment of schizophrenia has traditionally focused on decreasing patients negative symptoms. Today, an important shift is now ta(ing place. 1octors are now emphasizing patients ability to function ++ shop, eat, coo(, clean, do laundry, and in some cases, wor( independently. $arly )reatment. The earlier schizophrenia is detected and treated, the better the outcome. 7atients who receive antipsychotic drugs and other treatments during their first episode are admitted to the hospital less often during the following # years and may re'uire less time to control symptoms than those who do not see( help as 'uic(ly. *n spite of strong evidence for the

positive effects of early treatment, patients usually do not receive treatment until after $ months of serious symptoms.
Classes of "rugs .sed for Schi!ophrenia

Most drugs that treat schizophrenia wor( by bloc(ing receptors of the neurotransmitter dopamine. 1opamine is thought to play a ma9or role in psychotic symptoms. 2lthough the drugs used to treat schizophrenia have important benefits, they may also cause side effects. The most disturbing and common side effects are those (nown as extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. The following drug classes are generally used for schizophrenia;

%ypical antipsychotics. Bntil recently, these drugs were the mainstay treatments for schizophrenia. "hey include haloperidol (#aldol), chlorpromazine ("horazine), perphenazine ("rilafon), thioridazine ($ellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), and fluphenazine (%roli&in). Side effects involving the nerves and muscle movement and coordination occur in up to '0( of patients. "ypical antipsychotics are sometimes referred to as first)generation to distinguish them from newer second) generation atypical antipsychotics. Atypical antipsychotics. "hese newer drugs may be better tolerated than the older antipsychotics but new research contradicts the belief that they are safer for the heart. "hey include clozapine (+lozaril), risperidone (,isperdal), olanzapine (-ypre&a), .uetiapine (Sero.uel), ziprasidone (/eodon), aripiprazole (*bilify), and palperidone (0nvega).

*hich )ype of !rug to Choose. 1octors have debated whether newer atypical antipsychotics carry a treatment advantage over the older typical antipsychotics, which are much less e&pensive. Most practicing psychiatrists feel that atypical antipsychotics may wor( better than the older drugs. 3owever, the additional benefits may be modest for most patients. @arge, high+'uality studies have compared newer and older drugs and generally found that newer atypical antipsychotics wor( 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 e'ually effective, but atypical antipsychotics carry a higher ris( for metabolic side effects. Side effect profiles between typical and atypical antipsychotics are different. 0oth groups cause e&trapyramidal side effects, (including muscle stiffness, tremors, and abnormal movements), but the newer atypical drugs do not seem to cause them as often. 3owever, the atypical antipsychotics pose a higher ris( for weight gain, which can lead to diabetes as well as heart disease. .ne 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.

*n "$$E, risperidone and aripiprazole became the first atypical antipsychotics approved for treatment of schizophrenia in adolescents (ages 3 + E years). 1octors caution that more research is needed to determine the long+term safety and efficacy of these drugs for pediatric patients.
*reating an Acute or Initial Phase

=or the severe, active phase of schizophrenia, in9ections of an antipsychotic drug are typically given every few hours until the patient is calm. 2nti+an&iety 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. *n patients who are being treated for the first time, improvement in psychotic symptoms may be evident within + " days of treatment, although the full benefit of the drug usually manifests over about ! + D wee(s. Thought disturbances tend to abate more gradually.
Maintenance

To reduce the ris( of relapse, many doctors recommend that drugs be given daily for at least year. 2typical 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 ad9ustments 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. Feeping patients on maintenance therapy, however, is very difficult, and many patients stop their medication. =actors that may contribute to poor compliance include;

9ower occupational status * history of alcohol or drugs abuse 2elusions of persecution * history of stopping medications within the first 1 months after diagnosis

Stopping Medications

,early all patients e&perience some relapse or worsening of symptoms within " years of stopping maintenance medication. 4ecognizing signs of relapse and starting medications immediately can help prevent rehospitalization for these patients.
Supporti%e "rugs

2ntidepressants and anti+an&iety 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 *reatments

7sychiatrists generally agree that current treatment should offer both medical and psychological treatment to the patient. ?ognitive+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 "rugs

Seven atypical antipsychotic drugs are currently approved in the Cnited States;

+lozapine (+lozaril) ,isperidone (,isperdal) lanzapine (-ypre&a) ?uetiapine (Sero.uel) *ripiprazole (*bilify) -iprasidone (/eodon) %aliperidone (0nvega)

?lozapine was the first atypical drug approved (in <D<), and paliperodine the most recent approved (in "$$E). ?lozapine appears to have more side effects than the other atypical antipsychotics. Most of these drugs come in pill form, but some may come in li'uid form or as an in9ection. *n general, it may ta(e up to ! months before an atypical drug has an effect. The atypical antipsychotics zotepine (Goleptil) and amisulpride (Solian) are not approved for use in the Cnited States. Benefits of Atypical Antipsychotics.

*ffect both dopamine receptors and other neurotransmitters responsible for psychotic symptoms. 0mprove negative and positive symptoms. $ay even improve wor!ing memory and mental functioning. $ay reduce depression and hostility. $ay reduce the ris! for suicide (clozapine may be particularly helpful for suicide prevention). "hese drugs, particularly the newer atypicals, have fewer e&trapyramidal side effects than the typical antipsychotics.

2typical antipsychotics have some significant limitations and complications, and their benefits compared to each other and to other antipsychotics are not always clear+cut. *n+depth comparative studies are needed to determine which specific drugs are more effective and have fewer side effects than others. 'ide $ffects of Atypical Antipsychotics.

4asal congestion or runny nose 2rooling 2izziness #eadache 2rowsiness )) although, sometimes the drugs may cause restlessness and insomnia +onstipation ,apid heart beat 2ifficulty urinating S!in rash 0ncreased body temperature +onfusion, short)term memory problems, disorientation, and impaired attention

The following are more severe side effects or complications that may occur with these drugs;

2iabetes 5eight gain and metabolic problems. "he ris! is highest for olanzapine, and lowest for aripiprazole and ziprasidone. Bnhealthy cholesterol levels. %articularly with olanzapine, increased ris! for high levels of trigylcerides and total cholesterol. Seizures. 3&treme and very serious increases in body temperature. Sudden drop in blood pressure (hypotension). * significant drop in white blood cell count (neutropenia), which can be severe, occurs in =( or more of patients, generally in the first 1 months after starting treatment. %atients should have their white blood count and absolute neutrophil count regularly monitored if they ta!e clozapine. 3&trapyramidal side effects +ataracts and worsening of any e&isting glaucoma.

0ncreased prolactin levels )) prolactin is a hormone associated with infertility and impotence. #igh levels can cause menstrual abnormalities and may increase the ris! for osteoporosis and possibly breast cancer. #eart problems, including sudden death.

"iabetes ,is' and Atypical Antipsychotics

2ll atypical antipsychotic drugs carry a blac( bo& warning on their prescribing labels advising that these drugs can increase the ris( of high blood sugar (hyperglycemia) and diabetes. (.lanzapine is more li(ely to cause high blood sugar levels than other atypical antipsychotic medicines.) The C.S. =ood and 1rug 2dministration (=12) recommends that;

%atients with an established diagnosis of diabetes who begin atypical antipsychotic treatment should be regularly monitored for worsening of blood sugar control. %atients with ris! 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. *ll patients treated with atypical antipsychotics should be monitored for high blood sugar (hyperglycemia) symptoms. %atients who develop hyperglycemia symptoms should undergo fasting blood sugar testing.

There may also be an increased bac(ground ris( of diabetes in patients with schizophrenia. 2s 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. 7atients should also have their lipid and cholesterol levels monitored. H=or more information, see (n-!epth %eport I!$; 1iabetes + type ".J
*ypical Antipsychotic "rugs

The standard typical antipsychotic drug used for schizophrenia is haloperidol (3aldol). .thers include;

+hlorpromazine ("horazine) %erphenazine ("rilafon) "hioridazine ($ellaril) $esoridazine (Serentil) "rifluoperazine (Stelazine) :luphenazine (%roli&in)

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. 0ecause of their significant side effects, many patient6s stop ta(ing the drug. 1epot therapy (long+lasting monthly in9ections, usually of haloperidol or fluphenazine) has been used with success in people who have difficulty complying with a daily regimen of these drugs. 4esearchers are studying low+dose regimens to discover if they can be effective and cause fewer side effects. 'ide $ffects of )ypical Antipsychotics. These drugs can have adverse side effects related to many organs and systems in the body. These drugs are also (nown as neuroleptics, a name that comes from the severe neurological side effects that these medications can cause. Side effects include;

3&trapyramidal symptoms Sleepiness and lethargy )) common in the beginning but usually decreases over time 0nsomnia and agitation )) in some cases 2ulling of the mind 4ausea, vomiting, diarrhea, constipation, and heartburn 2ry mouth and blurred vision *llergic reactions Se&ual dysfunction )) a common reason why patients stop ta!ing the drugC amantadine may help offset this side effect 4euroleptic malignant syndrome )) rare, but can be fatal without prompt treatment 0ncreased prolactin levels )) prolactin is a hormone associated with infertility and impotence. #igh levels can cause menstrual abnormalities and may increase the ris! for osteoporosis and possibly breast cancer * sudden drop in blood pressure (hypotension) *n increased ris! of sudden cardiac death

*n general, higher potency drugs cause less drowsiness and drops in blood pressure but pose a higher ris( for e&trapyramidal side effects. @ower+potency drugs (such as chlorpromazine, thioridazine) are more sedating and have milder side effects.
#/trapyramidal Symptoms

,early every drug used to date for schizophrenia can cause e&trapyramidal side effects to some degree. These side effects involve the nerves and muscles controlling movement and coordination.

!escription of $xtrapyramidal 'ide $ffects. These effects resemble some of the symptoms of 7ar(inson6s disease and include the following conditions;

%ardi&e dys inesia is the most serious e&trapyramidal side effect. 0t often manifests itself by repetitive and involuntary movements, or tics, most often of the mouth, lips, or of the legs, arms, or trun!. Symptoms range from mild to severe, and sometimes interfere with eating and wal!ing. "hey may appear months or even years after ta!ing the drugs. *fter the drug is stopped, symptoms can sometimes persist for wee!s or months and may be permanent. Some people are more li!ely to develop these symptoms, including older patients, women, smo!ers, people with diabetes, and patients with movement disorders. Acute dystonia typically develops shortly after ta!ing an antipsychotic drug. "his syndrome includes abnormal muscle spasms, particularly sustained contortions of the nec!, @aw, trun!, and eye muscles. 'ther e(trapyramidal symptoms. ther effects are agitation, slow speech, tremor, and retarded movement. 0t should be noted that sometimes these symptoms mimic schizophrenia itself. 0n response, the doctor may be tempted erroneously to increase the dosage.

)reatment of $xtrapyramidal 'ide $ffects. *n general, if e&trapyramidal side effects occur from neuroleptic drugs, the doctor may first try to reduce the dosage or switch to an atypical drug. .ther approaches to reduce these symptoms include;

*nti)par!insonism drugs !nown as anticholinergics increase dopamine levels and help to restore balance. *mong the anticholinergics sometimes used are trihe&yphenidyl (*rtane, "rihe&y) and benztropine (+ogentin). "hey are not helpful for tardive dys!inesia, however. Some of these drugs may also help in managing negative symptoms of schizophrenia. "he use of these drugs, however, adds to the cost and complicates management. "hese medicines also have their own, sometimes serious, side effects. $ost doctors recommend them only for patients who cannot be monitored regularly, need very high doses of powerful antipsychotic drugs, and are at ris! for severe side effects. "hey should be stopped after 3 or > months, if possible. 0f symptoms recur, the drugs can be reinstituted. 5ithdrawal from anticholinergics can cause depression that can worsen schizophrenia. 6enzodiazepines may also alleviate these symptoms.

Supporti%e Add$On "rugs

Antidepressants. 2ntidepressants are recommended along with antipsychotics to alleviate the depression that is so common in people with schizophrenia. .ne study indicated that ta(ing antidepressants may even help prevent relapse. *n spite of their benefits, fewer than half of all patients ta(e these medications. Anti-Anxiety !rugs. 0enzodiazepines are drugs normally used to treat an&iety. 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 attac(. 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 ta(ing anti+an&iety medication and clozapine. There is no evidence,

however, of a clear danger associated with the use of these two drugs. *n any case, prolonged use of anti+an&iety drugs is generally not recommended in schizophrenia. 8ithdrawal from these drugs should occur gradually. Lithium. @ithium, ordinarily used for bipolar disorder, is useful for some schizophrenic patients. *t appears to help those with fewer negative symptoms and without a family history of schizophrenia. 3owever, there are no reliable criteria to predict who will benefit. Anti-$pileptic !rugs. 1rugs ordinarily prescribed for epilepsy ++ such as carbamazepine (Tegretol), gabapentin (,eurontin), lamotrigine (@amictal), or others ++ are occasionally used in combination with antipsychotic drugs for patients who do not respond to standard drugs. $strogen %eplacement in *omen. %strogen may be nerve+protective. Some investigators have proposed using estrogen therapy to help with cognitive impairment. 3owever, evidence is wea(, and cancer and cardiovascular ris(s of estrogen therapy must be considered.

#s!chotherap!
.ne+fifth to one+third of all patients with schizophrenia do not respond ade'uately to drug treatment. Many patients who have been successfully treated with medications e&perience the -awa(enings- 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. 2s a result, psychological therapies can be helpful for many patients.
Cogniti%e$Beha%ioral and Other Psychosocial *herapies

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 patient6s capacity for normal thin(ing, using mental e&ercises and self+observation. More evidence is showing that improving patients6 ability to learn, remember, and pay attention allows them to better cope with ongoing positive symptoms and lead independent lives. 7atients with schizophrenia are taught to critically analyze hallucinations and e&amine underlying beliefs in them.
Family and Outside Support Structures

7ositive social interaction is e&tremely important for people with schizophrenia and may help reduce symptoms, including the number of delusional moments. #amily 'upport. *t is deeply painful for anyone to interact with a loved one whose behavior is determined by a mysterious internal mechanism that has gone awry. 5iven support and direction, however, families or other caregivers can be very helpful in a number of ways;

"hey can encourage patients to comply with drug treatments and to recognize early signs of serious treatment side effects.

"hey 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.)

Cnfortunately, the family6s own mental health is often threatened. 2s a result, careta(ers also need help. ,umerous 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;

5hen affection and reason have failed to bring a loved one bac! to reality, overly critical or emotional family members typically react with anger and frustration. "his generates an&iety and depression in patients. "he subse.uent e&pression of these emotions by the patient triggers yet more criticism or acting out. So the cycle continues. 3ventually, out of despair and fear, the family may re@ect the patient completely.

Studies indicate that once the patient receives appropriate treatment and support, the family6s 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 see( 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 )reatment "rograms. ?ommunity 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 fre'uent hospitalization). 2t this time, however, only a small percentage of patients participate in such programs. +ocational %ehabilitation. 7aid wor( may help the mental health of the patient. .ne study reported that after year, )$> of wor(ers with schizophrenia who were paid for their labor reported much improvement in all symptoms, and #$> reported much improvement in positive symptoms. Those who were not paid for their wor( 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.) Cnfortunately, at this time, few patients with schizophrenia are in programs that help them find and (eep 9obs, and up to <$> of patients with severe mental problems are unemployed.

$ther Treatments
%lectroconvulsive therapy (%?T), often called shoc( treatment, has received bad press since it was introduced in the <)$s. 3owever, refined techni'ues have revived its use, particularly for those with severe depression. *maging studies have not found that current %?T techni'ues cause any damage to the brain6s structure, and some doctors feel it is safer than drug therapy. 2 recent

review of many clinical trials indicated that %?T combined with antipsychotic medication can provide rapid improvements for patients who are suicidal or severely psychotic. The review found that the combined treatment wor(ed better than antipsychotics alone for these patients. %?T treatments are usually given " + 3 times a wee(, for a total of D + " sessions.

*ranscranial Magnetic Stimulation

*nvestigators are testing a procedure called slow repetitive transcranial magnetic stimulation (rTMS), which affects brain activity in the cerebral corte&. The procedure uses an electromagnet placed on the scalp to administer magnetic stimulation to the brains cerebral corte&. This region of the brain appears to be associated with auditory hallucinations. 2 review of # clinical trials indicated that rTMS may be an effective treatment for auditory hallucinations. =urther research is underway.