Schizophrenia Background Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that probably consists of several

separate illnesses. Symptoms include disturbances in thoughts (or cognitions), mood (or affects), perceptions, and relationships with others. The hallmark symptoms of schizophrenia are auditory hallucinations and delusions, which are fixed false beliefs. Impaired information processing is a less vivid symptom that is highly disruptive. People with schizophrenia have lower rates of employment, marriage, and independent living than other people.. Case study John P is a 25-year-old male with the diagnosis of schizophrenia. He was a healthy child, but his parents report that he was a bedwetter and seemed slower to develop than his brothers and sisters. A maternal uncle has also been diagnosed with schizophrenia. John had 2 brief hospitalizations in his late teens that were precipitated by anger at his boss, depression, and voices in his head. He found the hospital stays unhelpful. He was treated with haloperidol which gave him dystonic symptoms; he was then treated with olanzapine and gained 20 pounds and developed diabetes mellitus. John smokes marijuana and tobacco frequently to calm himself; he also drinks vodka. John's parents support him financially. His brothers are sisters are angry and frightened of him and have nothing to do with him. They are particularly upset by his lack of interest in the outside world. John lives in a boarding home and works in a sheltered workshop with difficulty. John sees a psychiatrist for 15 minutes every 2 months but sometimes misses his appointment. He has a social worker whom he sees often. The psychiatrist would like to switch him to long-acting injectable antipsychotic treatment, but John is afraid of injections and isn't sure that he needs medication. He usually misses his appointments with his primary care physician. Pathophysiology Neuroimaging studies have demonstrated anatomical abnormalities, such as enlargement of the ventricles and decreased brain volume in medial temporal areas, in patients with schizophrenia.1 These findings are of greater research interest than clinical use. The hippocampus is a small, cortical, seahorse-shaped part of the brain, curled within the medial border of the temporal lobe. The hippocampus is functionally part of the limbic system, where emotions are processed. The hippocampus is where we form declarative or episodic memories (memories of facts or events). The hippocampus is affected in Alzheimer disease, the preeminent disease of memory problems. The hippocampus is also one of the many parts of the brain affected in schizophrenia. Disturbances in declarative memory are common in schizophrenia, although not as marked as in Alzheimer disease. Changes in the hippocampus, such as volume loss, change in perfusion, and change in contour, observed in brains from patients with schizophrenia (including nonmedicated patients) and relatives may be related to the cognitive problems of schizophrenia.2 Interest has also focused on the various connections within the brain rather than localization in one part of the brain. Indeed, neuropsychological studies show impaired information processing in schizophrenia, and MRI studies show anatomic abnormalities in a network of neocortical and limbic regions and interconnecting white matter tracts.3
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The first clearly effective antipsychotic drugs, chlorpromazine and reserpine, were structurally different from each other, but they shared antidopaminergic properties. Drugs that diminish the firing rates of mesolimbic dopamine D2 neurons are antipsychotic, and drugs that stimulate these neurons (eg, amphetamines) exacerbate psychotic symptoms. Therefore, abnormalities of the dopaminergic system are thought to exist in schizophrenia; however, little direct evidence supports this. This theory has recently undergone considerable refinement. Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may coexist. (Negative and positive symptoms are defined below.) Moreover, the newer antipsychotic drugs block both dopamine D2 and 5-hydroxytryptamine (5-HT) receptors. Clozapine, perhaps the most effective antipsychotic agent, is a particularly weak dopamine D2 antagonist. Undoubtedly, other neurotransmitter systems, such as norepinephrine, serotonin, and gamma-aminobutyric acid (GABA), are involved. Some research focuses on the N -methyl-D-aspartate (NMDA) subclass of glutamate receptors because NMDA antagonists, such as phencyclidine hydrochloride and ketamine, can lead to psychotic symptoms in healthy subjects.4 Frequency International The prevalence of schizophrenia is approximately 1% worldwide. Mortality/Morbidity People with schizophrenia have a 10% lifetime risk of suicide. Mortality is also increased because of medical illnesses, due to a combination of unhealthy lifestyles, side effects of medication, and decreased health care. Race No known racial differences exist in the prevalence of schizophrenia. Some research indicates that schizophrenia is diagnosed more frequently in black people than in white people. This finding has been attributed to cultural bias of practitioners. Sex The prevalence of schizophrenia is about the same in men and women. The onset of schizophrenia is later and the symptomatology is less severe in women than in men. This may be because of the antidopaminergic influence of estrogen. Age The onset of schizophrenia usually occurs in adolescence, and symptoms remit somewhat in older patients. Most of the deterioration that occurs in patients with schizophrenia occurs in the first 5-10 years of the illness and is usually followed by decades of relative stability, although a return to baseline is unusual. Positive symptoms are more likely to remit than cognitive and negative symptoms.

Clinical History

Information about the medical and psychiatric history of the family, details about pregnancy and early childhood, history of travel, and history of medications and substance abuse are all important. This information is helpful in ruling out other causes of psychotic symptoms. The patient usually had an unexceptional childhood but began to experience a noticeable change in personality and a decrease in academic, social, and interpersonal functioning during mid-to-late adolescence. In retrospect, family members may describe the person with schizophrenia as a physically clumsy and emotionally aloof child. The child may have been anxious and preferred to play by himself or herself. The child may have been late to learn to walk and may have been a bedwetter.5,6 Usually, 1-2 years pass between the onset of these vague symptoms and the first visit to a psychiatrist.7 The first psychotic episode usually occurs between the late teenage years and mid 30s. The symptoms of schizophrenia may be divided into the following 4 domains: 1. Positive symptoms: These include psychotic symptoms, such as hallucinations, which are usually auditory; delusions; and disorganized speech and behavior. 2. Negative symptoms: These include a decrease in emotional range, poverty of speech, loss of interests, and loss of drive. The person with schizophrenia has tremendous inertia. 3. Cognitive symptoms: These include neurocognitive deficits, such as deficits in working memory and attention and executive functions such as the ability to organize and abstract. Patients also have difficulty understanding nuances and subtleties of interpersonal cues and relationships. A new initiative from the National Institutes of Mental Health, known as Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) is a collaboration between various programs to develop tools for measuring cognition in clinical trials and aiding drug development that is targeted at these symptoms. 4. Mood symptoms: Schizophrenia patients often seem cheerful or sad in a way that does not make sense to others. They often are depressed.

Physical Findings on a general physical examination are usually not contributory. This examination is necessary to rule out other illnesses. A neurologic examination is important to evaluate the patient for movement disorders, particularly those that might indicate Wilson disease or Huntington disease, or other disorders that are present, before the initiation of antipsychotic medications. Some patients with schizophrenia have motor disturbances before exposure to antipsychotic agents. Schizophrenia has been associated with left and mixed handedness, minor physical anomalies, and soft neurological signs. Mental Status Examination Patients with schizophrenia may show a repertoire of strange and poorly understood behaviors that are rarely observed in others. These include water drinking to the point of intoxication, staring at oneself in the mirror, stereotyped behaviors, hoarding useless objects, self-mutilation, and a disturbed wake-sleep cycle. They often experience difficulty dealing with change.

On a detailed Mental Status Examination in the office, the following observations are often made when talking with a person with schizophrenia: o The person may be dressed oddly, such as wearing heavy jackets in the summer. The person may pay insufficient attention to personal hygiene.
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This person may be unduly suspicious of the examiner or be very socially awkward. The person may endorse a variety of odd beliefs or delusions. He or she often has a flat affect, meaning that they have little range of expressed emotion. The person may admit to hallucinations or respond to auditory or visual stimuli not apparent to the examiner. o The person may show thought blocking in which long pauses occur before answers to questions or odd pauses in the middle of answers. o The person's speech may be difficult to follow, because of the looseness of his or her associations. This means that the sequence of thoughts follows a logic that is clear to the patient but not to the interviewer. o Conversation and initiation of speech may be limited. o Schizophrenia patients may demonstrate their difficulty in abstract thinking by not being able to understand common proverbs. Alternatively, the patient may give an interpretation that turns out to be idiosyncratic and meaningless on further investigation. o The speech of a person with schizophrenia can be circumstantial, meaning that the person takes a long time and uses a lot of words in answering a question, or tangential, meaning the person speaks at length but never actually answers the question. o The patient often shows poor attention, disorganized thinking, and stereotyped or perseverative thinking. o The patient may make odd movements (which may or may not be related to neuroleptic medication). o The person has little insight into his or her problems (ie, anosognosia). o The person should always be asked about suicide, violence, and homicidewhether or not they are having any thoughts about hurting or harming themselves or others in any way and whether or not they are hearing voices telling them to do so. o Attention is intact. (This is important in distinguishing psychosis from delirium.) o Orientation (knowing their own identity, where he or she is, and what the time is) is usually intact. According to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), the patient must have experienced at least 2 of the following symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms. Only 1 symptom is required if the delusions are bizarre or if auditory hallucinations occur in which the voices comment in an ongoing manner on the person's behavior, or if 2 or more voices are talking with each other. The patient must experience at least 1 month of symptoms (or less if successfully treated) during a 6-month period, and social or occupational deterioration problems occur over a significant amount of time. These problems must not be attributable to another condition for the diagnosis of schizophrenia to be made.8

o o o o

Causes The causes of schizophrenia are not known. Most likely, at least 2 groups of risk factors exist: genetic and perinatal.

Genetic o The risk of schizophrenia is elevated in biological relatives of patients but not in adopted relatives.9 o The risk of schizophrenia in first-degree relatives of people with schizophrenia is 10%. o If both parents have schizophrenia, the risk of schizophrenia in their child is 40%. o Concordance for schizophrenia is about 10% for dizygotic twins and 40-50% for monozygotic twins. o The gene variants that have been so far implicated are responsible for only a small fraction of schizophrenia, and these findings have not always been replicated in different studies. The genes that have been found mostly change a genes expression or a proteins function in a
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small way. Interactions with the rest of the genome and with environment will doubtless prove to be important. o Work by Bassett et al indicates that general mutation processes occurring with rare, copy number variations (such as 1q21.1 and 15q13.3 deletions) increase the risk of patients developing schizophrenia.10 This study points out the need for more attention to the genetic pathogenesis of schizophrenia. o Some loci of particular interest are the following: The catechol-O-methyltransferase (COMT) gene codes for the postsynaptic intracellular enzyme, COMT, which is involved in the methylation and degradation of the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several allelic variants of COMT affect its activity. The valine-valine variant degrades dopamine faster than does the valine-methionine variant; subjects with 2 copies of the methionine allele were less likely to develop psychotic symptoms if they used cannabis than other cannabis-using subjects.11 The RELN gene codes for the protein reelin, which plays a role in brain development and GABAergic activity. In an international study using a genome-wide association scan, a common variant in this gene increased the risk of schizophrenia, but only in women.12 A Canadian group has looked at the gene for nitric oxide synthase 1 adaptor, known as NOS1AP. This gene codes for the enzyme nitric oxide synthetase, which is found in high concentration in inhibitory neurons in the brain. Nitric oxide acts as an intracellular messenger. Using a newly developed statistical technique, the posterior probability of linkage disequilibrium, the authors identified a single nucleotide polymorphism associated with higher levels of expression of this gene in postmortem brain samples.13 Perinatal o Women who are malnourished or who have certain viral illnesses during their pregnancy may be at greater risk of giving birth to children who later develop schizophrenia. o Children born to Dutch mothers who were malnourished during World War II have a high incidence of schizophrenia. o The 1957 influenza A2 epidemics in Japan, England, and Scandinavia resulted in an increase in schizophrenia in the offspring of women who developed this flu during their second trimester. o Women in California who were pregnant between 1959 and 1966 were more likely to have children who developed schizophrenia if they had flu in the first trimester of their pregnancy.14 o Obstetric complications may be associated with a higher incidence of schizophrenia. 15 o Children born in the winter months may be at greater risk for developing schizophrenia. o A study in Finnish women by Clarke et al supports an interaction between genetic and environmental influences on causation of schizophrenia. A review of the 9,596 women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection between 1947 and 1990 found no overall significant increase in the risk of schizophrenia among their offspring but a 5-fold higher risk among the offspring of women who also had a family history of psychosis. Clarke et al estimated that, among offspring of women with both prenatal pyelonephritis and a positive family history of psychotic disorders, 38-46% of schizophrenia cases resulted from the synergistic action of both risk factors

DD Other Problems to Be Considered Other psychiatric illnesses

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Bipolar disorder: Schizophrenia and bipolar affective disorder (manic-depressive illness) may be difficult to distinguish from each other. Patients with manic-depressive illness predominantly have disturbances in their affect or mood. Psychotic symptoms may be prominent during a mania or depression. In classic manic-depressive illness, the psychotic symptoms are congruent with mania or depression, and the person has periods of euthymia (normal mood) with no psychotic symptoms between the episodes. However, some patients have, in the absence of depression or mania, periods of psychotic symptoms. The diagnosis of schizoaffective disorder is used in these cases. Delusional disorder: In this disorder, the person has a variety of paranoid beliefs, but these beliefs are not bizarre and are not accompanied by any other symptoms of schizophrenia. For example, a person who is functioning well at work but becomes unreasonably convinced that his or her spouse is having an affair has a delusional disorder rather than schizophrenia. Schizotypal personality disorder: In this personality disorder, a pervasive pattern of discomfort in close relationships with others exists, and odd thoughts and behaviors occur. The oddness in this disorder is not as extreme as that observed in schizophrenia. Schizoid personality disorder: In this personality disorder, the person has difficulty and lack of interest in forming close relationships with others and prefers solitary activities. No other symptoms of schizophrenia are present. Paranoid personality disorder: In this personality disorder, the person is distrustful and suspicious of others. No actual delusions or other symptoms of schizophrenia are present.

Medical illnesses

Anatomic lesions o Brain tumors: Patients with these conditions rarely initially present with psychosis. But brain tumors have no predictable set of symptoms. Because brain tumors can be treated and can be lethal, it is important to consider brain imaging studies for every person with a new onset of a psychotic illness or, perhaps, a marked change in symptomatology. o Idiopathic calcification of the basal ganglia: This is a rare disorder in which patients may present early in adulthood with psychosis.17 o Intracranial bleeds: Patients who report head trauma or who, for whatever reason, are not able to provide a clear history, probably should have brain imaging performed to rule out subdural hematomas, which can manifest as changes in mental status.

Metabolic illnesses

Wilson disease: This illness, also known as hepatolenticular degeneration, is a disorder of the metabolism of copper. It is an autosomal recessive illness, the gene for which has been located on chromosome 13. The first symptoms are often vague changes in behavior during adolescence, followed by the appearance of odd movements. The diagnosis can be indicated by the laboratory findings of increased urinary copper levels and low levels of serum copper and ceruloplasmin or the detection of Kayser-Fleischer rings (copper deposits around the cornea) with or without a slit-lamp examination. The diagnosis is usually confirmed by finding increased hepatic copper at biopsy. The diagnosis can be quite difficult to make because not all patients with Wilson disease have low serum ceruloplasmin or Kayser-Fleischer rings, the 2 findings most commonly associated with this disorder. Because the treatment of this disease is also difficult, some experts recommend liver biopsy so that a tissue diagnosis may be made before chelating therapy is started. This is an important diagnosis to make because of the existence of a very specific treatment. Porphyria: Patients with this disorder of heme biosynthesis can present with psychiatric symptoms. There may be a family history of psychosis. The psychiatric symptoms may be associated with electrolyte changes, peripheral neuropathy, and episodic severe abdominal pain. Abnormally high levels of porphyrins in 24-hour urine collections confirm the diagnosis.
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Other metabolic disturbances: Patients with hypoxemia or electrolyte disturbances may present with confusion and psychotic symptoms. A hypoglycemic person is particularly likely to be confused, irritable, and mistaken for a person who is psychotic. Delirium: Delirium, from whatever cause (eg, metabolic or endocrine disorders), is an important condition to consider, especially in the elderly or hospitalized person.

Endocrine disorders

Thyroid dysfunction: Severe hypothyroidism or hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is usually associated with depression. If the depression is severe, associated psychotic symptoms may exist. A hyperthyroid person is typically depressed, anxious and irritable. In infrequent cases, the presentation may be confused with schizophrenia. Adrenal dysfunction: Mental status changes may occur in hypoadrenalism (Addison disease) and hyperadrenalism (Cushing disease). Artificially induced hyperadrenalism, as when patients are treated with high doses of steroids for medical illnesses, is associated with changes in mental status. Parathyroid dysfunction: Hypoparathyroidism or hyperparathyroidism with changes in calcium can on occasion be associated with vague mental status changes.

Infectious illnesses Many infectious illnesses, such as influenza, Lyme disease, hepatitis C, and any of the encephalitides (particularly those caused by the herpes viruses), can cause mental status changes such as depression, anxiety, irritability, or psychosis. Elderly people with pneumonias or urinary tract infections may become confused or frankly psychotic. The infectious illnesses of particular interest are the following:

Neurosyphilis: This can be divided into meningovascular syphilis, tabes dorsalis, or general paresis. Patients with general paresis may present with behavioral changes, psychosis or dementia. The diagnosis can be suggested by a history of exposure, personality changes, and pupillary changes such as the Argyll Robertson pupil. The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are nontreponemal tests that use antigens to detect antibodies to Treponema pallidum. Antibodies decline during the disease, so these tests have a high false-negative rate. If neurosyphilis is strongly suspected, the more specific treponemal tests, such as the fluorescenttreponemal antibody absorption test (FTA-ABS) can be useful. HIV: HIV penetrates the blood-brain barrier early in the course of HIV infection, so HIV infection is associated with a number of mental status changes, particularly dementia or other neuropsychological impairment. Patients with HIV are at risk for opportunistic infections, such as neurosyphilis, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalopathy, and tuberculous meningitis, all of which can lead to altered mentation. Persons infected with HIV are also at risk for primary central nervous system lymphoma and may present with vague symptoms such as confusion and memory loss. Many drugs used to treat HIV may cause mental status changes. Finally, persons infected with HIV are at risk for nutritional deficiencies that also contribute to mental status changes. Cerebral abscess: Patients with cerebral abscesses rarely initially present with psychosis, but brain imaging should be considered to rule out this treatable possibility. Immunosuppressed or persons living in or traveling in underdeveloped countries are particularly at risk. Creutzfeldt-Jakob disease: Prions cause the rare Creutzfeldt-Jakob disease (CJD), one of the transmissible spongiform encephalopathies. The disease usually occurs in people older than 50 years and is marked by rapid deterioration, dementia, abnormal EEG complexes, and myoclonic jerks. A variant of this illness, vCJD, is the human form of mad cow disease, bovine spongiform encephalopathy. Fewer than 200 cases of vCJD have occurred worldwide, and only 2 cases have
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occurred in the United States (as of 2003). Unlike CJD, this disease seems to affect people aged 2040 years. The illness is much longer lasting than CJD and begins with behavioral changes. In several cases, the person was diagnosed with schizophrenia before the diagnosis of vCJD was made. Other illnesses

Multiple sclerosis: This illness is notoriously difficult to diagnose in its early stages. The physical symptoms can be overlooked, and psychological symptoms may occasionally be the presenting feature. Huntington disease: In this neurodegenerative disorder, neuronal loss throughout the brain occurs, especially in the striatum. This is an autosomal dominant disorder, the gene for which has been located on chromosome 4. Family history is essential to making the diagnosis, but it can be misleading. The occurrence of choreoathetoid movements well before exposure to antipsychotic agents is suggestive of Huntington disease. About three fourths of patients with Huntington disease initially present with psychiatric symptoms, and most need inpatient psychiatric care at some point in their illness. Dementia with Lewy bodies: Patients with the second most common type of dementia (after Alzheimer disease) present with fluctuating mental status and prominent psychiatric symptoms, including depression and visual hallucinations. This is an important disorder to diagnose because these patients are reported to do poorly when treated with antipsychotic drugs. Lipid storage disorders: These disorders include metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, and ceroid lipofuscinosis. These illnesses usually occur in childhood but may occasionally come to medical attention during adolescence. Patients may present with psychiatric symptoms such as cognitive deterioration and changes in personality. Patients may be diagnosed with schizophrenia until the neurologic symptoms of these illnesses become more prominent.18 Paraneoplastic neurologic syndromes: Malignancies can occasionally lead to dramatic mental status changes early in their course and before they have been diagnosed or metastasized to the brain. The etiology is not clear. Various syndromes have been described, including subacute cerebellar degeneration, encephalopathy with brainstem involvement, diffuse encephalopathies with mental symptoms, and limbic encephalopathy. The carcinoma is typically a bronchial oat-cell carcinoma. Seizure disorder: Occasionally, patients with a seizure disorder, especially temporal lobe epilepsy, may display odd behavior before, during, or after a seizure. Aura and ictal symptoms can include hallucinations, disturbances of memory, or affective and cognitive changes. Ictal and postictal phenomena can include motor abnormalities, which can be quite complex. Systemic lupus erythematosus: Patients with this connective tissue disease, typically young women, present with unexplained fever and/or joint pain in association with psychiatric symptoms, such as psychosis or cognitive deficit. The diagnosis can be suggested by the physical findings of malar flush and the laboratory findings of anemia, renal dysfunction, and elevated erythrocyte sedimentation rate (ESR) and, most specifically, antinuclear antibody (ANA) levels. Vasculitis: In cases of systemic vasculitides, such as polyarteritis nodosa, Churg-Strauss syndrome, Wegener granulomatosis, or Behcet disease, patients may present with personality changes. Other symptoms such as weight loss and fever usually occur. MRI scans show characteristic lesions of vasculitis.

Other conditions

Heavy metal toxicity: People exposed to heavy metals, usually in the course of their work, may develop changes in their personality, cognitions, or mood. Heavy metals sometimes contaminate herbal medications. Medication: Many medications have been associated with mental status changes. The more commonly implicated ones are corticosteroids (psychosis or mania); levodopa (hallucinations or
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insomnia); antidepressants (mania); interferon-alpha (depression); and beta-blockers, including betablockers in eye drops (depression). Substance abuse (eg, alcohol, cocaine, opiates, psychostimulants, hallucinogens): Disturbed perceptions, thought, mood, and behavior associated with substance abuse are not uncommon. Anabolic steroids used by body builders can lead to psychotic symptoms.19 Anticholinergic medications can lead to delirium and can be abused.

Vitamin deficiency

Thiamine deficiency: People who rely on alcohol for calories or patients with advanced malignancies or malabsorption syndromes may become deficient in this vitamin. Acute and severe depletion of this vitamin can lead to Wernicke encephalopathy, marked by oculomotor disturbances, ataxia, and confabulation. If untreated, Korsakoff psychosis may develop. Wernicke encephalopathy is a common cause of chronic cognitive impairment in people with alcoholism, and it is underdiagnosed.20 Vitamin B-12 and/or folate deficiency: Patients with either deficiency may present with depression or dementia or, very rarely, delusional thinking.

Workup Laboratory Studies No characteristic laboratory results are found in schizophrenia. The following blood work should be performed on all patients, at the beginning of the illness and periodically afterwards:

Complete blood count Liver, thyroid, and renal function tests Electrolyte, glucose, B12, folate, and calcium level If the patient's history provides any reason for suspicion, check HIV; RPR; ceruloplasmin; ANA; urine for culture and sensitivity and/or drugs of abuse; a.m. cortisol, and 24-hour urine collections for porphyrins, copper, or heavy metals. If the patient is a woman of childbearing age, a pregnancy test is important. If a strong suspicion of neurosyphilis exists, specific treponemal tests may be helpful.

Imaging Studies

Brain imaging is indicated to rule out subdural hematomas, vasculitis, cerebral abscesses, and tumors. A chest x-ray should be done if pulmonary illness or occult malignancy is suspected.

Other Tests

Neuropsychological testing in patients with schizophrenia often shows poor information processing, impaired memory, difficulty in abstraction and recognizing social cues, and easy distractibility. Determination of the patient's cognitive weaknesses and strengths can be helpful in treatment planning. If indicated, an electroencephalogram can be useful. Dexamethasone suppression test and adrenocorticotropic hormone (ACTH) stimulation tests are used to establish the diagnosis of hypercortisolism and hypocortisolism, respectively.

Procedures

If a strong suspicion of Wilson disease exists, consider a liver biopsy (or multiple biopsies) to confirm the diagnosis

Medical Care The use of antipsychotic medications, also known as neuroleptic medication or major tranquilizers, is the mainstay of treatment for schizophrenia. These medications have repeatedly been shown to diminish the positive symptoms of schizophrenia and prevent relapses. Approximately 80% of patients relapse within 1 year if antipsychotic medications are stopped, while only 20% relapse if treated. Novel antipsychotic medications are associated with fewer extrapyramidal adverse effects and may be less likely to exacerbate negative and cognitive symptoms of schizophrenia compared to the conventional antipsychotic agents. Kane et al evaluated the efficacy and tolerability of olanzapine long-acting intramuscular injection for maintenance treatment in patients with schizophrenia stabilized on oral olanzapine. Patients were randomly assigned to olanzapine long-acting injection at low (150 mg q2wk, n=140), medium (405 mg q4wk, n=318), or high (300 mg q2wk, n=141) doses; a very low dose (45 mg q4wk, n=144); or their previously stabilized PO dose (n=322). Results at 24 weeks showed the majority of those taking olanzapine PO (93%) remained exacerbation free. Most patients who received olanzapine long-acting injection also did not experience exacerbation of schizophrenia (high dose 95%, medium dose 90%, low dose 84%, and very low doses, 69%).21 The following adverse effects are those typically associated with conventional antipsychotic agents or with risperidone at doses greater than 6 mg/d.

Akathisia is a subjective sense of inner restlessness, mental unease, irritability, and dysphoria. Dystonia is the occurrence of painful and frightening muscle cramps that usually occur within 12-48 hours of the beginning of treatment or an increase in dose. This typically occurs in young muscular men. It affects the head and neck, but it may extend to the trunk and limbs. Hyperprolactinemia is associated with galactorrhea, amenorrhea, gynecomastia, impotence, and osteoporosis. Neuroleptic malignant syndrome presents with hyperthermia, muscular rigidity, altered mental state, and autonomic instability. Laboratory findings include increased creatine kinase and myoglobinuria. Acute renal failure may be present. A significant mortality rate exists. Rarely, neuroleptic malignant syndrome associated with clozapine and other atypical antipsychotic agents has been reported. Parkinsonism presents with tremor, bradykinesia, akinesia, and, sometimes, rigidity or bradyphrenia (slowed thinking). This occurs particularly in women and elderly patients. Tardive dyskinesia o The incidence of tardive dyskinesia (TD) is as high as 70% in elderly patients. It presents as involuntary and repetitive (but not rhythmic) movements of the mouth and face. Chewing, sucking, grimacing, or pouting movements of the facial muscles may occur. People may rock back and forth or tap their feet. Occasionally, diaphragmatic dyskinesia exists, which leads to loud and irregular gasping and/or "jerky" speech. The patient is often not aware of these movements. o Risk factors for TD include age, female sex, and negative symptoms. Duration of therapy and dose seem to be logical risk factors, but this has not been demonstrated conclusively. o TD is probably less common with the use of novel antipsychotic drugs but, until many patients have been exposed to these drugs for several years, this will not be known with certainty.

The following adverse effects may occur with all antipsychotic agents, except as noted.
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Anticholinergic side effects include dry mouth, exacerbation of glaucoma, confusion, decreased memory, agitation, visual hallucinations, and constipation. Risperidone, aripiprazole, and ziprasidone are relatively free of anticholinergic adverse effects. The QT interval is the electrocardiogram interval between the beginning of the QRS complex and the end of the T wave. It reflects the time required for the ventricles to depolarize and repolarize. When the QT interval is corrected for heart rate, it is called QTc. A prolonged QTc interval puts a person at risk for torsade de pointes, a malignant arrhythmia associated with syncope and sudden death. QTc intervals are lengthened by the conventional antipsychotic agents thioridazine, pimozide, and mesoridazine and, to a lesser extent, by the novel antipsychotic agent ziprasidone. Risk is increased by individual susceptibility, heart failure, bradycardias, electrolyte imbalance (especially hypokalemia), hypomagnesemia, and female gender.22 As of 2003, no novel antipsychotic agents had been reported to lead to torsade de pointes. Haloperidol has only a small influence on the ECG but it has been implicated, although very rarely, in causing torsades de pointes.23 All antipsychotic agents may be associated with esophageal dysmotility, aspiration, and the subsequent risk of pneumonia. Orthostatic hypotension can be problematic at the beginning of therapy, with dose increases, and in elderly patients. This is related to alpha1-blockade and is particularly severe with risperidone and clozapine. Venous thromboembolism may be associated with the use of antipsychotic drugs. Patients treated with clozapine may be at particular risk for this complication. The reasons for this possible association are not understood.24,25 Altered glucose and lipid metabolism, with or without weight gain, may occur with most antipsychotic agents, as can weight gain itself.26 Aripiprazole and ziprasidone are the antipsychotic drugs least likely, and olanzapine and clozapine the most likely, to lead to these adverse effects. The mechanism of weight gain associated with psychotropic drugs is not understood. Sensitivity to insulin may be increased, or increased leptin levels may be present. Weight gain is associated both with psychological problems (eg, decreased self-esteem) and with medical problems (eg, diabetes, coronary artery disease, arthritis). Some approaches to the problem of weight gain include educational programs on nutrition and exercise, and cognitive behavioral therapy. Various medications have been tried but with little success.

The conventional antipsychotic agents are available in generic forms and are less expensive than the newer agents. They are available in a variety of vehicles, including liquid and intramuscular preparations. Most importantly, they are also available as depot preparations. In other countries, several different antipsychotic depot preparations exist, but, in the United States, only haloperidol and fluphenazine are available in depot forms. With respect to the newer agents, risperidone is now available as a long-acting injection (Risperdal Consta) that uses biodegradable polymers. Therapeutic drug monitoring is the measurement of medication levels in the blood to ensure that the levels are in the therapeutic range. This is important in schizophrenia for several reasons.

Patients may not always take their medications; checking the level can be a clue to this. Patients often have other medical illnesses; medicines used in these illnesses can interact with psychotropic medications. Patients may not always be the best reporters of their symptoms, and medication levels can occasionally detect clinically silent toxicity. Smoking tobacco products induces the liver enzyme CYP1A2, which metabolizes clozapine. Patients who stop smoking while being treated with clozapine often experience an increase in their clozapine levels. (Nicotine patches and nicotine inhalers and chewing tobacco do not induce this enzyme.)

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However, many medications do not have clear dose-response curves established. Plasma concentrations of haloperidol are somewhat correlated with clinical effects. Levels of about 15-25 ng/mL are thought to be optimal. Plasma concentrations of clozapine of around 300-400 ng/mL may be optimal.

Anticholinergic agents (eg, benztropine, procyclidine, trihexyphenidyl, diphenhydramine) or amantadine are often used in conjunction with the conventional antipsychotic agents to prevent dystonic movements or to treat extrapyramidal symptoms. Akathisia is particularly difficult to treat, but it occasionally responds to an anticholinergic agent, a benzodiazepine, or a beta-blocker. Clozapine is the oldest atypical antipsychotic agent and probably the most effective.27 It is associated with about a 1% risk of agranulocytosis, so patients must have weekly white blood cell count monitoring for the first 6 months28 (the period of greatest risk) and then monitoring every 2 weeks for 6 months, and then every 4 weeks, as long as the absolute neutrophil count (ANC) is normal. (If the ANC drops, then a strict protocol of monitoring and possibly medication cessation must be followed). Clozapine is also associated with anticholinergic adverse effects, sedation, and drooling.28 Constipation and cardiac side effects (cardiomyopathy and myocarditis) can be life threatening. However, approximately one third of patients who have not responded to conventional antipsychotic agents do better on clozapine. Violence, substance abuse, smoking, and suicidality are diminished with the use of clozapine.

Many patients with schizophrenia are treated with other psychotropic medications in addition to antipsychotic agents. Very little rigorous evidence for the use of polypharmacy in schizophrenia exists, but it is widely practiced. Medications often used include the antidepressants, mood stabilizers, and anxiolytic agents. Note that carbamazepine and clozapine should not be used together. Using 2 or even 3 different antipsychotic agents together is common, although no research supports this (and it is difficult to imagine how such research could be done). Psychological interventions Psychosocial treatment for the person with schizophrenia is essential, since medications alone are insufficient. Psychosocial treatments are currently oriented according to the recovery model, which proposes that the successfully treated person with schizophrenia has few or stable symptoms, is not hospitalized, manages his or her own funds and medications, and is either in work or school at least half-time. Hope, empowerment, choice, and community integration are emphasized in this treatment approach. The best studied psychosocial treatments are social skills training, cognitive behavioral therapy, cognitive remediation, and social cognition training.29 Consultations Social work: Schizophrenia affects the person's whole family. The effects of familial "high expressed emotion" (hostile overinvolvement and intrusiveness) on the outcome of persons with schizophrenia who return home have generated interest. Some studies have found that family therapy or family interventions may prevent relapse, but these findings have not always been replicated. Vocational rehabilitation: Few patients with schizophrenia are able to maintain competitive employment. Supported employment programs are associated with higher rates of employment but not with increases in global functioning, self-esteem, time out of the hospital, or quality of life. Diet Many psychotropic medications are associated with weight gain and changes in glucose or lipid metabolism. Occasionally the person with schizophrenia develops odd food preferences. Many persons with
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schizophrenia have limited funds, do not cook for themselves, and live in areas where fast food outlets are abundant. Therefore, nutritional counseling is difficult but important. Activity Because many psychotropic medications are associated with weight gain, persons with schizophrenia should be encouraged to be as physically active as possible.

Most patients with schizophrenia smoke. This may be a result of previous conventional antipsychotic treatment because nicotine may ameliorate some of the adverse effects of these drugs. Smoking may also be related to the boredom associated with hospitalizations, the peer pressure from other patients to smoke, or the anomie associated with unemployment. The health risks from smoking are well known, and patients should be encouraged to stop smoking. Cessation of tobacco smoking, however, may result in the unexpected increase of clozapine levels. Involving people outside the usual medical settings is also helpful. The National Alliance for the Mentally Ill (NAMI) is a helpful advocacy group that is supportive for family members. NAMI also advocates funding and research. Patients with schizophrenia often have difficulty finding housing; therefore, working with associations that may provide housing assistance is important.

Medication The medications listed below diminish the positive symptoms of schizophrenia and prevent relapses. The newer, or atypical, antipsychotic drugs may be more effective in treating negative symptoms and cognitive impairment. All medications should be used in lower doses with children and elderly patients and with great caution in women who are pregnant or breastfeeding. Antipsychotics Mainstay of treatment of schizophrenia. Some clinicians routinely perform ECGs on patients before beginning treatment with antipsychotic medication. Note that the use of antipsychotic medications for the treatment of behavioral symptoms in elderly patients with dementia has not been shown to be effective and is associated with an increased risk of mortality. Because suicide is not uncommon in patients with psychotic illnesses, the clinicians should write prescriptions for the smallest quantity that is consistent with good clinical care. Patients should be urged to avoid substance abuse. Aripiprazole (Abilify) A partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors. Also antagonizes alpha1 receptors. Available as tab, orally disintegrating tab, or oral solution. Dosing Adult 10-15 mg PO qd; if needed, may increase dose gradually q2wk, not to exceed 30 mg/d Alternatively, 9.75 mg IM initially (dose range 5.25 to 15 mg); may give second dose after minimum of 2 h; not to exceed total cumulative dose of 30 mg/d; replace injection with oral dose (10-30 mg/d) as soon as possible Interaction - CYP450 3A4 and 2D6 isoenzyme substrate, thus, inhibitors (ie, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (ie, carbamazepine) may increase or decrease serum levels respectively
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Contraindication - Documented hypersensitivity Precaution Pregnancy : C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Common adverse effects include headache, anxiety, somnolence, or insomnia; rare reports of tardive dyskinesia and neuroleptic malignant syndrome; may cause orthostatic hypotension, seizure, dysphagia, or suicidal ideation; hyperglycemia may occur and in some cases be extreme, resulting in ketoacidosis, hyperosmolar coma, or death Clozapine (Clozaril) Antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors. Has some D2 antagonism and high D4 affinity. Adult : 25 mg PO qd or bid initial, gradually increase to a therapeutic target dose of 300-450 mg/d; maximum dose is 900 mg/d Pediatric Not established

Epinephrine and phenytoin may decrease effects; tricyclic antidepressants, neuroleptics, CNS depressants, guanabenz, and anticholinergics may increase effects; do not administer with carbamazepine or any drugs known to suppress bone marrow function; benzodiazepines should be used with clozapine with caution because of some cases of cardiopulmonary collapse Documented hypersensitivity; paralytic ileus; WBC count <3500 cells/mm3 or absolute neutrophil count (ANC) < 2000/mm before or during therapy; history of myeloproliferative disorder or uncontrolled seizure disorder Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Do not stop the medication abruptly; perform ANC count testing qwk for the first 6 mo, then q2wk for 6 months, then q4wk for the duration; monitor for treatment-emergent adverse effects such as hypotension, myoclonic jerks and seizures, urinary incontinence or retention, and constipation; there are clearly outlined parameters for blood monitoring which must be followed; some clinicians follow electrocardiograms, temperature, and vital signs closely in first few weeks of treatment because of possibility of myocarditis or cardiomyopathy Olanzapine (Zyprexa) Olanzapine is a selective monoaminergic antagonist at the following receptors: serotonin, D1-4, muscarinic, H1, and alpha1 adrenergic.
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Adult- 5-10 mg PO qd, increase to 10 mg PO qd within 5-7 d, adjust by 5 mg/d at 1-wk intervals to a recommended maximum of 20 mg/d; many clinicians use higher doses Pediatric <13 years: Not established Adolescents (13-17 years): 2.5-5 mg PO qd initially; target dose is 10 mg/day; adjust by dose increments/decrements of 2.5-5 mg Dosage range: 2.5-20 mg/day Weight gain and hyperlipidemia: Consider increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia; clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents Fluvoxamine may increase effects of olanzapine; antihypertensives may increase risk of hypotension and orthostatic hypotension; levodopa, pergolide, bromocriptine, charcoal, carbamazepine, omeprazole, rifampin, and cigarette smoking may decrease the effects of olanzapine Documented hypersensitivity Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in narrow-angle glaucoma, cardiovascular disease, cerebrovascular disease, prostatic hypertrophy, seizure disorders, hypovolemia, and dehydration; may lead to weight gain and disturbances in glucose and lipid regulation; a small risk of seizures may exist Paliperidone (Invega) Major active metabolite of risperidone and first oral agent allowing once-daily dosing. Indicated for treatment of acute schizophrenia. Mechanism of action not completely understood but thought to mediate central receptor antagonism of dopamine type 2 (D2) and serotonin type 2 (5HT2A). Also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Has no affinity for cholinergic, muscarinic, or beta-adrenergic receptors. Available as extended-release drug delivery system via osmotic pressure. Adult 6 mg PO qd initially; if needed, may increase by 3-mg increments after at least 5 d; not to exceed 12 mg/d; some patients respond to lower doses of 3 mg/d CrCl >50 to <80 mL/min: Not to exceed daily dose of 6 mg CrCl 10 to <50 mL/min: Not to exceed daily dose of 3 mg Pediatric<18 years: Not established

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Not substantially metabolized by cytochrome P450 isoenzymes and does not inhibit P-glycoprotein; may increase arrhythmia risk when coadministered with other drugs known to prolong QTc (eg, class IA [quinidine, procainamide] or class III [amiodarone, sotalol] antiarrhythmics, antipsychotics [chlorpromazine, thioridazine], antibiotics [gatifloxacin, moxifloxacin]); coadministration with other CNS depressants, including alcohol, may cause additive effects; coadministration with other drugs causing orthostatic hypotension (eg, alpha-blockers, diuretics) may increase hypotension risk; may antagonize effect of dopamine agonists (eg, levodopa, pramipexole) Documented hypersensitivity to paliperidone or risperidonePregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Decrease dose in renal impairment; causes modest QTc prolongation; other adverse effects include tachycardia, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia (some with associated ketoacidosis, hyperosmolar coma, or death), orthostatic hypotension and syncope, hyperprolactinemia, sedation, priapism, thrombotic thrombocytopenia purpura, disrupted body temperature regulation, and antiemetic effector dysphagia Avoid with preexisting gastrointestinal narrowing (eg, esophageal motility disorders, small bowel inflammatory disease, short gut syndrome, peritonitis, cystic fibrosis, chronic pseudoobstruction, Meckel diverticulum) because tab is nondeformable and does not appreciably change in shape or size through gut and is eliminated intact in feces; swallow tab whole (do not chew or split) Risperidone (Risperdal) Has both D2 and serotonin 5HT2 antagonism. Now available in long-acting form using microspheres made of biodegradable polymers. Adult 1 mg PO bid initial, slowly increase to optimum range of 4-8 mg/d; doses >10 mg/d do not appear to offer additional benefit; use lower doses in elderly patients If using long-acting risperidone (Risperdal Consta), dose can be started at 25 mg IM q2wk, this needs to be supplemented with PO risperidone for first 3 wk Coadministration with carbamazepine may decrease effects; risperidone may inhibit effects of levodopa; clozapine may increase risperidone levelsDocumented hypersensitivityPregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions May cause extrapyramidal reactions, hyperprolactinemia, hypotension, tachycardia, and arrhythmias

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