Background

Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that probably consists of several separate illnesses. The hallmark symptoms of schizophrenia are psychotic symptoms, such as auditory hallucinations (voices) and delusions (fixed false beliefs). Impaired cognition or a disturbance in information processing is a less vivid symptom that is highly disruptive. People with schizophrenia have lower rates of employment, marriage, and independent living compared with 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 muscle cramps; 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 has no primary care physician.

Pathophysiology
Neuroimaging studies have demonstrated anatomical abnormalities, such as enlargement of the ventricles and decreased brain volume in medial temporal areas.[1] These findings are of greater research interest than clinical use. The hippocampus is a small, cortical, supposedly 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] Mattai et al studied a group of children with schizophrenia and their healthy siblings and controls.[3] The average age at the beginning of the study was 12 years. The hippocampal volume of the ill children was less than that of their siblings and controls and steadily decreased over 12 years of follow up, although not at an increasing rate. The children with schizophrenia were administered antipsychotic medications. The

authors concluded that the hippocampal volume deficit was more likely due to the illness itself rather than the use of antipsychotic medication. 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.[4] A meta-analysis of studies using diffusion tensor imaging to examine white matter found that 2 networks of white matter tracts are reduced in schizophrenia. [5] Other studies reveal less specific changes. In the Edinburgh High-Risk Study, researchers examined brain images of people at high genetic risk for schizophrenia. Seventeen of 146 people had reductions in whole brain volume and left and right prefrontal and temporal lobes. The changes in prefrontal lobes were associated with increasing psychotic symptoms.[6] In a meta-analysis of 27 longitudinal structural MRI studies of patients with schizophrenia compared with controls, the authors found that schizophrenia was associated with loss of whole brain volume in both gray and white matter and an increase in ventricular volume over time.[7] 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 gammaaminobutyric 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.[8]

Epidemiology
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.

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. 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.[9, 10] The person often begins to experience a noticeable change in personality and a decrease in academic, social, and interpersonal functioning during mid-to-late adolescence. Usually, 1-2 years pass between the onset of these vague symptoms and the first visit to a psychiatrist. [11] 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 sometimes helpful before the initiation of antipsychotic medications as a baseline, because these drugs can change the findings. 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

On a detailed Mental Status Examination in the office, the following observations are often made when talking with a person with schizophrenia:

The person may be dressed oddly, such as wearing heavy jackets in the summer. The person may pay insufficient attention to personal hygiene. The person may be unduly suspicious of the examiner or be socially awkward. The person may admit to 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. The person may show thought blocking in which long pauses occur before he or she answers a question. 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. Conversation and initiation of speech may be limited. Schizophrenia patients may demonstrate their difficulty in abstract thinking by not being able to understand common proverbs or by giving idiosyncratic interpretation. 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. The patient often shows poor attention, disorganized thinking, and stereotyped or perseverative thinking. The patient may make odd movements (which may or may not be related to neuroleptic medication). The person has little insight into his or her problems (the term for this is anosognosia). The person may have thoughts about hurting or harming themselves or others or may hear voices telling them to commit some kind of violence. (Note that suicide in schizophrenia is not uncommon; violence towards others is. Both of these issues are discussed in greater detail below.) Attention is intact. (This is important in distinguishing psychosis from delirium.) Orientation (knowing their own identity, where he or she is, and what the time is) is usually intact.

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. According to the American Psychiatric Association'sDiagnostic 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.[12]

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

Genetic
The risk of schizophrenia is elevated in biological relatives of patients but not in adopted relatives. [13] The risk of schizophrenia in first-degree relatives of people with schizophrenia is 10%. If both parents have schizophrenia, the risk of schizophrenia in their child is 40%. Concordance for schizophrenia is about 10% for dizygotic twins and 40-50% for monozygotic twins. The gene variants that have been implicated so far 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 small way. Interactions with the rest of the genome and with environment will doubtless prove to be important. 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 valinemethionine 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 without that variant.[14] 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.[15] 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.[16]

Other genetic changes involve the structure of the gene. For example, copy number variants are deletions and duplications of segments of DNA. Copy number variants can involve genes or regulatory regions. These variants are usually inherited, but can spontaneously arise. Copy number variants, such as deletions found at 1q21.1, 15q13.3, and 22q11.2 increase the risk of patients developing schizophrenia. [17] These findings account for only a small part of the heritability of schizophrenia. Also, the effects of some of these copy number variants are not restricted to schizophrenia. Some copy number variant disorders include autism, intellectual disability, attention-deficit hyperactivity disorder, and epilepsy.[18] In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy number variant at one of the following loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. Clinically, these people had various neurological/psychiatric disorders, including developmental delay, intellectual disability and autism-related disorders. Subjects also had congenital anomalies.[19] Many people with

schizophrenia have no family history of the disorder. This may be due to the occurrence of new mutations in the patient. De novo mutations in the exome, which is the part of the chromosome that codes for proteins, seem to be more common in patients with schizophrenia than is otherwise expected.[20, 21]

Perinatal
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. Children born to Dutch mothers who were malnourished during World War II have a high incidence of schizophrenia. 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. 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.[22] Obstetric complications may be associated with a higher incidence of schizophrenia. Children born in the winter months may be at greater risk for developing schizophrenia. [23] 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.[24]

Other
Finally, undefined socio-environmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities.[25

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 Electrolytes, glucose, B12, serum methylmalonic acid, 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. Consider testing for Lyme disease.

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 executive functioning, meaning difficulty in 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. The first antipsychotic medications were dopamine 2 antagonists, such as chlorpromazine and haloperidol. Medications that are similar to these are known as first-generation, typical, or conventional antipsychotics. Other antipsychotics, beginning with clozapine, are known as second-generation, atypical, or novel antipsychotics. The first-generation antipsychotic drugs tend to cause extrapyramidal adverse effects and elevated prolactin levels. The second-generation drugs are more likely to cause weight gain and abnormalities in glucose and lipid control. The choice of which drug to use in schizophrenia depends on numerous issues, such as effectiveness, cost, side-effect burden, method of delivery, availability, and tolerability. Many studies are funded by pharmaceutical companies and compare antipsychotic drugs to one another. Little consensus has been reached. For some years it was believed that the newer drugs were more effective, but that belief is now fading. The exception is clozapine, which consistently outperforms the other antipsychotic drugs. An influential study has been the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). This is a large study funded by the federal government to examine the effectiveness of several different antipsychotic drugs in more than 1400 patients. By multiple measures, perphenazine, a first-generation drug, was almost or about as good as the second-generation drugs.[32] In a study from the United Kingdom, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), more than 200 patients who were about to change antipsychotic medication were randomly assigned to either a first-generation or second-generation agent. In this study, the firstgeneration drugs seemed to perform slightly better than the newer ones. Clozapine was the exception, in that it outperformed all of the other drugs.[33] In a large study from Finland, researchers used a database to review the effectiveness of antipsychotic agents in the treatment of 2600 people after their first episode of schizophrenia. [34] The study found that slightly less than half of patients continued treatment for longer than 30 days after discharge. With respect to rehospitalization, patients treated with depot haloperidol did the best, followed by those treated with

clozapine. Patients treated with depot haloperidol, perphenazine, or risperidone stayed on these medications longer than those treated with the oral equivalents and had a lower rehospitalization rate. These findings are difficult to translate to practice in the United States for a few reasons. Medical care is delivered differently in Finland, with the cost of antipsychotic medication fully reimbursed, according to the authors. The average age at admission was 38 years, which is much older than is expected for the first episode. Finally, depot perphenazine and zuclopenthixol are not available in the United States. Depot olanzapine was not used. However, the authors findings that patients who had their first episode did best in terms of avoiding more hospitalizations when treated with depot haloperidol or clozapine are noteworthy. The following adverse effects are those typically associated with conventional antipsychotic agents or with risperidone, a novel antipsychotic agent, 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 (high levels of prolactin) is associated with galactorrhea, amenorrhea, gynecomastia, impotence, and osteoporosis. Neuroleptic malignant syndrome is marked by fever, 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. 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. 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. 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.

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.[35] As of 2003, no novel antipsychotic agents had been reported to lead to torsade de pointes. In a large simple trial, more than 18,000 patients in 18 countries were randomly assigned to receive either ziprasidone or olanzapine. No cases of torsade de pointes were reported, although this event is so rare that this finding is not entirely surprising. No increase in nonsuicide mortality was

reported. In particular, no increase in cardiac mortality was found, which is somewhat reassuring in terms of the cardiac safety of ziprasidone.[36] Haloperidol has only a small influence on the ECG but it has been implicated, although very rarely, in causing torsades de pointes.[37] 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.[38, 39] Altered glucose and lipid metabolism, with or without weight gain, may occur with most antipsychotic agents, as can weight gain itself.[40] 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. Kessing et al examined nearly 346,000 patient records where individuals purchased antipsychotics and nearly 1.5 million unexposed individuals registered in Denmark to compare risk for diabetes. [41] Treatment with antipsychotics has been associated with an increased risk for diabetes. The rate ratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the rate ratio varied widely for second-generation antipsychotics (RR = 1.32; range, 1.17-1.57).

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, and a long-acting olanzapine intramuscular injection also is available. 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 detect this. Patients may not always be the best reporters of their side effects, and medication levels can occasionally detect clinically silent toxicity. Smoking tobacco products induces the liver enzyme CYP1A2, which metabolizes a number of antipsychotic drugs. For example, patients who stop smoking while being treated with clozapine or olanzapine often experience an increase in their antipsychotic levels. (Nicotine patches and nicotine inhalers and chewing tobacco do not induce this enzyme.)

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. [42] It is associated with about a 1% risk of agranulocytosis, so patients must have weekly white blood cell count monitoring for the first 6 months[43] (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.[43] 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 also common. Recent reports suggest that patients prefer this.[44] A recent meta-analysis of 19 studies involving more than 1200 subiects also found an advantage for antipsychotic polypharmacy.[45] Some studies have explored the potential neurotoxic effects of antipsychotic medications; however, no clear conclusions have been reached. For example, Ho et al performed structural brain imaging in more than 200 patients with schizophrenia over 7 years. Those patients treated with higher doses of antipsychotic medications seemed to lose gray matter throughout their brain (except the cerebellum); those treated with lower doses of antipsychotic medications seemed to have a small increase in white matter of the brain.[46] The clinical significance of these findings is unclear. Whether these changes are associated with any clinical symptoms directly or if the changes are reversible is unknown. Whether higher doses of medication were in response to the gray matter loss or the other way around is unclear. No choice of antipsychotic medication in schizophrenia is clear. Clozapine is the most effective medication but is rarely initially used because it is so burdensome. It has not outperformed other medications in firstepisode patients.[47, 48] Numerous guidelines or algorithms for the treatment of schizophrenia are available. Treatment guidelines are recommendations that need clinical judgment in their application and regular updating based on new evidence.[49] Few studies have examined the outcome of trials using these algorithms. In a study from Canada, Agid et al described the outcome of treatment among 244 patients with first-episode schizophrenia using a 2003 algorithm. If no response to the first antipsychotic trial was observed, a second antipsychotic was used. Most patients were treated with olanzapine or risperidone. Response rates fell from about 75% in the first trial to less than 20% in the second trial. The patients who did not respond to either trial were offered clozapine, and 75% responded. Unanswered questions from this study include the role of first-generation antipsychotic medications, newer second-generation antipsychotic medications, and when clozapine should be used.[50] As noted above, medication decisions are difficult. If the patient has not responded to a medication, physicians can switch medications or add another one. Physicians sometimes choose what seems to be a simpler option, which is to increase the dose of the original medication. For example, quetiapine is

sometimes prescribed at higher than approved doses for patients with schizophrenia or schizoaffective disorder. Honer et al found that doses greater than 800 mg/d did not show any advantage beyond the approved dose range.[51]

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. The goal of treatment, according to this model, is for the person with schizophrenia to have few or stable symptoms, not be hospitalized, manage his or her own funds and medications, and either be 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.[52] In one study from China, the authors randomly assigned over a thousand patients with schizophrenia to either antipsychotic medication alone or medication with a psychosocial intervention. The authors chose an interesting way of delivering a psychosocial intervention. Each month, the patients and their families received a day of 4 types of evidence-based interventions: psychoeducation, family intervention, skills training, and cognitive behavior therapy. After a year, the patients in the group receiving the extra interventions were more compliant with their medications and had fewer rehospitalizations and greater quality of life.[53] Cognitive impairment, a core feature of schizophrenia, is less dramatic than other symptoms (eg, hallucinations, delusions) but can be more problematic with respect to work, social relationships, and independent living. Cognitive impairment responds poorly to medication. Cognitive remediation is a treatment modality that is based on principles of neuropsychological rehabilitation. It is based, in part, on the idea that the brain has some plasticity, and that brain exercises can encourage neurons to grow and can develop the neurocircuitry underlying many mental activities. Numerous different models of cognitive remediation are available. Some models emphasize drill practice of isolated cognitive skills with the aid of computers, whereas others help people to develop strategies to overcome areas of weakness. Other forms of this therapy are known as cognitive rehabilitation, cognitive enhancement, or metacognitive therapy. Cognitive remediation works best when patients are stable. People improve across numerous cognitive functions, and changes are found on brain imaging that reflect these changes in brain functioning. These techniques are time-intensive and labor-intensive and seem to work best when individualized to the particular person. This is because cognitive deficits are multiple and vary from person to person. When combined with other therapies, such as supported employment, cognitive remediation leads to clinically relevant improvements.[54] These effects are durable; the effects last even after the training has stopped.[55] In a study by Grant et al, low-functioning patients with prominent negative symptoms were assigned to recovery-oriented cognitive behavioral therapy or standard treatment. After 18 months, the authors found that both negative and positive symptoms had decreased. The study was not blind, and the treatment was delivered by enthusiastic doctoral level therapists, which may limit the generalizability of these findings. [56]

Consultations
Social work
Social work: Schizophrenia affects the person's whole family, and the familys responses can affect the trajectory of the persons illness. Familial "high expressed emotion" (hostile over involvement and

intrusiveness) leads to more frequent relapses. Some studies have found that family therapy or family interventions may prevent relapse, reduce hospital admission, and improve medication compliance. [57]

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, selfesteem, 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 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 Summary
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
Class Summary
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.

View full drug information

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. View full drug information

Clozapine (Clozaril)
Antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors. Has some D2 antagonism and high D4 affinity. View full drug information

Olanzapine (Zyprexa)
Olanzapine is a selective monoaminergic antagonist at the following receptors: serotonin, D1-4, muscarinic, H1, and alpha1 adrenergic. View full drug information

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. View full drug information

Risperidone (Risperdal)
Has both D2 and serotonin 5HT2 antagonism. Now available in long-acting form using microspheres made of biodegradable polymers. View full drug information

Quetiapine (Seroquel)
May act by antagonizing dopamine and serotonin effects. Newer antipsychotic used for long-term management. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive dyskinesia. View full drug information

Ziprasidone (Geodon)
Antipsychotic agent that antagonizes dopamine type-2, 5-HT2, histamine H1, and alpha1-adrenergic receptors. View full drug information

Iloperidone (Fanapt)
Atypical antipsychotic agent indicated for acute treatment of schizophrenia. Precise mechanism of action unknown. Antagonizes receptors for dopamine-2 and serotonin type 2 (5-HT2). Approved by FDA in May 2009. View full drug information

Asenapine (Saphris)
Mechanism of action unknown. Efficacy thought to be mediated through a combination of antagonist activity at dopamine 2 and serotonin (5-HT2) receptors. Exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors; dopamine D2, D3, D4, and D1 receptors; alpha1- and alpha2-adrenergic receptors; and histamine H1 receptors, with moderate affinity for H2 receptors. In vitro assays suggest antagonistic activity elicited at these receptors. Indicated for acute treatment of schizophrenia. The prescribing information was updated in September 2011 to include data from 52 reports of type 1 hypersensitivity reactions. View full drug information

Lurasidone (Latuda)
Atypical antipsychotic. Precise mechanism unknown. Suggested efficacy thought to be mediation of central dopamine type-2 and serotonin type-2 (5HT-2A) receptor antagonism. Indicated for schizophrenia. View full drug information

Fluphenazine hydrochloride (Prolixin)

High-potency typical antipsychotic that blocks postsynaptic dopaminergic D1 and D2 receptors in the brain. Some alpha-adrenergic and anticholinergic effects and may depress the reticular activating system. View full drug information

Haloperidol (Haldol)
Drug of choice for patients with acute psychosis when no contraindications exist. Haloperidol is a D2 antagonist. Butyrophenone noted for high potency and low potential for causing orthostasis. The drawback

is the high potential for EPS/dystonia. Parenteral dosage form may be admixed in same syringe with 2 mg of lorazepam for better anxiolytic effects.

Further Inpatient Care

Inpatient hospitalizations are preceded by an exacerbation of symptoms, due to medication noncompliance, substance abuse, medication adverse effects or toxicity, medical illness, psychosocial stress, or the waxing and waning of the illness itself. Admission to the hospital is stressful for anyone, but for someone with schizophrenia, who can find change difficult and who is suffering an exacerbation of his or her symptoms, it can be particularly frightening. The role of the inpatient staff, particularly the psychiatric nurse, is to assess the cause for the hospitalization; monitor response to therapy; and provide education, support, reassurance, and encouragement. Hospitalizations are usually brief and for the purposes of crisis management or symptom stabilization. Some patients are so disorganized because of their symptoms that they are unable to live in the community. Some live on long-term inpatient units. These units are usually found in state hospitals or Veterans Administration hospitals, and are becoming increasingly rare.

Further Outpatient Care

The bulk of care for patients with schizophrenia occurs in an outpatient setting. This probably is best carried out by a multidisciplinary team. Suggested members of the team include a psychopharmacologist, counselor or therapist, social worker, nurse, vocational counselor, and case manager. Clinical pharmacists and internists can be valuable members. Treatment requires an integration of medical, psychological, and psychosocial inputs. In the United States, many people with schizophrenia do not live with their families. They do not always have the skills needed for independent living, so a system of alternative housing arrangements has emerged. At their most basic, these systems may consist of boarding houses or single-room occupancy (SRO) hotels with no supervision. Many organizations, often statesupported, provide communal-living settings with 24-hour supervision in halfway houses. Veterans Administration (VA) facilities have developed a sophisticated system of family care homes. Therapeutic halfway houses in which independence and social skills training are encouraged also exist. One form of case management known as assertive case treatment is typically used for patients who have had multiple inpatient hospitalizations. The treatment involves active outreach to patients. Case managers usually have a fairly small outpatient load of about 10 patients and are able to go into the community to work with their clients. The managers coordinate and integrate care. The case managers, who may come from various disciplines, identify indications for treatment, make referrals to appropriate services, and promote engagement with interventions. This kind of treatment is very expensive but may be associated with a better clinical and social outcome and decrease in hospitalization.

Deterrence/Prevention
Many have wondered if the prognosis of this illness would be better if treatment could be started as early as possible. The North American Prodrome Longitudinal Study involves a group of 8 research centers that identifies young people at risk. These are people with brief psychotic symptoms or those with a genetic risk for schizophrenia who begin to have a decrease in functioning. The results of this study are mixed. Whether people who meet these criteria should be treated with medications is unclear. [58]

Complications
Alcohol and drug abuse (including nicotine) are common. Of patients with schizophrenia, 20-70% have a comorbid substance abuse problem. Comorbid substance abuse, particularly common in younger men, is associated with increased hostility, crime, violence, suicidality, noncompliance with medication, homelessness, poor nutrition, and poverty. Patients who abuse substances may fare better in dual diagnosis treatment programs, in which principles from both mental health and chemical dependency fields can be integrated. Drug use and abuse can increase the symptoms of this disorder. For example, cannabis use has been shown to correlate with adverse symptoms in persons with schizophrenia. [59] Noncompliance or nonadherence with medication is difficult to estimate but is common, and it is one of the reasons for the use of intramuscular (IM) preparations of antipsychotic medications. A regular routine of IM medication is preferred by some patients, and it is easier for the clinician to monitor medication adherence when IM medication is used. Clinicians in the United States tend to use less IM medication than clinicians in Europe. A large trial compared long-acting injectable risperidone to the psychiatrists choice of oral antipsychotic agent. The study found, somewhat to the surprise of many, that the injectable risperidone was not superior to oral medication and was associated with more side effects. [60] Adherence is usually overestimated by both patient and physician. Nonadherence can be partial or complete, but even partial adherence is associated with relapse.[61] In the past, nonadherence was thought to be due at least in part to the side effects of the conventional antipsychotic agents, such as akathisia. Nonadherence remains a major clinical problem, even with second-generation antipsychotic agents. Family and treaters should encourage the person to take their medication, while at the same time respecting his or her autonomy. This is a difficult balance to achieve. Many patients with schizophrenia report symptoms of depression. Considerable uncertainty exists as to whether depression is part of schizophrenia, a reaction to the illness, or a complication of treatment. This is a particularly important problem because of the high rate of suicide in patients with schizophrenia. The research evidence for the use of antidepressant agents in schizophrenia is mixed. Further complicating the situation are the findings that antipsychotic agents, even the older conventional agents, may have antidepressant properties.[62] A recent meta-analysis suggests that antidepressants added to antipsychotics might help treat the negative symptoms of chronic schizoprenia, which can be difficult to distinguish from depression.[63] A few patients may be violent, sometimes due to hallucinations or delusions. Because the violence may be unpredictable and bizarre, these events are often highly publicized. An unfortunate consequence is the exacerbation of stigma. Violence may be associated with command hallucinations or substance abuse. [63] Most patients are not violent and are usually afraid of others rather than threatening to others. However, the rate of violence in patients with schizophrenia who do not abuse substances is higher than in people without schizophrenia.[64]

Prognosis
The prognosis of schizophrenia is guarded.

Patients with schizophrenia have a 10% risk of suicide. Full recovery is unusual. Symptoms usually follow a waxing and waning course. The patient's pattern of symptoms may change over years. Positive symptoms respond fairly well to antipsychotic medication, but the other symptoms are quite persistent. Early onset of illness, family history of schizophrenia, structural brain abnormalities, and prominent cognitive symptoms are associated with poor prognosis.

This illness is little understood, and the available treatment is unacceptably poor. Research is ongoing into the pathophysiology and treatment of this illness. With earlier intervention with improved agents the goal is complete resolution of all symptoms of this illness and continuation or resumption of a full meaningful life. Prognosis is better for people living in low-income and middle-income countries.[65] Mortality is higher in patients with schizophrenia than in people without this disease due to many factors, including suicide, lifestyle factors, and, perhaps, poorer medical care and complications of medications. A study from Britain shows that this "mortality gap" is increasing.[66]

Patient Education
Because of the nature of schizophrenia, the patients may have difficulty understanding the illness. Nevertheless, teaching the patient to understand the importance of medication compliance and abstinence from alcohol and other drugs of abuse is important. Working with the patient so that patient and family can learn to recognize early signs of a decompensation, such as insomnia or increased irritability, is helpful. A review of 44 studies showed that education of patients about the nature of their illness and treatment, when added to standard care, led to a reduction of rehospitalization and of symptoms. [67] Education may help with adherence to medication and may help the patient cope with their illness better in other ways. Family members should be referred to the National Alliance on Mental Illness (NAMI) (or other appropriate support group if available), which provides many educational opportunities. Social skills training is helpful, but the effects are not long-lived. This kind of training, as well as other sorts of problem-solving therapy, may need to be continued on an indefinite basis, similar to the medication. Physical illnesses in schizophrenia are common. The importance of a healthy lifestyle and regular health care should be stressed. Counseling with respect to sexuality, pregnancy, and sexually transmitted diseases is important for patients with schizophrenia. Side effects of antipsychotic medications may affect the physical appearance of people; this, in turn, can affect relationships with others and self esteem.[68]