esquizofrenia emedicine

8/2/2019 esquizofrenia emedicine

http://slidepdf.com/reader/full/esquizofrenia-emedicine 1/17

Background

Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that probablyconsists 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 adisturbance in information processing is a less vivid symptom that is highly disruptive. People withschizophrenia have lower rates of employment, marriage, and independent living compared with otherpeople.

Case study

John P is a 25-year-old male with the diagnosis of schizophrenia. He was a healthy child, but his parentsreport that he was a bedwetter and seemed slower to develop than his brothers and sisters. A maternaluncle 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 diabetesmellitus.

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 havenothing to do with him. They are particularly upset by his lack of interest in the outside world. John lives ina 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 asocial worker whom he sees often. The psychiatrist would like to switch him to long-acting injectableantipsychotic treatment, but John is afraid of injections and isn't sure that he needs medication. He has noprimary care physician.

Pathophysiology

Neuroimaging studies have demonstrated anatomical abnormalities, such as enlargement of the ventriclesand decreased brain volume in medial temporal areas . [1] These findings are of greater research interestthan clinical use.

The hippocampus is a small, cortical, supposedly seahorse-shaped part of the brain, curled within themedial border of the temporal lobe. The hippocampus is functionally part of the limbic system, whereemotions are processed. The hippocampus is where we form declarative or episodic memories (memoriesof facts or events). The hippocampus is affected in Alzheimer disease, the preeminent disease of memoryproblems.

The hippocampus is also one of the many parts of the brain affected in schizophrenia. Disturbances indeclarative 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 inbrains from patients with schizophrenia (including nonmedicated patients) and relatives may be related tothe cognitive problems of schizophrenia . [2]

Mattai et al studied a group of children with schizophrenia and their healthy siblings and controls .[3] Theaverage age at the beginning of the study was 12 years. The hippocampal volume of the ill children wasless than that of their siblings and controls and steadily decreased over 12 years of follow up, although notat an increasing rate. The children with schizophrenia were administered antipsychotic medications. The

http://emedicine.medscape.com/article/117853-overview






authors concluded that the hippocampal volume deficit was more likely due to the illness itself rather thanthe 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, andMRI studies show anatomic abnormalities in a network of neocortical and limbic regions andinterconnecting white matter tracts . [4] A meta-analysis of studies using diffusion tensor imaging to examinewhite 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 brainimages of people at high genetic risk for schizophrenia. Seventeen of 146 people had reductions in wholebrain volume and left and right prefrontal and temporal lobes. The changes in prefrontal lobes wereassociated with increasing psychotic symptoms .[6]

In a meta-analysis of 27 longitudinal structural MRI studies of patients with schizophrenia compared withcontrols, the authors found that schizophrenia was associated with loss of whole brain volume in both grayand 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 arethought to exist in schizophrenia; however, little direct evidence supports this. This theory has recentlyundergone considerable refinement.

Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, andhyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may coexist.(Negative and positive symptoms are defined below.) Moreover, the newer antipsychotic drugs block bothdopamine 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 andketamine, 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 decreasedhealth care.

Race





No known racial differences exist in the prevalence of schizophrenia. Some research indicates thatschizophrenia is diagnosed more frequently in black people than in white people. This finding has beenattributed 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 theantidopaminergic 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 theillness 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.

HistoryInformation about the medical and psychiatric history of the family, details about pregnancy and earlychildhood, history of travel, and history of medications and substance abuse are all important. Thisinformation is helpful in ruling out other causes of psychotic symptoms.

The patient usually had an unexceptional childhood. In retrospect, family members may describe theperson with schizophrenia as a physically clumsy and emotionally aloof child. The child may have beenanxious and preferred to play by himself or herself. The child may have been late to learn to walk and mayhave 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 usuallyauditory; 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 andattention and executive functions such as the ability to organize and abstract. Patients also havedifficulty understanding nuances and subtleties of interpersonal cues and relationships. A newinitiative from the National Institutes of Mental Health, known as Measurement and TreatmentResearch to Improve Cognition in Schizophrenia (MATRICS), is a collaboration between variousprograms to develop tools for measuring cognition in clinical trials and aiding drug developmentthat is targeted at these symptoms.

4. Mood symptoms: Schizophrenia patients often seem cheerful or sad in a way that does not makesense to others. They often are depressed.

Physical

Findings on a general physical examination are usually not contributory. This examination is necessary torule out other illnesses.



A neurologic examination is sometimes helpful before the initiation of antipsychotic medications as abaseline, because these drugs can change the findings. Some patients with schizophrenia have motordisturbances before exposure to antipsychotic agents. Schizophrenia has been associated with left andmixed 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 whentalking with a person with schizophrenia:

The person may be dressed oddly, such as wearing heavy jackets in the summer. The person maypay 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 aquestion. 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 theinterviewer.

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 speaksat length but never actually answers the question.

The patient often shows poor attention, disorganized thinking, and stereotyped or perseverativethinking.

The patient may make odd movements (which may or may not be related to neurolepticmedication).

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 arerarely observed in others. These include water drinking to the point of intoxication, staring at oneself in themirror, 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'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 1symptom 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 eachother. The patient must experience at least 1 month of symptoms (or less if successfully treated) during a6-month period, and social or occupational deterioration problems occur over a significant amount of time.


http://www.psych.org/

http://www.psych.org/




These problems must not be attributable to another condition for the diagnosis of schizophrenia to bemade .[12]

Causes

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

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 havebeen found mostly change a gene’s expression or a protein’s function in a small way. Interactions with therest 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 catecholamineneurotransmitters 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 developpsychotic symptoms if they used cannabis than other cannabis-using subjects without thatvariant .[14]

The RELNgene codes for the protein reelin, which plays a role in brain development and GABAergicactivity. In an international study using a genome-wide association scan, a common variant in thisgene 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 ininhibitory neurons in the brain. Nitric oxide acts as an intracellular messenger. Using a newlydeveloped statistical technique, the posterior probability of linkage disequilibrium, the authors

identified a single nucleotide polymorphism associated with higher levels of expression of this genein postmortem brain samples .[16]

Other genetic changes involve the structure of the gene. For example, copy number variants are deletionsand duplications of segments of DNA. Copy number variants can involve genes or regulatory regions. Thesevariants are usually inherited, but can spontaneously arise. Copy number variants, such as deletions foundat 1q21.1, 15q13.3, and 22q11.2 increase the risk of patients developing schizophrenia . [17] These findingsaccount 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 copynumber variant disorders include autism, intellectual disability, attention-deficit hyperactivity disorder, andepilepsy .[18] In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy numbervariant 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, intellectualdisability 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 mutationsin the patient. De novo mutations in the exome, which is the part of the chromosome that codes forproteins, 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 inschizophrenia 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 whodeveloped 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 environmentalinfluences on causation of schizophrenia. A review of the 9,596 women in Helsinki who received hospitaltreatment during pregnancy for an upper urinary tract infection between 1947 and 1990 found no overallsignificant increase in the risk of schizophrenia among their offspring but a 5-fold higher risk among theoffspring of women who also had a family history of psychosis. Clarke et al estimated that, among offspringof 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 internationalmigrants or urban populations of ethnic minorities . [25

Laboratory Studies

No characteristic laboratory results are found in schizophrenia. The following blood work should beperformed 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 forporphyrins, 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, andtumors.



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 andrecognizing social cues, and easy distractibility. Determination of the patient's cognitive weaknessesand 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) toconfirm the diagnosis.

Medical Care

The use of antipsychotic medications, also known as neuroleptic medication or major tranquilizers, is themainstay of treatment for schizophrenia. These medications have repeatedly been shown to diminish thepositive symptoms of schizophrenia and prevent relapses. Approximately 80% of patients relapse within 1year 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 novelantipsychotics. The first-generation antipsychotic drugs tend to cause extrapyramidal adverse effects andelevated prolactin levels. The second-generation drugs are more likely to cause weight gain andabnormalities 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 bypharmaceutical companies and compare antipsychotic drugs to one another. Little consensus has beenreached.

For some years it was believed that the newer drugs were more effective, but that belief is now fading. Theexception is clozapine, which consistently outperforms the other antipsychotic drugs. An influential studyhas been the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). This is a large study fundedby the federal government to examine the effectiveness of several different antipsychotic drugs in morethan 1400 patients. By multiple measures, perphenazine, a first-generation drug, was almost or about asgood as the second-generation drugs .[32]

In a study from the United Kingdom, the Cost Utility of the Latest Antipsychotic Drugs in SchizophreniaStudy (CUtLASS), more than 200 patients who were about to change antipsychotic medication wererandomly assigned to either a first-generation or second-generation agent. In this study, the first-generation drugs seemed to perform slightly better than the newer ones. Clozapine was the exception, inthat it outperformed all of the other drugs . [33]

In a large study from Finland, researchers used a database to review the effectiveness of antipsychoticagents in the treatment of 2600 people after their first episode of schizophrenia . [34] The study found thatslightly less than half of patients continued treatment for longer than 30 days after discharge. With respectto 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 thesemedications 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 isdelivered differently in Finland, with the cost of antipsychotic medication fully reimbursed, according tothe authors. The average age at admission was 38 years, which is much older than is expected for the firstepisode. Finally, depot perphenazine and zuclopenthixol are not available in the United States. Depotolanzapine was not used. However, the authors’ findings that patients who had their first episode did bestin terms of avoiding more hospitalizations when treated with depot haloperidol or clozapine arenoteworthy.

The following adverse effects are those typically associated with conventional antipsychotic agents or withrisperidone, 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 muscularmen. 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, andautonomic instability. Laboratory findings include increased creatine kinase and myoglobinuria.Acute renal failure may be present. A significant mortality rate exists. Rarely, neuroleptic malignantsyndrome associated with clozapine and other atypical antipsychotic agents has been reported.

Parkinsonism presents with tremor, bradykinesia, akinesia, and, sometimes, rigidity orbradyphrenia (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 asinvoluntary 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 forthor tap their feet. Occasionally, diaphragmatic dyskinesia exists, which leads to loud and irregulargasping and/or "jerky" speech. The patient is often not aware of these movements. Risk factors forTD include age, female sex, and negative symptoms. Duration of therapy and dose seem to belogical risk factors, but this has not been demonstrated conclusively. TD is probably less commonwith the use of novel antipsychotic drugs but, until many patients have been exposed to thesedrugs 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, decreasedmemory, agitation, visual hallucinations, and constipation. Risperidone, aripiprazole, andziprasidone are relatively free of anticholinergic adverse effects.

The QT interval is the electrocardiogram interval between the beginning of the QRS complex andthe 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 aperson at risk for torsade de pointes, a malignant arrhythmia associated with syncope and suddendeath. 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 eventis 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 interms 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 thesubsequent 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 andclozapine.

Venous thromboembolism may be associated with the use of antipsychotic drugs. Patients treatedwith clozapine may be at particular risk for this complication. The reasons for this possibleassociation are not understood .[38, 39]

Altered glucose and lipid metabolism, with or without weight gain, may occur with mostantipsychotic agents, as can weight gain itself . [40] Aripiprazole and ziprasidone are the antipsychoticdrugs 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 toinsulin 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 includeeducational programs on nutrition and exercise, and cognitive behavioral therapy. Variousmedications have been tried but with little success.

Kessing et al examined nearly 346,000 patient records where individuals purchased antipsychoticsand 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 rateratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the rate ratio varied widelyfor 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 neweragents. They are available in a variety of vehicles, including liquid and intramuscular preparations. Mostimportantly, they are also available as depot preparations. In other countries, several differentantipsychotic depot preparations exist, but, in the United States, only haloperidol and fluphenazine areavailable in depot forms. With respect to the newer agents, risperidone is now available as a long-actinginjection (Risperdal Consta) that uses biodegradable polymers, and a long-acting olanzapine intramuscularinjection also is available.

Therapeutic drug monitoring is the measurement of medication levels in the blood to ensure that thelevels 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 orolanzapine often experience an increase in their antipsychotic levels. (Nicotine patches and nicotineinhalers 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) oramantadine 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 isassociated with about a 1% risk of agranulocytosis, so patients must have weekly white blood cellcount monitoring for the first 6 month s [43] (the period of greatest risk) and then monitoring every 2weeks for 6 months, and then every 4 weeks, as long as the absolute neutrophil count (ANC) isnormal. (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, anddrooling .[43] Constipation and cardiac side effects (cardiomyopathy and myocarditis) can be lifethreatening. However, approximately one third of patients who have not responded toconventional antipsychotic agents do better on clozapine. Violence, substance abuse, smoking, andsuicidality are diminished with the use of clozapine.

Many patients with schizophrenia are treated with other psychotropic medications in addition toantipsychotic agents. Very little rigorous evidence for the use of polypharmacy in schizophrenia exists, butit is widely practiced. Medications often used include the antidepressants, mood stabilizers, and anxiolyticagents. 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 thatpatients prefer this .[44]

A recent meta-analysis of 19 studies involving more than 1200 subiects also found an advantage forantipsychotic polypharmacy .[45]

Some studies have explored the potential neurotoxic effects of antipsychotic medications; however, noclear conclusions have been reached.

For example, Ho et al performed structural brain imaging in more than 200 patients with schizophreniaover 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 antipsychoticmedications 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 clinicalsymptoms directly or if the changes are reversible is unknown. Whether higher doses of medication werein 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 medicationbut is rarely initially used because it is so burdensome. It has not outperformed other medications in first-episode patients .[47, 48]

Numerous guidelines or algorithms for the treatment of schizophrenia are available. Treatment guidelinesare recommendations that need clinical judgment in their application and regular updating based on newevidence .[49]

Few studies have examined the outcome of trials using these algorithms. In a study from Canada, Agid et aldescribed the outcome of treatment among 244 patients with first-episode schizophrenia using a 2003algorithm. 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 firsttrial to less than 20% in the second trial. The patients who did not respond to either trial were offeredclozapine, and 75% responded. Unanswered questions from this study include the role of first-generationantipsychotic 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 asimpler 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 schizoaffectivedisorder. Honer et al found that doses greater than 800 mg/d did not show any advantage beyond theapproved 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 leasthalf-time. Hope, empowerment, choice, and community integration are emphasized in this treatmentapproach.

The best studied psychosocial treatments are social skills training, cognitive behavioral therapy, cognitiveremediation, and social cognition training . [52]

In one study from China, the authors randomly assigned over a thousand patients with schizophrenia toeither 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 familiesreceived a day of 4 types of evidence-based interventions: psychoeducation, family intervention, skillstraining, and cognitive behavior therapy. After a year, the patients in the group receiving the extrainterventions were more compliant with their medications and had fewer rehospitalizations and greaterquality 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, andindependent living. Cognitive impairment responds poorly to medication. Cognitive remediation is atreatment modality that is based on principles of neuropsychological rehabilitation. It is based, in part, onthe idea that the brain has some plasticity, and that brain exercises can encourage neurons to grow andcan develop the neurocircuitry underlying many mental activities.

Numerous different models of cognitive remediation are available. Some models emphasize drill practiceof isolated cognitive skills with the aid of computers, whereas others help people to develop strategies toovercome areas of weakness. Other forms of this therapy are known as cognitive rehabilitation, cognitiveenhancement, or metacognitive therapy.

Cognitive remediation works best when patients are stable. People improve across numerous cognitivefunctions, and changes are found on brain imaging that reflect these changes in brain functioning. Thesetechniques are time-intensive and labor-intensive and seem to work best when individualized to theparticular person. This is because cognitive deficits are multiple and vary from person to person. Whencombined with other therapies, such as supported employment, cognitive remediation leads to clinicallyrelevant 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 torecovery-oriented cognitive behavioral therapy or standard treatment. After 18 months, the authors foundthat both negative and positive symptoms had decreased. The study was not blind, and the treatment wasdelivered 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 family’s responses can affect thetrajectory of the person’s illness. Familial "high expressed emotion" (hostile over involvement and



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

Vocational rehabilitation

Few patients with schizophrenia are able to maintain competitive employment. Supported employmentprograms 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 lipidmetabolism. Occasionally the person with schizophrenia develops odd food preferences. Many personswith schizophrenia have limited funds, do not cook for themselves, and live in areas where fast foodoutlets are abundant. Therefore, nutritional counseling is difficult but important.

Activity

Because many psychotropic medications are associated with weight gain, persons with schizophreniashould be encouraged to be as physically active as possible.

Most patients with schizophrenia smoke. This may be a result of previous conventionalantipsychotic treatment because nicotine may ameliorate some of the adverse effects of thesedrugs. Smoking may also be related to the boredom associated with hospitalizations, the peerpressure from other patients to smoke, or the anomie associated with unemployment. The healthrisks from smoking are well known, and patients should be encouraged to stop smoking. Cessationof 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 theMentally Ill (NAMI) is a helpful advocacy group that is supportive for family members. NAMI alsoadvocates 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. Thenewer, 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 inwomen who are pregnant or breastfeeding.

Antipsychotics

Class Summary

Mainstay of treatment of schizophrenia. Some clinicians routinely perform ECGs on patients beforebeginning treatment with antipsychotic medication. Note that the use of antipsychotic medications for thetreatment of behavioral symptoms in elderly patients with dementia has not been shown to be effectiveand is associated with an increased risk of mortality. Because suicide is not uncommon in patients withpsychotic illnesses, the clinicians should write prescriptions for the smallest quantity that is consistent withgood clinical care. Patients should be urged to avoid substance abuse.

http://www.nami.org/










Ziprasidone (Geodon)

Antipsychotic agent that antagonizes dopamine type-2, 5-HT2, histamine H1, and alpha1-adrenergicreceptors.

View full drug information

Iloperidone (Fanapt)

Atypical antipsychotic agent indicated for acute treatment of schizophrenia. Precise mechanism of actionunknown. Antagonizes receptors for dopamine-2 and serotonin type 2 (5-HT2). Approved by FDA in May2009.


Asenapine (Saphris)

Mechanism of action unknown. Efficacy thought to be mediated through a combination of antagonistactivity 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 H2receptors. In vitro assays suggest antagonistic activity elicited at these receptors. Indicated for acutetreatment of schizophrenia.

The prescribing information was updated in September 2011 to include data from 52 reports of type 1hypersensitivity reactions.


Lurasidone (Latuda)

Atypical antipsychotic. Precise mechanism unknown. Suggested efficacy thought to be mediation of centraldopamine type-2 and serotonin type-2 (5HT-2A) receptor antagonism. Indicated for schizophrenia.


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.


Haloperidol (Haldol)

Drug of choice for patients with acute psychosis when no contraindications exist. Haloperidol is a D2antagonist. Butyrophenone noted for high potency and low potential for causing orthostasis. The drawback

http://reference.medscape.com/drug/geodon-ziprasidone-342985

http://reference.medscape.com/drug/fanapt-iloperidone-999104


http://reference.medscape.com/drug/saphris-asenapine-999301


http://reference.medscape.com/drug/latuda-lurasidone-999605


http://reference.medscape.com/drug/fluphenazine-342973


http://reference.medscape.com/drug/haldol-decanoate-haloperidol-342974












http://reference.medscape.com/drug/geodon-ziprasidone-342985



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

Further Inpatient Care

Inpatient hospitalizations are preceded by an exacerbation of symptoms, due to medicationnoncompliance, 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 findchange difficult and who is suffering an exacerbation of his or her symptoms, it can be particularlyfrightening.

The role of the inpatient staff, particularly the psychiatric nurse, is to assess the cause for thehospitalization; monitor response to therapy; and provide education, support, reassurance, andencouragement.

Hospitalizations are usually brief and for the purposes of crisis management or symptomstabilization.

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 hospitalsor 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 isbest carried out by a multidisciplinary team. Suggested members of the team include apsychopharmacologist, counselor or therapist, social worker, nurse, vocational counselor, and casemanager. 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 housingarrangements has emerged. At their most basic, these systems may consist of boarding houses orsingle-room occupancy (SRO) hotels with no supervision. Many organizations, often state-supported, provide communal-living settings with 24-hour supervision in halfway houses. VeteransAdministration (VA) facilities have developed a sophisticated system of family care homes.Therapeutic halfway houses in which independence and social skills training are encouraged alsoexist.

One form of case management known as assertive case treatment is typically used for patients whohave 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 gointo the community to work with their clients. The managers coordinate and integrate care. Thecase managers, who may come from various disciplines, identify indications for treatment, makereferrals 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 anddecrease in hospitalization.

Deterrence/Prevention

Many have wondered if the prognosis of this illness would be better if treatment could be started as earlyas possible. The North American Prodrome Longitudinal Study involves a group of 8 research centers thatidentifies young people at risk. These are people with brief psychotic symptoms or those with a genetic riskfor 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 acomorbid substance abuse problem. Comorbid substance abuse, particularly common in younger men, isassociated with increased hostility, crime, violence, suicidality, noncompliance with medication,homelessness, poor nutrition, and poverty. Patients who abuse substances may fare better in dualdiagnosis treatment programs, in which principles from both mental health and chemical dependencyfields 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 routineof IM medication is preferred by some patients, and it is easier for the clinician to monitor medicationadherence when IM medication is used. Clinicians in the United States tend to use less IM medication thanclinicians in Europe. A large trial compared long- acting injectable risperidone to the psychiatrist’s choice of oral antipsychotic agent. The study found, somewhat to the surprise of many, that the injectablerisperidone 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 orcomplete, but even partial adherence is associated with relapse . [61] In the past, nonadherence was thoughtto 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 timerespecting his or her autonomy. This is a difficult balance to achieve.

Many patients with schizophrenia report symptoms of depression. Considerable uncertainty exists as towhether depression is part of schizophrenia, a reaction to the illness, or a complication of treatment. Thisis a particularly important problem because of the high rate of suicide in patients with schizophrenia. Theresearch evidence for the use of antidepressant agents in schizophrenia is mixed. Further complicating thesituation are the findings that antipsychotic agents, even the older conventional agents, may haveantidepressant properties .[62] A recent meta-analysis suggests that antidepressants added to antipsychoticsmight help treat the negative symptoms of chronic schizoprenia, which can be difficult to distinguish fromdepression .[63]

A few patients may be violent, sometimes due to hallucinations or delusions. Because the violence may beunpredictable and bizarre, these events are often highly publicized. An unfortunate consequence is theexacerbation 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 peoplewithout 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 theother symptoms are quite persistent.

Early onset of illness, family history of schizophrenia, structural brain abnormalities, and prominentcognitive symptoms are associated with poor prognosis.



This illness is little understood, and the available treatment is unacceptably poor. Research isongoing into the pathophysiology and treatment of this illness. With earlier intervention withimproved agents the goal is complete resolution of all symptoms of this illness and continuation orresumption 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 manyfactors, 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 andabstinence 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 mayhelp 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 appropriatesupport 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 sortsof 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 patientswith schizophrenia.

Side effects of antipsychotic medications may affect the physical appearance of people; this, in turn, canaffect relationships with others and self esteem . [68]



Documents

esquizofrenia emedicine