Schizophrenia

Schizophrenia 

• Author: Frances R Frankenburg, MD; Chief Editor: Eduardo Dunayevich, MD

Background

Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that probably comprises several separate illnesses. The hallmark symptoms of schizophrenia are psychotic ones, 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 than other people do.

Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and medical illnesses, as well as disorders such as heavy metal toxicity, adverse effects of drugs, and vitamin deficiencies. (See DDx and Workup.)

Treatment of schizophrenia requires an integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and probably is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment.

The use of antipsychotic m edications, also known as neuroleptic medications or major tranquilizers, is the mainstay of medical treatment for schizophrenia. These medications diminish the positive symptoms of schizophrenia and prevent relapses. Unfortunately, they are also associated with a number of adverse effects. (See Treatment and Medication.)

Pathophysiology

Both anatomic and neurotransmitter system abnormalities have been implicated in the pathophysiology of schizophrenia.

Anatomic abnormalities

Neuroimaging studies in patients with schizophrenia show abnormalities such as enlargement of the ventricles, decreased brain volume in medial temporal areas, and changes in the hippocampus.^{[1, 2, 3]} These findings are of interest more for research purposes than for clinical application.

Interest has also focused on the various connections within the brain rather than on localization in a single part of the brain. Magnetic resonance imaging (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 (DTI) to examine white matter found that 2 networks of white-matter tracts are reduced in schizophrenia.^[5]

In the Edinburgh High-Risk Study, brain imaging showed reductions in whole-brain volume and in left and right prefrontal and temporal lobe volumes in 17 of 146 people who were at high genetic risk for schizophrenia. The changes in prefrontal lobes were associated with increasing severity of psychotic symptoms.^[6]

In a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients with control subjects, Olabi et al found that schizophrenia was associated with structural brain abnormalities that progressed over time. The abnormalities identified included loss of whole-brain volume in both gray and white matter and increases in lateral ventricular volume.^[7]

Neurotransmitter system abnormalities

Abnormalities of the dopaminergic system are thought to exist in schizophrenia; however, there is little direct evidence to support this belief. 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.

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; see Presentation.) 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. Thus, other neurotransmitter systems, such as norepinephrine, serotonin, and gamma-aminobutyric acid (GABA), are undoubtedly involved. Some research focuses on the N -methyl-D-aspartate (NMDA) subclass of glutamate receptors because NMDA antagonists, such as phencyclidine and ketamine, can lead to psychotic symptoms in healthy subjects.^[8]

Inflammation and immune function

Immune system function is disturbed in schizophrenia.^[9] Overactivation of the immune system (eg, from prenatal infection or postnatal stress) may result in overexpression of inflammatory cytokines and subsequent alteration of brain structure and function. For example, schizophrenic patients have elevated levels of proinflammatory cytokines that activate the kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids; these acids regulate NMDA receptor activity and may also be involved in dopamine regulation.

Insulin resistance and metabolic disturbances, which are common in the schizophrenic population, have also been linked to inflammation. Thus, inflammation might be related to both the psychopathology of schizophrenia and to metabolic disturbances seen in patients with schizophrenia.^[10]

Etiology

The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk factors, genetic and perinatal. Undefined socioenvironmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities.^{[11, 12, 13]}

Genetics

The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted relatives.^[14] The risk of schizophrenia in first-degree relatives of persons 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.

Genome-wide association studies have identified many candidate genes, but the gene variants that have been implicated so far account for only a small fraction of schizophrenia cases, and these findings have not always been replicated in different studies. The genes that have been found mostly change a gene’s expression or a protein’s function in a small way. Interactions with the rest of the genome and with the environment will doubtless prove to be important.

Loci of particular interest include the following:

• The catechol-O-methyltransferase (COMT) gene
• The RELN gene
• The gene for nitric oxide synthase 1 adaptor, NOS1AP

The COMT gene codes for the postsynaptic intracellular enzyme, COMT, which is involved in the methylation and degradation of the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several allelic variants of COMT affect its activity. The valine-valine variant degrades dopamine faster than does the valine-methionine variant; subjects with 2 copies of the methionine allele were less likely to develop psychotic symptoms with cannabis use than were other cannabis-using subjects without that variant.^[15]

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.^[16]

The NOS1AP 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, researchers have identified a single-nucleotide polymorphism associated with higher levels of expression of this gene in postmortem brain samples from individuals with schizophrenia.^[17]

Other genetic changes involve the structure of the gene. For example, copy number variants are deletions and duplications of segments of DNA; they can involve genes or regulatory regions. These variants are usually inherited, but can arise spontaneously. Copy number variants such as the deletions found at 1q21.1, 15q13.3, and 22q11.2 increase the risk of developing schizophrenia.^{[18, 19]} At most, however, these findings probably account for only a small part of the heritability of schizophrenia.

In addition, the effects of some of these copy number variants are not restricted to schizophrenia. Other copy number variant disorders include autism, intellectual disability, attention-deficit hyperactivity disorder, and epilepsy.^[20]

In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy number variant at 1 of the following loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. Clinically, these people had various neurologic or psychiatric disorders, including developmental delay, intellectual disability and autism-related disorders. Subjects also had congenital anomalies.^[21]

Many studies have also looked for abnormalities in neurodevelopmental genes, in accordance with the neurodevelopmental hypothesis of schizophrenia. Disruptions in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with schizophrenia, albeit with significant variability between studies.^{[22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]} These findings also lend support to the hypothesis that schizophrenia is a disease in which multiple rare genetic variants lead to a common clinical outcome.

Some people with schizophrenia have no family history of the disorder. These cases may be the result of new mutations. 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 would otherwise be expected.^{[35, 36]}

As can be seen, working out the details of these genetic factors is difficult. Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about four fifths of liability to schizophrenia.^[37]

Perinatal factors

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.^[38] For example, children born to Dutch mothers who were malnourished during World War II have a high rate of schizophrenia.

After the 1957 influenza A2 epidemics in Japan, England, and Scandinavia, rates of schizophrenia were higher among offspring of women who contracted influenza during their second trimester. Women in California who were pregnant between 1959 and 1966 were more likely to have a child who developed schizophrenia if they had influenza in the first trimester of their pregnancy.^[39]

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.^[40]

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.^[41]

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.^[41]

Epidemiology

The lifetime prevalence of schizophrenia has generally been estimated to be approximately 1% worldwide.^[42] However, a systematic review by Saha et al of 188 studies drawn from 46 countries found a lifetime risk of 4.0 per 1000 population. Prevalence estimates from countries considered least developed were significantly lower than those from countries classed as emerging or developed.^[43] Immigrants to developed countries show increased rates of schizophrenia, with the risk extending to the second generation.^{[11, 12, 13]}

People with schizophrenia have a 5% lifetime risk of suicide.^[44] Mortality is also increased because of medical illnesses, which result from a combination of unhealthy lifestyles, side effects of medication, decreased health care, and perhaps even some fundamental vulnerability to medical comorbidities.

To date, no racial differences in the prevalence of schizophrenia have been positively identified. 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. The prevalence of schizophrenia is about the same in men and women. The onset of schizophrenia is later in women than in men, and the clinical manifestations are less severe. This may be because of the antidopaminergic influence of estrogen. The onset of schizophrenia usually occurs in adolescence, and symptoms remit somewhat in older patients. The first 5-10 years of the illness can be stormy; they are usually followed by decades of relative stability (though a return to baseline is unusual). Positive symptoms are more likely to remit than cognitive and negative symptoms are (see Presentation for a description of symptoms).

Prognosis

The prognosis for patients with schizophrenia is guarded. Full recovery is unusual. Early onset of illness, family history of schizophrenia, structural brain abnormalities, and prominent cognitive symptoms are associated with a poor prognosis. The prognosis is better for people living in low-income and middle-income countries.^[45]

Symptoms usually follow a waxing and waning course. A patient’s pattern of symptoms may change over years. Positive symptoms respond fairly well to antipsychotic medication, but the other symptoms are quite persistent.

Because of vocational difficulties, many patients with schizophrenia also have to cope with the burdens of poverty. These include limited access to medical care, which may lead to poor control of the disease; homelessness; and incarceration, typically for minor offenses.

People with schizophrenia have a 5% lifetime risk of suicide.^[44] Other factors that contribute to an increased mortality in people with schizophrenia include lifestyle issues such as cigarette smoking, poor nutrition, and lack of exercise, and perhaps poorer medical care and complications of medications. A study from Britain shows that this “mortality gap” is increasing.^[46]

Schizophrenia is not well understood, and the available treatment is unacceptably poor. Research is ongoing into the pathophysiology and treatment of this illness. It is hoped that such efforts will eventually allow earlier intervention with better pharmacologic agents, the goal being to achieve complete resolution of all symptoms of the illness and continuation or resumption of a full and meaningful life.

Patient Education

The nature of schizophrenia makes it a potentially difficult illness for patients to understand. 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 (eg, 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 reductions in rehospitalization and symptoms.^[47] Education may help with adherence to medication and may help the patient cope with the illness better in other ways.

Family members should be referred to the National Alliance on Mental Illness (NAMI) (or another appropriate support group, if one is available). These groups can provide many educational opportunities.

Social skills training is helpful, but the effects are not long-lived. Such training, like other sorts of problem-solving therapy, may have to be continued on an indefinite basis, much as pharmacologic therapy is. People with schizophrenia have also championed self-help recovery-based approaches to care, with an emphasis on developing the personal strengths and resilience to combat this illness.

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 physical appearance; this, in turn, can affect self-esteem and relationships with others.^[48]

The following resources may also be helpful:

• Mayo Clinic -Schizophrenia
• National Institute of Mental Health -Schizophrenia
• Medline Plus -Schizophrenia

For patient education, see the Schizophrenia Health Center, as well as Schizophrenia.

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.^{[49, 50]}

A noticeable change in personality and a decrease in academic, social, and interpersonal functioning often begin during mid-to-late adolescence. Usually, 1-2 years pass between the onset of these vague symptoms and the first visit to a psychiatrist.^[51] The first psychotic episode usually occurs between the late teenage years and the 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 drive; the person with schizophrenia has tremendous inertia
3. Cognitive symptoms – These include neurocognitive deficits (eg, deficits in working memory and attention and in executive functions, such as the ability to organize and abstract); patients also find it difficult to understand nuances and subtleties of interpersonal cues and relationships
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 Examination

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 neurologic signs.

Mental Status Examination

On a detailed Mental Status Examination in a patient with schizophrenia, the following observations may be made in the severely ill person:

• The patient may be dressed oddly (eg, may be wearing heavy jackets in the summer)
• The patient may pay insufficient attention to personal hygiene
• The patient may be unduly suspicious of the examiner or be socially awkward
• The patient may express a variety of odd beliefs or delusions
• The patient often has a flat affect (ie, little range of expressed emotion)
• The patient may admit to hallucinations or respond to auditory or visual stimuli that are not apparent to the examiner
• The patient may show thought blocking, in which long pauses occur before he or she answers a question
• The patient’s speech may be difficult to follow because of the looseness of his or her associations; 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
• The patient has difficulty with abstract thinking, demonstrated by inability to understand common proverbs or idiosyncratic interpretation of them
• The speech may be circumstantial (ie, the patient takes a long time and uses many words in answering a question) or tangential (ie, the patient speaks at length but never actually answers the question)
• The patient often shows poor attention

· The patient’s thoughts may be disorganized, stereotyped or perseverative

• The patient may make odd movements (which may or may not be related to neuroleptic medication)
• The patient may have little insight into his or her problems (the term for this is anosognosia)
• Patients 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 is not uncommon in people with schizophrenia, but violence towards others is uncommon (see below)
• Orientation is usually intact (ie, patients know who and where they are and what time it is)

Persons with schizophrenia may display strange and poorly understood behaviors. These include drinking water to the point of intoxication, staring at themselves in the mirror, performing stereotyped activities, hoarding useless objects, and mutilating themselves. Their wake-sleep cycle may be disturbed. They often experience difficulty dealing with change.

Diagnostic Criteria

According to the American Psychiatric Association’sDiagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR), to meet the criteria for diagnosis of schizophrenia, in most cases the patient must have experienced at least 2 of the following symptoms^[52] :

• Delusions
• Hallucinations
• Disorganized speech
• Disorganized or catatonic behavior
• Negative symptoms

Only 1 symptom is required under the following circumstances:

• The delusions are bizarre
• Auditory hallucinations occur in which the voices comment in an ongoing manner on the person’s behavior
• Two 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, with social or occupational deterioration problems occurring over a significant amount of time. These problems must not be attributable to another condition.

Classification of Schizophrenia

Schizophrenia can be divided into the following types on the basis of the symptom pattern:

• Paranoid schizophrenia – This is characterized by delusions and auditory hallucinations but relatively normal intellectual functioning and affect. Delusions of persecution or grandeur are common
• Disorganized schizophrenia – This involves both speech and behavior, as well as flattened or inappropriate emotions
• Catatonic schizophrenia – This is characterized by disturbances of movement that may render the person incapable of caring for himself or herself
• Undifferentiated schizophrenia

Residual schizophrenia is the term used to describe the illness of a person who has a history of at least 1 episode of schizophrenia but who currently has rather mild symptoms. Patients with residual schizophrenia may progress to complete remission or continue in this state for years without experiencing any further psychotic episodes.

Diagnostic Considerations

Other problems to be considered in the differential diagnosis of schizophrenia include the following:

• Other psychiatric illnesses
• Anatomic lesions
• Metabolic illnesses
• Endocrine disorders
• Infectious illnesses
• Miscellaneous disorders
• Vitamin deficiency

Other psychiatric illnesses

Schizophrenia and bipolar affective disorder (manic-depressive illness) may be difficult to distinguish from each other. Patients with manic-depressive illness predominantly have disturbances in their affect or mood. Psychotic symptoms may be prominent during a mania or depression.

In classic manic-depressive illness, the psychotic symptoms are congruent with mania or depression, and the person has periods of euthymia (normal mood) with no psychotic symptoms between the episodes. However, some patients have periods of psychotic symptoms in the absence of depression or mania. In these cases, the diagnosis of schizoaffective disorder is applied.

In delusional disorder, the person has a variety of paranoid beliefs, but these beliefs are not bizarre and are not accompanied by any other symptoms of schizophrenia. For example, a person who is functioning well at work but becomes unreasonably convinced that his or her spouse is having an affair has a delusional disorder rather than schizophrenia.

Schizotypal personality disorder is characterized by a pervasive pattern of discomfort in close relationships with others, along with the presence of odd thoughts and behaviors. The oddness in this disorder is not as extreme as that observed in schizophrenia.

In schizoid personality disorder, the person has difficulty and lack of interest in forming close relationships with others and prefers solitary activities. No other symptoms of schizophrenia are present.

In paranoid personality disorder, the person is distrustful and suspicious of others. No actual delusions or other symptoms of schizophrenia are present.

Anatomic lesions

In rare cases, brain tumors may be confused with a psychotic illness. Because brain tumors are potentially lethal but treatable, it is important to consider brain imaging studies for every person with a new onset of a psychotic illness or, perhaps, a marked change in symptoms.

Subdural hematomas can manifest as changes in mental status. Intracranial bleeds should be considered in patients who report head trauma or who, for whatever reason, are not able to provide a clear history. Brain imaging may be appropriate in these cases.

Idiopathic calcification of the basal ganglia is a rare disorder that tends to present as psychosis in patients who become symptomatic early in adulthood; those presenting later in life typically present with dementia and a motor system disorder. Schizophrenialike symptoms may precede the onset of intellectual deterioration and extrapyramidal motor disturbances.^[53]

Metabolic illnesses

Wilson disease, also known as hepatolenticular degeneration, is a disorder of the metabolism of copper. It is an autosomal recessive illness, the gene for which has been located on chromosome 13. The first symptoms are often vague changes in behavior during adolescence, which are followed by the appearance of odd movements.

The diagnosis can be indicated by the laboratory findings of increased urinary levels of copper and low serum levels of copper and ceruloplasmin or by the detection of Kayser-Fleischer rings (copper deposits around the cornea) with or without a slit-lamp examination. The diagnosis is usually confirmed by finding increased hepatic copper at biopsy.

Not all patients with Wilson disease have low serum ceruloplasmin or Kayser-Fleischer rings, the 2 findings most commonly associated with this disorder. Because the treatment of this disease is burdensome, some experts recommend liver biopsy so that a tissue diagnosis may be made before chelating therapy is started. This is an important diagnosis to make because of the existence of a very specific treatment.

Porphyria is a disorder of heme biosynthesis that can present as psychiatric symptoms. Patients may have a family history of psychosis. The psychiatric symptoms may be associated with electrolyte changes, peripheral neuropathy, and episodic severe abdominal pain. Abnormally high levels of porphyrins in a 24-hour urine collection confirm the diagnosis.

Patients with hypoxemia or electrolyte disturbances may present with confusion and psychotic symptoms. Hypoglycemia can produce confusion and irritability and may be mistaken for psychosis.

Delirium from whatever cause (eg, metabolic or endocrine disorders) is an important condition to consider, especially in the elderly or hospitalized patient. Although patients with delirium may have a wide range of neuropsychiatric abnormalities, the clinical hallmarks are decreased attention span and a waxing-and-waning type of confusion.

Endocrine disorders

Infrequently, thyroid illness may be confused with schizophrenia. Severe hypothyroidism or hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is usually associated with depression, which if severe may be accompanied by psychotic symptoms. A hyperthyroid person is typically depressed, anxious, and irritable.

Both adrenocortical insufficiency (Addison disease) and hypercortisolism (Cushing syndrome) may result in mental status changes. However, both disorders also produce physical signs and symptoms that can suggest the diagnosis. In addition, most patients with Cushing syndrome will have a history of long-term steroid therapy for a medical illness.

Hypoparathyroidism or hyperparathyroidism can on occasion be associated with vague mental status changes. These are related to abnormalities in serum calcium concentrations.

Infectious illnesses

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

The infectious illnesses of particular interest are the following:

• Neurosyphilis
• HIV infection
• Cerebral abscess
• Creutzfeldt-Jakob disease (CJD)

Neurosyphilis

Neurosyphilis can be divided into the following 3 categories:

• Meningovascular syphilis
• Tabes dorsalis
• General paresis

Patients with general paresis may present with behavioral changes, psychosis or dementia. The diagnosis can be suggested by a history of exposure, personality changes, and pupillary changes such as the Argyll Robertson pupil.

The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are nontreponemal tests that use antigens to detect antibodies to Treponema pallidum. Antibodies decline during the disease, and so these tests have a high false-negative rate. If neurosyphilis is strongly suspected, more specific treponemal tests, such as the fluorescent-treponemal antibody absorption test (FTA-ABS), can be useful.

HIV infection

HIV penetrates the blood-brain barrier early in the course of the infection and thus can cause a number of mental status changes, particularly dementia or other neuropsychological impairment. In addition, patients with HIV are at risk for opportunistic infections, such as neurosyphilis, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalopathy, and tuberculous meningitis, all of which can lead to mental status changes.

Persons infected with HIV are also at risk for primary central nervous system lymphoma and have vague symptoms such as confusion and memory loss. Many drugs used to treat HIV may cause mental status changes. Finally, persons infected with HIV are at risk for nutritional deficiencies that also contribute to mental status changes.

Cerebral abscess

Patients with cerebral abscesses rarely have psychotic symptoms, but brain imaging should be considered to rule out this treatable possibility. Immunosuppressed persons and people living in or traveling in underdeveloped countries are particularly at risk.

Creutzfeldt-Jakob disease

Prions cause the rare CJD, one of the transmissible spongiform encephalopathies. The disease usually occurs in people older than 50 years and is marked by rapid deterioration, dementia, abnormal electroencephalographic complexes, and myoclonic jerks.

A variant of this illness, vCJD, is the human form of bovine spongiform encephalopathy (so-called mad cow disease). Fewer than 200 cases of vCJD have occurred worldwide, and as of 2003, only 2 cases had occurred in the United States. Unlike CJD, vCJD seems to affect people aged 20-40 years. It lasts much longer than CJD and begins with behavioral changes. In several cases, the patient was diagnosed with schizophrenia before the diagnosis of vCJD was made.

Miscellaneous disorders

Multiple sclerosis is notoriously difficult to diagnose in its early stages. The physical symptoms may be overlooked, and psychological symptoms may occasionally be an early feature.

Huntington disease is a neurodegenerative disorder marked by neuronal loss throughout the brain, especially in the striatum. This is an autosomal dominant disorder, the gene for which has been located on chromosome 4. A family history is essential to making the diagnosis, but it can be misleading. The maternity and paternity of a patient are not always what they are represented to be, and causes of death are often misreported.

The occurrence of choreoathetoid movements well before exposure to antipsychotic agents is suggestive of Huntington disease. About three-fourths of patients with Huntington disease initially present with psychiatric symptoms, and most need inpatient psychiatric care at some point in their illness.

Dementia with Lewy bodies is the second most common type of dementia, after Alzheimer disease. Patients present with fluctuating mental status and prominent psychiatric symptoms, including depression and visual hallucinations. This is an important disorder to diagnose because these patients are reported to do poorly when treated with antipsychotic drugs.

Lipid storage disorders include metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, and ceroid lipofuscinosis. These illnesses usually occur in childhood but may occasionally come to medical attention during adolescence. Patients may present with psychiatric symptoms such as cognitive deterioration and changes in personality. Patients may be diagnosed with schizophrenia until the neurologic symptoms of these illnesses become more prominent.^[54]

Malignancies (typically, bronchial oat-cell carcinoma) can occasionally lead to dramatic mental status changes early in their course and before they have been diagnosed or metastasized to the brain. The etiology is not clear. Various paraneoplastic neurologic syndromes have been described, including subacute cerebellar degeneration, encephalopathy with brainstem involvement, diffuse encephalopathies with mental symptoms, and limbic encephalopathy.

Patients with a seizure or ictal disorder, especially temporal lobe epilepsy, may occasionally display odd behavior before, during, or after a seizure. Aura and ictal symptoms can include hallucinations, disturbances of memory, or affective and cognitive changes. Ictal and postictal phenomena can include complex motor abnormalities.

Patients with systemic lupus erythematosus, typically young women, may present with psychiatric symptoms, such as psychosis or cognitive deficit, in association with unexplained fever or joint pain. The diagnosis can be suggested by the physical findings of malar flush and the laboratory findings of anemia, renal dysfunction, elevated erythrocyte sedimentation rate (ESR), and, most specifically, elevated antinuclear antibody (ANA) levels.

Presenting features of systemic vasculitides (eg, polyarteritis nodosa, Churg-Strauss syndrome, Wegener granulomatosis, and Behçet disease) may include personality changes. Other symptoms, such as weight loss and fever, usually occur. Magnetic resonance imaging (MRI) shows characteristic lesions of vasculitis.

Heavy metal toxicity may cause changes in personality, thinking, or mood. Occupational exposure is the usual source of heavy metal toxicity, but cases have also resulted from ingestion of herbal medications contaminated with heavy metals.

Many medications have been associated with mental status changes, especially the following:

• Corticosteroids (psychosis or mania)
• Levodopa (hallucinations or insomnia)
• Antidepressants (mania)
• Interferon alfa (depression)
• Beta blockers, including those in eye drops (depression)

Substance abuse (eg, abuse of alcohol, cocaine, opiates, psychostimulants, or hallucinogens) not uncommonly leads to disturbed perceptions, thought, mood, and behavior. The anabolic steroids used by body builders and athletes can lead to psychotic symptoms.^[55] Anticholinergic medications can lead to delirium, especially if abused.

Vitamin deficiency

Thiamine deficiency can occur in people who rely on alcohol for calories or patients with advanced malignancies or malabsorption syndromes. Acute and severe thiamine depletion can lead to Wernicke encephalopathy, marked by oculomotor disturbances, ataxia, and confabulation. If this condition is left untreated, Korsakoff psychosis may develop. Wernicke encephalopathy is a common and underdiagnosed cause of chronic cognitive impairment in people with alcoholism.^[56]

Deficiency of vitamin B-12, folate, or both may produce depression or dementia. Very rarely, these deficiencies may result in delusional thinking.

Differential Diagnoses

• Alcohol-Related Psychosis
• Bipolar Affective Disorder
• Brief Psychotic Disorder
• Cocaine-Related Psychiatric Disorders
• Delusional Disorder
• Depression
• Mental Disorders Secondary to General Medical Conditions
• Schizoaffective Disorder
• Schizophreniform Disorder
• Shared Psychotic Disorder

Approach Considerations

Schizophrenia is not associated with any characteristic laboratory results. The following blood tests should be performed on all patients, both at the beginning of the illness and periodically afterwards:

• Complete blood count (CBC)
• Liver, thyroid, and renal function tests
• Electrolyte, glucose, vitamin B12, serum methylmalonic acid, folate, and calcium levels

Other tests to consider, if the history provides any reason for suspicion (see Differentials), are as follows:

• HIV
• Rapid plasma reagin (RPR); if a strong suspicion of neurosyphilis exists, specific treponemal tests may be helpful
• Ceruloplasmin; if a strong suspicion of Wilson disease exists, consider a liver biopsy (or multiple biopsies)
• Antinuclear antibody (ANA) for systemic lupus erythematosus
• Urine for culture and sensitivity or drugs of abuse
• AM cortisol for adrenal disorders
• 24-hour urine collections for porphyrins, copper, or heavy metals
• Pregnancy testing, if the patient is a woman of childbearing age
• Lyme disease
• Brain imaging to rule out subdural hematomas, vasculitis, cerebral abscesses, and tumors
• Chest x-ray for pulmonary illness or occult malignancy
• Dexamethasone suppression test and adrenocorticotropic hormone (ACTH) stimulation test for hypercortisolism and hypocortisolism, respectively
• Electroencephalography (EEG)

Neuropsychological testing may be considered; determination of the patient’s cognitive weaknesses and strengths can be helpful in treatment planning. Common findings in patients with schizophrenia are as follows:

• Poor executive functioning (ie, poor planning, organizing, or initiation of activities)
• Impaired memory
• Difficulty in abstraction and recognizing social cues
• Easy distractibility

Approach Considerations

Treatment of schizophrenia requires integration of medical, psychological, and psychosocial inputs. The bulk of care occurs in an outpatient setting and probably is best carried out by a multidisciplinary team, which should include a psychopharmacologist, a counselor or therapist, a social worker, a nurse, a vocational counselor, and a case manager. Clinical pharmacists and internists can be valuable members of the team.

It is vital not to neglect the medical care of the person with schizophrenia. Obesity, diabetes, cardiovascular disease, and lung diseases are prevalent in schizophrenia, and the person with schizophrenia often does not receive adequate medical care for such conditions.^[57]

The use of antipsychotic medications, also known as neuroleptic medications or major tranquilizers, is the mainstay of medical treatment for schizophrenia. These medications diminish the positive symptoms of schizophrenia and prevent relapses. Approximately 80% of patients relapse within 1 year if antipsychotic medications are stopped, whereas only 20% relapse if treated. Children, pregnant or breastfeeding women, and elderly patients present special challenges. In all of these cases, medications must be used with particular caution.

The choice of which drug to use for treatment of a patient with schizophrenia depends on many issues, including effectiveness, cost, side-effect burden, method of delivery, availability, and tolerability. Pharmaceutical companies have sponsored many studies comparing antipsychotic drugs with one another, but little consensus has been reached. In the absence of clinical or pharmacogenetic predictors of treatment response, the current treatment approach is largely one of trial and error across sequential medication choices.

Although treatment is primarily provided on an outpatient basis, patients with schizophrenia may require hospitalization for exacerbation of symptoms. This may result from medication noncompliance, substance abuse, medication adverse effects or toxicity, medical illness, psychosocial stress, or the waxing and waning of the illness itself. Hospitalizations are usually brief and for the purposes of crisis management or symptom stabilization.

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.

Treatment of patients with schizophrenia, particularly during a psychotic episode, may raise the issue of informed consent. Consent is a legal term and should be used with respect to specific tasks. A person who is delusional in some but not all areas of life may still have the capacity to make medical and financial decisions for himself or herself.

Insurance concerns

In the United States, patients with schizophrenia who are unable to work may be eligible for governmental programs, such as Medicare and Medicaid. These programs pay the cost of medical care. Unfortunately, if individuals begin to work and earn a sufficient salary, they are at risk of losing these benefits. This is particularly awkward because they may be working in a job that provides minimal or no health benefits. This situation is complicated and must be monitored closely by professionals with a good understanding of health benefits.

Antipsychotic Drugs: Comparative Efficacy

The first antipsychotic medications were dopamine D2 antagonists, including chlorpromazine and haloperidol. Medications similar to these agents are known as first-generation, typical, or conventional antipsychotics. Other antipsychotics, beginning with clozapine, are known as second-generation, atypical, or novel antipsychotics.

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 (IM) preparations. Most important, these agents are also available as depot preparations. Of the second-generation agents, risperidone is now available as a long-acting injection (Risperdal Consta) that uses biodegradable polymers, and a long-acting olanzapine IM injection also is available.

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; in addition, they are more expensive than the first-generation drugs.

For some years, it was believed that the newer antipsychotic drugs were more effective, but that belief is now fading. An exception is clozapine, which consistently outperforms the other antipsychotic drugs.

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a large nationwide trial that compared the first-generation antipsychotic perphenazine with the second-generation drugs olanzapine, risperidone, quetiapine, and ziprasidone, found that olanzapine was slightly better than the other drugs but also was associated with significant weight gain. Surprisingly, perphenazine performed about as well as the other 3 second-generation agents.^[58]

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 first-generation drugs seemed to perform slightly better than the newer ones. Clozapine was the exception, in that it outperformed all of the other drugs.^[59]

First-episode schizophrenia

In the European First Episode Schizophrenia Trial (EUFEST), which studied treatment discontinuance as the main outcome measure, patients were more likely to stop low-dose haloperidol than to stop olanzapine, quetiapine, ziprasidone, or amisulpride (not available in the United States); however, all medications were associated with similar decreases in symptoms.^[60] EUFEST was a year-long open-label study conducted in nearly 500 patients in 13 European countries and Israel.

Similarly, the randomized, double-blind Comparison of Atypicals for First Episode (CAFE) study found few differences between olanzapine, quetiapine, and risperidone in 400 patients experiencing a first episode of psychosis, with all-cause treatment discontinuance rates in the vicinity of 70% by week 52. Drowsiness and weight gain were along the most common adverse events with all 3 drugs; in addition, insomnia was seen with olanzapine, longer sleep time with quetiapine, and menstrual irregularities in women with risperidone.^[61]

The Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland recommends that any antipsychotic medication, with the exceptions of clozapine and olanzapine, can be used as first-line treatment for patients with schizophrenia who are experiencing their first episode of acute positive symptoms.^[62]

PORT notes that early treatment with antipsychotic drugs is associated with significant symptom reduction and that first- and second-generation antipsychotics may have equivalent significant short-term efficacy. However, because of the adverse side-effect profile of clozapine and the significant metabolic risks associated with olanzapine, PORT advises that neither drug should be considered as a first-line treatment for first-episode schizophrenia.^[62]

PORT notes that both responsiveness to treatment and sensitivity to adverse effects are greater in patients with first-episode schizophrenia than in those who have had multiple episodes. Therefore, PORT recommends starting antipsychotic treatment for the former at doses lower than those recommended for the latter. An exception is quetiapine, which may not be effective in lower doses; in addition, low doses of aripiprazole or ziprasidone have not been evaluated in first-episode schizophrenia.^[62]

The National Institute of Mental Health (NIMH) has initiated a research project, Recovery After an Initial Schizophrenia Episode (RAISE), to determine whether coordinated and aggressive treatment in the earliest stages of illness can prevent long-term disability from schizophrenia. The RAISE Early Treatment Program (ETP), an integrated program delivered in community clinics, will be compared with the RAISE Connection program, a program offered in Baltimore and Manhattan in partnership with state mental health programs.

Antipsychotic Drugs: Choice of Agent

There is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the most effective medication but is not recommended as first-line therapy. It has a high burden of side effects and requires regular blood work. Clozapine has not outperformed other medications in first-episode patients.^{[63, 64]}

Numerous guidelines or algorithms for the treatment of schizophrenia are available. Treatment guidelines are recommendations that require clinical judgment in their application and must be regularly updated on the basis of new evidence.^[65]

Few studies have examined the outcome of treatment 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.^[66] If no response to the first antipsychotic 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.^[66] The patients who did not respond to either trial were offered clozapine, and 75% responded. Unanswered questions from this study include the respective roles of first-generation and second-generation antipsychotic medications and the issue of when clozapine should be used.

If the patient has not responded to a medication, physicians can switch medications or add another one. Using 2 or even 3 different antipsychotic agents together is common, though the evidence base for this is not compelling and it does increase the complexity of the medication regimen. Nonetheless, in one large study the discontinuation of one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued.^[67] A meta-analysis of 19 studies involving more than 1200 subjects found a modest advantage for antipsychotic polypharmacy.^[68]

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 dosages higher than 800 mg/day did not show any advantage over dosages in the approved range.^[69]

PORT provided a detailed review addressing the choice of antipsychotic medications; this review included recommendations and discussions regarding acute, maintenance, first-episode, and targeted intermittent treatment, as well as treatment of individual symptoms.^[62]

Clozapine

Clozapine is the oldest atypical antipsychotic agent and probably the most effective.^[70] Because it is associated with about a 1% risk of agranulocytosis, patients must undergo white blood cell (WBC) count monitoring every week for the first 6 months^[71] (the period of greatest risk), then every 2 weeks for 6 months, and finally every 4 weeks, as long as the absolute neutrophil count (ANC) is normal. If the ANC drops, a strict protocol of monitoring and possibly medication cessation must then be followed.

Clozapine is also associated with anticholinergic adverse effects, sedation, and drooling.^[71] 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, hostility, and suicidality may be diminished with the use of clozapine.

Antipsychotic Drugs: Maximizing Compliance

Noncompliance with or nonadherence to pharmacologic therapy is difficult to estimate but is known to be common, and it is one of the reasons for the use of IM preparations of antipsychotic medications. A regular routine of IM medication is preferred by some patients, and it permits easier monitoring of medication adherence by the clinician. IM medication is less widely used in the United States than in Europe.

A large trial that compared long-acting injectable risperidone to the psychiatrist’s choice of oral antipsychotic agent found, somewhat to the surprise of many, that injectable risperidone was not superior to the oral form and was associated with more side effects.^[72]

Adherence is usually overestimated by both patient and physician. Nonadherence can be partial or complete, but even partial adherence is associated with relapse.^[73] 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. Nevertheless, nonadherence remains a major clinical problem, even with second-generation antipsychotic agents.

Family members of people with schizophrenia, as well as clinicians providing care for them, should encourage them to take their medication, while at the same time respecting their autonomy. This is a difficult balance to achieve.

Antipsychotic Drugs: Adverse Effects

The following are adverse effects typically associated with conventional antipsychotic agents and with risperidone, a novel antipsychotic agent, at dosages higher than 6 mg/day:

• Akathisia
• Dystonia
• Hyperprolactinemia
• Neuroleptic malignant syndrome (NMS)
• Parkinsonism
• Tardive dyskinesia (TD)

Akathisia is a subjective sense of inner restlessness, mental unease, irritability, and dysphoria. Dystonia consists of painful and frightening muscle cramps, which affect the head and neck but may extend to the trunk and limbs. Dystonia usually occurs within 12-48 hours of the beginning of treatment or an increase in dose. Muscular young men are typically affected. Hyperprolactinemia is associated with galactorrhea, amenorrhea, gynecomastia, impotence, and osteoporosis.

NMS is marked by fever, muscular rigidity, altered mental state, and autonomic instability. Laboratory findings include increased creatine kinase levels and myoglobinuria. Acute kidney injury may result. Mortality is significant. NMS is thought to be less common in patients taking clozapine or other atypical antipsychotic agents.

Parkinsonism presents as tremor, bradykinesia, akinesia, and, sometimes, rigidity or bradyphrenia (slowed thinking). This is particularly likely to occur in women and elderly patients.

The incidence of 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 or “jerky” speech. The patient is often not aware of these movements.

Risk factors for TD include older age, female sex, and negative symptoms. Logically, duration of therapy and dosage would be risk factors, but this has not been conclusively demonstrated to be the case. TD appears to be less common with the novel antipsychotic drugs, but whether this is actually so will not be known with certainty until many patients have been exposed to these drugs for several years.

Physicians should warn patients, especially those being treated with conventional antipsychotic agents about the risk of TD. Regular examinations, using the abnormal involuntary movement scale (AIMS), should be performed to document its presence or absence.

Anticholinergic effects

Anticholinergic side effects occur with most antipsychotics (though risperidone, aripiprazole, and ziprasidone are relatively free of them). Such effects include the following:

• Dry mouth
• Exacerbation of glaucoma
• Confusion
• Decreased memory
• Agitation
• Visual hallucinations
• Constipation

QT interval prolongation

The QT interval is the interval between the beginning of the QRS complex and the end of the T wave on an electrocardiogram (ECG). It reflects the time required for the ventricles to depolarize and repolarize. The QT interval corrected for heart rate is called the QTc. A prolonged QTc interval puts a person at risk for torsades 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.^[74]

No cases of torsades de pointes were reported in a large trial of more than 18,000 patients in 18 countries who were randomly assigned to receive either ziprasidone or olanzapine, though the 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 with respect to the cardiac safety of ziprasidone.^[75]

Haloperidol has only a small influence on the ECG. Nevertheless, this agent has been implicated, albeit very rarely, in causing torsades de pointes.^[76]

Clinicians should be alert to the ability of antipsychotic medications to cause ECG changes in patients with any of the above risk factors or in patients taking other medications that can lengthen the QTc interval. Particular caution is advised with regard to using these medications in patients who are elderly or medically ill.

Altered glucose and lipid metabolism and weight gain

Altered glucose and lipid metabolism, with or without weight gain, may occur with most antipsychotic agents, as can weight gain itself.^[77] Aripiprazole and ziprasidone are the antipsychotic drugs least likely to lead to these adverse effects, whereas olanzapine and clozapine are the drugs most likely to do so. The newer agents asenapine, iloperidone, and lurasidone may also share a lower liability for weight gain and metabolic disturbances.

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, and arthritis). Some approaches to the problem of weight gain include educational programs on nutrition and exercise, as well as cognitive behavioral therapy. Various medications have been tried but with little success.

A Danish study of the risk for diabetes with antipsychotics found that the rate ratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the RR varied widely for second-generation antipsychotics (1.32; range, 1.17-1.57). This study compared nearly 346,000 patient records where individuals purchased antipsychotics and nearly 1.5 million unexposed individuals.^[78]

Stroup et al reported that patients experiencing cardiovascular or metabolic side effects of an antipsychotic medication may fare better if they switch to a different agent, provided that they are closely monitored.^[79] This study included 215 patients whose psychotic symptoms were stabilized on olanzapine, quetiapine or risperidone. After 24 weeks, those who switched to aripiprazole showed improvement with regard to cholesterol levels and other metabolic factors, and they lost more weight than those who stayed on their original medication.

Relapse or worsening of psychotic symptoms occurred no more frequently in patients who switched medications than in those who stayed on their original medication.^[79] However, patients who switched to aripiprazole were more likely to discontinue the assigned medication; 43.9% of those who switched discontinued their medication, versus 24.5% of those who stayed on their original medication.

It is unclear whether weight-reducing drugs should be added to antipsychotic therapy, although Wang et al found that the diabetes drug metformin (1000 mg daily) was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance.^[80] This randomized, placebo-controlled study was conducted in 72 patients with first-episode schizophrenia who gained more than 7% of their predrug weight.

Miscellaneous adverse effects

All antipsychotic agents may be associated with esophageal dysmotility, aspiration, choking, 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 seems to be 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; however, the reasons for this possible association are not understood.^{[81, 82]}

Neurotoxic effects

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 and found that whereas patients treated with higher doses of antipsychotic medications seemed to lose gray matter throughout their brain (except the cerebellum), those treated with lower doses seemed to have a small increase in white matter of the brain.^[83]

The clinical significance of these findings is unclear. It is not known whether these changes are directly associated with any clinical symptoms and whether they are reversible. It also is not known whether the higher medication doses were in response to the gray matter loss or whether it was the other way around.

Antipsychotic Drugs: Monitoring of Blood levels

Regular measurement of blood medication levels in the blood would be helpful in schizophrenia, for the following reasons:

• Patients may not always take their medications, and checking drug levels can detect this noncompliance
• Patients may not always be the best reporters of side effects, and monitoring medication levels can occasionally help the clinician detect toxicity
• Smoking tobacco products induces the liver enzyme CYP1A2 (though nicotine patches, nicotine inhalers, and chewing tobacco do not), which metabolizes a number of antipsychotic drugs, so that, for example, patients who stop smoking while being treated with clozapine or olanzapine often experience increased antipsychotic levels; a patient who has stopped smoking may have a variety of complaints, and checking drug levels can help determine their etiology

For most antipsychotic medications, however, clear dose-response curves have not been established, and the reasons listed above are not compelling enough to induce clinicians to monitor drug levels. In clinical practice, drug levels are rarely monitored.

There are 2 exceptions to this general statement. Plasma concentrations of haloperidol are correlated to some degree with clinical effects. levels in the range of 15-25 ng/mL are thought to be optimal. Plasma concentrations of clozapine in the range of 300-400 ng/mL may be optimal.

Other Medications

Anticholinergic agents (eg, benztropine, trihexyphenidyl, and 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.

Many patients with schizophrenia are treated with other psychotropic medications in addition to antipsychotic agents. Polypharmacy in schizophrenia is supported by very little rigorous evidence but is widely practiced nonetheless. Medications often used include antidepressants, mood stabilizers, and anxiolytic agents. Note that carbamazepine and clozapine should not be used together.

Benzodiazepines are often used and are perceived as being quite safe. Nevertheless, they can be addictive and can lead to falls, especially in the elderly. There has long been a concern that they might increase mortality.^[84]

Psychosocial Interventions

Psychosocial treatment is essential for people with schizophrenia, in that medications alone are insufficient. The best-studied psychosocial treatments are social skills training, cognitive behavioral therapy, cognitive remediation, and social cognition training.^[85] PORT, referred to above, also provides a detailed review of psychosocial interventions.^[86]

Psychosocial treatments are currently oriented according to the recovery model. According to this model, the goals of treatment for a person with schizophrenia are as follows:

• To have few or stable symptoms
• Not to be hospitalized
• To manage his or her own funds and medications
• To be either working or in school at least half-time

Hope, empowerment, choice, and community integration are emphasized in this treatment approach.

A large study from China demonstrated the benefits of medication plus psychosocial intervention over medication alone.^[87] In the psychosocial intervention arm, each month patients and their families received a day of 4 types of evidence-based interventions: psychoeducation, family intervention, skills training, and cognitive-behavioral therapy. After a year, the patients in the group receiving the extra interventions were more compliant with their medications, had fewer rehospitalizations, and experienced better quality of life.

Cognitive remediation

Cognitive impairment, a core feature of schizophrenia, is less dramatic than other symptoms of the disease (eg, hallucinations and 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 derived from principles of neuropsychological rehabilitation. It is based, in part, on the ideas 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-based practicing of isolated cognitive skills with the aid of computers, whereas others help people develop strategies for overcoming 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. Improvement occurs across numerous cognitive functions, and changes are found on brain imaging that reflect these changes in brain functioning.

Cognitive remediation techniques are time-intensive and labor-intensive. Because cognitive deficits are multiple and vary from person to person, such techniques seem to work best when specifically tailored to each patient. When combined with other therapies, such as supported employment, cognitive remediation leads to clinically relevant improvements.^[88] These effects are durable, lasting even after the training has stopped.^[89]

In a study by Grant et al, low-functioning patients with prominent negative symptoms were assigned to either recovery-oriented cognitive behavioral therapy or standard treatment; after 18 months, the authors found that both negative and positive symptoms had decreased.^[90] The study was not blinded, and the treatment was delivered by enthusiastic doctoral level therapists, which may limit the generalizability of these findings.

None of the antipsychotic medications currently available are particularly effective at addressing cognitive symptoms. A new initiative from NIMH, 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.

Vocational rehabilitation

Most patients with schizophrenia would like to work. Employment can improve income, self-esteem and social status. However few people with the disorder are able to maintain competitive employment.^[91] Supported employment programs currently thought to be most effective are those that offer individualized, supported, and rapid job assignments and that are integrated with other services. These programs are associated with higher rates of employment but gains in other domains are surprisingly difficult to discern.^[92]

Assertive community treatment

Assertive community treatment is a form of case management that is typically used for patients who have had multiple hospitalizations. The treatment involves active outreach to patients. Case managers usually have a fairly small outpatient load (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 form of treatment is expensive but may be associated with better clinical and social outcomes and lower hospitalization rates.

Family intervention

Schizophrenia affects the person’s whole family, and the family’s responses can affect the trajectory of the person’s illness. Familial “high expressed emotion” (hostile overinvolvement 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.^[93]

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.

Smoking Cessation

Most patients with schizophrenia smoke. This may be a result of previous conventional antipsychotic treatment, as 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.

Whatever the cause of the high incidence of smoking, the health risks from smoking are well known, and all schizophrenic patients should be encouraged to stop smoking.

Diet and Activity

Many psychotropic medications can cause weight gain and changes in glucose or lipid metabolism. Occasionally, a person with schizophrenia develops odd food preferences. Finally, 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.

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

Alternative Housing

In the United States, many people with schizophrenia do not live with their families. Because they do not always have the skills needed for independent living, a system of alternative housing arrangements has emerged. At their most basic, such arrangements may consist of boarding houses or single-room occupancy (SRO) hotels with no supervision. Patients with schizophrenia often have difficulty finding housing; therefore, working with associations that may provide housing assistance is important.

Many organizations, often state-supported, provide communal-living settings with 24-hour supervision in halfway houses. Veterans Affairs (VA) facilities have developed a sophisticated system of family care homes. Therapeutic halfway houses also exist in which independence and social skills training are encouraged.

In the past, long-term inpatient units offered an alternative for patients whose symptoms left them too disorganized to live in the community. These units were usually found in state hospitals or VA hospitals but are now increasingly rare.

Complications

Substance abuse

Alcohol and drug abuse (especially involving nicotine) are common in schizophrenia. The reasons for this are not entirely clear. For some people, these drugs provide relief from symptoms of the illness or the adverse effects of antipsychotic drugs, and the drive for this relief is strong enough to allow even patients who are impoverished and disorganized to find substances to abuse.^[94]

Comorbid substance abuse occurs in 20-70% of patients with schizophrenia, particularly younger male patients, and is associated with increased hostility, crime, violence, suicidality, noncompliance with medication, homelessness, poor nutrition, and poverty. Drug use and abuse can also increase symptoms. For example, cannabis use has been shown to correlate, in a bidirectional way, with an adverse course of psychotic symptoms in persons with schizophrenia.^[95]

Patients who abuse substances may fare better in dual-diagnosis treatment programs, in which principles from both the mental health field and the chemical dependency field can be integrated.

Depression

Many patients with schizophrenia report symptoms of depression. It is not clear whether the depression is part of the schizophrenia, a reaction to the schizophrenia, or a complication of treatment. Addressing this issue is important because of the high rate of suicide in patients with schizophrenia.

The research evidence for the use of antidepressant agents in schizophrenic patients is mixed. Further complicating the situation are the findings that antipsychotic agents, even the older conventional ones, may have antidepressant properties.^[96] One meta-analysis suggested that the addition of antidepressants to antipsychotics might help treat the negative symptoms of chronic schizophrenia, which can be difficult to distinguish from depression.^[97]

Anxiety

Anxiety is common in patients with schizophrenia. It may be an aspect of schizophrenia itself, a side effect of medication (eg, akathisia and obsessions/compulsions), or a comorbid disorder. Anxiety may precede the onset of schizophrenia by several years.^[98]

Treatment is keyed to the source of the anxiety. Antipsychotics usually relieve anxiety that is part of an acute psychotic episode; only limited data are available on treatment of comorbid anxiety disorders. Following treatment recommendations for primary anxiety disorder would be reasonable in many cases; however, fluvoxamine and other selective serotonin reuptake inhibitors should be used cautiously in patients receiving clozapine; they can raise clozapine blood levels. Benzodiazepines may be helpful but carry their own risks.^{[84, 99]}

Violence

Most people with schizophrenia are not violent, tending to be afraid of others rather than threatening toward them. However, a few may act violently, sometimes as a result of command hallucinations or delusions.^[97] Because the violent acts carried out by these few patients may be unpredictable and bizarre, they are often highly publicized, and the intense publicity has the unfortunate consequence of exacerbating the stigma of the disease.

Violence may be associated with substance abuse. However, the rate of violence in patients with schizophrenia who do not abuse substances is higher than that in people without schizophrenia.^{[100, 101]} Clozapine is sometimes recommended for treatment of patients with schizophrenia who are violent.

Prevention

Many have wondered whether patients with schizophrenia would have a better prognosis if treatment could be started as early as possible. A study from Scandinavia found that early detection and intervention in first-episode psychosis led to higher recovery and employment rates at 10-year follow-up.^[102]

The North American Prodrome Longitudinal Study is exploring whether the incorporation of biologic measures into prediction algorithms can provide more accurate identification of young people who are at greatest risk for developing a psychotic disorder. The goal of this study is to establish objective criteria that can be used to develop preventive approaches.

There are several studies of prodromal schizophrenia under way to inform early intervention strategies. In the absence of highly reliable methods of predicting schizophrenia, however, intervention during the prodromal stage could result in the unnecessary administration of antipsychotic medication to young people who are mistakenly identified as being at risk for schizophrenia.^[103]

One approach to this problem is to use psychological therapies rather than pharmacotherapy. A German study of young people at risk for schizophrenia showed that the use of a psychological intervention involving cognitive-behavioral therapy, group skills training, cognitive remediation and multifamily psychoeducation delayed the onset of psychosis for at least 2 years.^[104]

Medication Summary

Antipsychotic agents are the mainstay of medical treatment of schizophrenia. These medications diminish the positive symptoms of schizophrenia and prevent relapses. The second-generation (novel or atypical) antipsychotic drugs may be more effective in treating negative symptoms and cognitive impairment.

Some clinicians routinely perform electrocardiography (ECG) before beginning treatment with antipsychotic medications. Because suicide is not uncommon in patients with psychotic illnesses, clinicians should write prescriptions for the lowest dosage that is consistent with good clinical care. Patients should be urged to avoid substance abuse. All medications should be given at lower dosages in children and elderly patients and used with great caution in women who are pregnant or breastfeeding.

Antipsychotics are not indicated for the control of agitation in dementia. In clinical practice, however, these agents are often given for that purpose.

Antipsychotics, 1st Generation

Class Summary

First-generation antipsychotics, also known as conventional or typical antipsychotics, are strong dopamine D2 antagonists. However, each drug in this class has various effects on other receptors, such as 5-HT2 serotonin, alpha₁, histaminic, and muscarinic receptors.

First-generation antipsychotics have a high rate of extrapyramidal side effects, including rigidity, bradykinesia, tremor, and akathisia. Tardive dyskinesia (TD; involuntary moments in the face and extremities) is another side effect that can occur with first-generation antipsychotics. However, first-generation antipsychotics have large cost advantages over second-generation antipsychotics.

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Chlorpromazine (Thorazine)

Chlorpromazine, which was the first conventional antipsychotic developed and is still in wide use for treatment of schizophrenia, is a phenothiazine antipsychotic that is a dopamine D2 receptor antagonist. Chlorpromazine is available in oral tablets, syrup, and concentrate; as an injectable solution for intramuscular administration; and in suppository form.

Extrapyramidal symptoms from chlorpromazine include akathisia, TD, dystonia, and infrequently, neuroleptic malignant syndrome (NMS). Common adverse effects include anticholinergic effects, sedation, and weight gain.

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Fluphenazine hydrochloride (Prolixin)

Fluphenazine is a high-potency typical antipsychotic that blocks postsynaptic dopaminergic D1 and D2 receptors in the brain. It has some alpha-adrenergic and anticholinergic effects and may depress the reticular activating system. It is available in a depot formulation (fluphenazine decanoate). A short-acting intramuscular (IM) injection is also available for acute agitation. Fluphenazine is clinically comparable to haloperidol, a first-generation antipsychotic with similar potency, route of administration, side effects, and efficacy.

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Haloperidol (Haldol, Haldol Decanoate, Haloperidol LA, Peridol)

Haloperidol is indicated for management of schizophrenia when no contraindications exist. It is a D2 antagonist noted for high potency and low potential for causing orthostasis. The drawback is the high potential for extrapyramidal symptoms or dystonia. Haloperidol can interact with CYP3A4 and CYP2D6 inhibitors and inducers. It also can interact with drugs that prolong QTc intervals. Haloperidol is available in tablets, as a liquid concentrate, in IM and intravenous (IV) forms, and in long-acting IM form for depot injection.

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Perphenazine (Trilafon)

Perphenazine is a phenothiazine antipsychotic that is indicated for the treatment of schizophrenia and severe nausea and vomiting. It blocks postsynaptic dopamineric receptors in the brain and exhibits alpha-adrenergic blocking effects. It has slightly lower potency than haloperidol and it sometimes classified as a midpotency drug. It is available in an oral formulation.

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Thiothixene (Navane)

Thiothixene is a dopamine D2 antagonist that also elicits anticholinergic and alpha-blocking effects.

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Trifluoperazine (Stelazine)

Trifluoperazine is a piperazine phenothiazine agent. It elicits antagonist action on the postsynaptic mesolimbic dopaminergic D2 receptors in the brain and also decreases the release of hypothalamic and hypophyseal hormones.

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Loxapine inhaled (Adasuve)

Loxapine's mechanism of action is unknown, but is theorized to antagonize central dopamine D2 and serotonin 5-HT2a receptors. The inhaled dosage form is indicated for acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

Antipsychotics, 2nd Generation

Class Summary

Second-generation antipsychotics are also known as atypical antipsychotics. These drugs, with the exception of aripiprazole, are dopamine D2 antagonists. They are associated with lower rates of extrapyramidal side effects and TD than the first-generation antipsychotics are; however, they have higher rates of metabolic side effects and weight gain.

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Aripiprazole (Abilify)

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, alpha1, and H1 receptors. It is available in tablets, orally disintegrating tablets, and short-term IM injection (a long-acting depot preparation is under development). The most common side effects include headache, nausea, vomiting, insomnia, tremor, and constipation.

Oral aripiprazole is indicated for acute and maintenance treatment of schizophrenia. It is also used for acute and maintenance treatment of bipolar I disorder, adjunctive therapy for major depressive disorder, and treatment of irritability associated with autistic disorder.

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Asenapine (Saphris)

Asenapine is indicated for acute and maintenance treatment of schizophrenia. It is absorbed poorly in the gastrointestinal (GI) tract and thus is available in a sublingual form. The most common side effects include sedation, weight gain, dizziness, extrapyramidal symptoms, and oral hypoesthesia.

The mechanism of action of asenapine is unknown. The efficacy of this agent is thought to be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2 receptors.

Asenapine 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.

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Clozapine (Clozaril)

Clozapine is an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors. It has some dopamine D2 antagonism and high D4 affinity. It is indicated for treating refractory schizophrenia and for reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.

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Iloperidone (Fanapt)

Iloperidone is indicated for acute treatment of schizophrenia. Its precise mechanism of action is unknown, but it is known to antagonize dopamine D2 and serotonin 5-HT2 receptors. Side effects include dizziness, orthostatic hypotension, tachycardia, weight gain, dry mouth, and sedation. Iloperidone causes fewer extrapyramidal symptoms than other antipsychotics do.

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Lurasidone (Latuda)

Lurasidone is an atypical antipsychotic whose precise mechanism of action is unknown. Its efficacy thought to involve mediation of central dopamine D2 and serotonin 5-HT2A receptor antagonism. It is indicated for treatment of schizophrenia. This drug has not been tested in children or adolescents.

A major route of metabolism for lurasidone is via CYP3A4. Dose reduction is recommended in the presence of moderate CYP3A4 inhibitors. Coadministration with strong CYP3A4 inducers is not recommended.

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Olanzapine (Zyprexa)

Olanzapine is a selective monoaminergic antagonist at the following receptors: serotonin, dopamine D1-4, muscarinic, histamine H1, and alpha¬1-adrenergic. It is available in regular tablet form, rapid-disintegrating tablets, short-acting injectable solution, and long-acting injectable formulation. The most common side effects of olanzapine include weight gain, sedation, akathisia, hypotension, dry mouth, and constipation.

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Paliperidone (Invega)

Paliperidone is the major active metabolite of risperidone and was the first oral agent to allow once-daily dosing. It is indicated for acute and maintenance treatment of schizophrenia. Its mechanism of action not completely understood but is thought to involve mediation of central antagonism of dopamine D2 and serotonin 5HT-2A receptors. Paliperidone also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine H1 receptors. Paliperidone is available in an osmotic delivery capsule.

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Quetiapine (Seroquel)

Quetiapine may act by antagonizing dopamine and serotonin effects. It is used for treatment of schizophrenia. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and TD. Quetiapine is available in immediate-release and extended-release tablets. Major side effects include sedation, orthostatic hypotension, akathisia, dry mouth, and weight gain.

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Risperidone (Risperdal , Risperdal Consta, Risperdal M-Tab)

Risperidone has both dopamine D2 and serotonin 5-HT2 antagonism. It is available in tablets, oral disintegrating tablets, and oral solution, as well as a long-acting form for IM injection that uses microspheres made of biodegradable polymers. It has no anticholinergic effects and little effect on muscarinic receptors. Primary side effects of risperidone include mild sedation, hypotension, akathisia, increase in prolactin, and weight gain.

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Ziprasidone (Geodon)

Ziprasidone antagonizes dopamine D2, serotonin 5-HT2, histamine H1, and alpha1-adrenergic receptors. It is available in capsule and short-acting IM injection forms. It is indicated for treatment and acute agitation in patients with schizophrenia. Ziprasidone appears to cause less weight gain, hyperglycemia, and hyperlipidemia than other drugs in its category do.

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