Schizophrenia 

Updated: Mar 16, 2018
Author: Frances R Frankenburg, MD; Chief Editor: Glen L Xiong, MD 

Overview

Practice Essentials

Schizophrenia is a brain disorder that affects how people think, feel, and perceive. The hallmark symptom of schizophrenia is psychosis, such as experiencing auditory hallucinations (voices) and delusions (fixed false beliefs).

Signs and symptoms

The symptoms of schizophrenia may be divided into the following 4 domains:

  • Positive symptoms - Psychotic symptoms, such as hallucinations, which are usually auditory; delusions; and disorganized speech and behavior

  • Negative symptoms - Decrease in emotional range, poverty of speech, and loss of interests and drive; the person with schizophrenia has tremendous inertia

  • Cognitive symptoms - 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

  • Mood symptoms - Patients often seem cheerful or sad in a way that is difficult to understand; they often are depressed

See Clinical Presentation for more detail.

Diagnosis

Schizophrenia is not associated with any characteristic laboratory results.

Diagnostic criteria

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), to meet the criteria for diagnosis of schizophrenia, the patient must have experienced at least 2 of the following symptoms[1] :

  • Delusions

  • Hallucinations

  • Disorganized speech

  • Disorganized or catatonic behavior

  • Negative symptoms

At least 1 of the symptoms must be the presence of delusions, hallucinations, or disorganized speech.

Continuous signs of the disturbance must persist for at least 6 months, during which the patient must experience at least 1 month of active symptoms (or less if successfully treated), with social or occupational deterioration problems occurring over a significant amount of time. These problems must not be attributable to another condition.

The American Psychiatric Association (APA) removed schizophrenia subtypes from the DSM-5 because they did not appear to be helpful for providing better-targeted treatment or predicting treatment response.

See Workup for more detail.

Management

Antipsychotic medications diminish the positive symptoms of schizophrenia and prevent relapses.

There is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the most effective medication but is not recommended as first-line therapy.

Psychosocial treatment is essential. The best-studied psychosocial treatments are social skills training, cognitive-behavioral therapy, cognitive remediation, and social cognition training.

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

See Treatment and Medication for more detail.

Background

Schizophrenia is a brain disorder that probably comprises multiple etiologies. The hallmark symptom of schizophrenia is psychosis, such as experiencing auditory hallucinations (voices) and delusions (fixed false beliefs). Impaired cognition or a disturbance in information processing is an underappreciated symptom that interferes with day-to-day life. People with schizophrenia have lower rates of employment, marriage, and independent living compared with other people.

Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and medical illnesses, as well as from 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 is best carried out by a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment.

Antipsychotic medications, also known as neuroleptic medications or major tranquilizers, diminish the positive symptoms of schizophrenia and prevent relapses. Unfortunately, they are also associated with a number of adverse effects. (See Treatment and Medication.)

Diagnostic criteria (DSM-5)

The specific DSM-5 criteria for schizophrenia are as follows[1] :

  • The presence of 2 (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated), with at least 1 of them being (1), (2), or (3): (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior, and (5) negative symptoms

  • For a significant portion of the time since the onset of the disturbance, level of functioning in 1 or more major areas (eg, work, interpersonal relations, or self-care) is markedly below the level achieved before onset; when the onset is in childhood or adolescence, the expected level of interpersonal, academic or occupational functioning is not achieved

  • Continuous signs of the disturbance persist for a period of at least 6 months, which must include at least 1 month of symptoms (or less if successfully treated); prodromal symptoms often precede the active phase, and residual symptoms may follow it, characterized by mild or subthreshold forms of hallucinations or delusions

  • Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms or (2) any mood episodes that have occurred during active-phase symptoms have been present for a minority of the total duration of the active and residual periods of the illness

  • The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of abuse or a medication) or another medical condition

  • If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms or schizophrenia are also present for at least 1 month (or less if successfully treated)

In addition to the 5 symptom domain areas identified in the first diagnostic criterion, assessment of cognition, depression, and mania symptom domains is vital for distinguishing between schizophrenia and other psychotic disorders.

Various course specifiers are used, though only if the disorder has been present for at least 1 year and if they do not contradict diagnostic course criteria. These specifiers include the following[1] :

  • First episode, currently in acute episode

  • First episode, currently in partial remission

  • First episode, currently in full remission

  • Multiple episodes, currently in acute episode

  • Multiple episodes, currently in partial remission

  • Multiple episodes, currently in full remission

  • Continuous

  • Unspecified

The presence or absence of catatonia is specified. Individuals meeting the criteria for catatonia receive an additional diagnosis of catatonia associated with schizophrenia to indicate the presence of the comorbidity.

Finally, the current severity of the disorder is specified by evaluating the primary symptoms of psychosis and rating their severity on a 5-point scale ranging from 0 (not present) to 4 (present and severe).

Schizophrenia subtypes were removed from DSM-5 because they did not appear to help with providing better-targeted treatment or predicting treatment response.

Pathophysiology

Anatomic, neurotransmitter, and immune system abnormalities have been implicated in the pathophysiology of schizophrenia.

Anatomic abnormalities

Neuroimaging studies show differences between the brains of those with schizophrenia and those without this disorder. For example, the ventricles are somewhat larger, there is decreased brain volume in medial temporal areas, and changes are seen in the hippocampus.[2, 3, 4]

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.[5] 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.[6]

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.[7]

In a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients with control subjects, 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.[8]

These findings are of interest more for research purposes than for clinical application.

Neurotransmitter system abnormalities

Abnormalities of the dopaminergic system are thought to exist in schizophrenia. 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 elsewhere; see Presentation.) Moreover, the newer antipsychotic drugs block both dopamine D2 and serotonin (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.

Much 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.[9, 10] Some researchers consider schizophrenia, in large part, a hypoglutamatergic disorder.

Inflammation and immune function

Immune function is disturbed in schizophrenia.[11] 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 both to the psychopathology of schizophrenia and to metabolic disturbances seen in patients with schizophrenia.[12]

Etiology

The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk factors, genetic and perinatal. In addition, undefined socioenvironmental factors may increase the risk of schizophrenia in international migrants or urban populations of ethnic minorities.[13, 14, 15] Increased paternal age is associated with a greater risk of schizophrenia.

Genetic factors

The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted relatives.[16] 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 individual 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.

In a 2014 study, researchers identified new genetic loci not previously known to be associated with schizophrenia. Of the 108 genetic loci linked to schizophrenia that were identified in the study, 83 had not previously been found. The investigators also determined that among 128 independent associations related to the 108 loci, enriched associations existed not only among genes expressed in the brain, but also among those expressed in tissues related to immunity, giving support to the theory linking the immune system to schizophrenia.[17, 18]

Some loci of particular interest include the following:

  • Catechol-O-methyltransferase (COMT) gene

  • RELN gene

  • Nitric oxide synthase 1 adaptor protein (NOS1AP) gene

  • Metabotropic glutamate receptor 3 (GRM3) gene

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 the valine-methionine variant does; 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.[19]

The RELN gene codes for the protein reelin, which plays a role in brain development and GABAergic activity. In an international study, a common variant in this gene increased the risk of schizophrenia, but only in women.[20]

The NOS1AP gene codes for the enzyme nitric oxide synthase, 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.[21]

The GRM3 gene is a protein-coding gene associated with bipolar affective disorder. In a 2014 study, researchers found a variant in the GRM3 gene that was associated with a two- to three-fold increase in the risk of developing schizophrenia or alcohol dependence and an approximately three-fold greater risk of developing bipolar disorder. In the study, researchers performed a genetic analysis of 4971 patients with schizophrenia, bipolar disorder, or alcoholism and of 1309 healthy controls. The GRM3 variant associated with schizophrenia, alcohol dependence, and bipolar disorder in the study, which is seen in about 1 of every 200 people, may be a nonspecific risk factor for mental disorders and a potential treatment target.[17, 22]

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.[23, 24] 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.[25]

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.[26]

Many studies have also looked for abnormalities in neurodevelopmental genes. Disruptions in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with schizophrenia, albeit with significant variability between studies.[27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] 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 (the part of the chromosome that codes for proteins) seem to be more common in patients with schizophrenia than would otherwise be expected.[40, 41] In a pair of exome sequencing studies, researchers identified de novo genetic mutations in patients with schizophrenia that cluster in specific proteins involved in brain function and overlap with mutations that have been identified in patients with autism, mental retardation and intellectual disability.[42, 43]

A recent genome-wide association study beginning with a Swedish sample of 5,000 cases and 6,000 controls compared the results with a previous genome-wide association study and findings of single-nucleotide polymorphisms (SNP) in independent examples. It found a clustering at 22 loci, 14 of which were new. Most of the SNPs were common and, collectively, could account for perhaps as much as one third of the variance in liability for schizophrenia. In other words, common genetic variation may be involved in schizophrenia. This is somewhat similar to the understanding of other complex trait diseases such as coronary artery disease.[44]

Schizophrenia and bipolar disorder are likely to have a large overlap in genetic risk factors, but only a small portion of this genetic risk has been identified.[45]

As can be seen, working out the details of these genetic factors is difficult. Interactions with the rest of the genome and with the environment will doubtless prove to be important. Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about four fifths of liability to schizophrenia.[46]

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.[47] 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.[48]

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.[49]

A study of Finnish women supported an interaction between genetic and environmental influences on causation of schizophrenia.[50] In this study, a review of 9596 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. The authors 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 the 2 risk factors.[50]

Drug use

A new study suggests that heavy marijuana use in teenagers aged 15–17 years may hasten the onset of psychosis in those at high risk for developing a psychotic disorder. In an analysis of 247 hospitalized patients who had experienced first-episode psychosis, the Allied Cohort on the Early course of Schizophrenia (ACES) II project found that the onset of psychosis in those who used cannabis from age 15 to 17 years occurred at a mean age of 21.07 years, compared with a mean age of 23.86 years in patients who did not use cannabis during those same teenage years. However, the researchers could not say whether marijuana use may actually cause psychosis to develop early or whether people who have a predilection for earlier onset of psychosis also may be more likely, owing to various factors, to use marijuana.[51]

Epidemiology

United States and international statistics

The lifetime prevalence of schizophrenia has generally been estimated to be approximately 1% worldwide.[52] 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.[53] Immigrants to developed countries show increased rates of schizophrenia, with the risk extending to the second generation.[13, 14, 15]

Age-, race-, and sex-related demographics

The onset of schizophrenia usually occurs between the late teens and the mid-30s.[1] For males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for females, it is in the late 20s. The first 5–10 years of the illness can be stormy, but this initial period is usually followed by decades of relative stability (though a return to baseline is unusual). Positive symptoms are more likely to remit than are cognitive and negative symptoms (see Presentation).

Although some variation by race or ethnicity has been reported, 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.

Prognosis

The prognosis 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.[54]

Symptoms usually follow a waxing-and-waning course and their nature may change over time. 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.[55] Other factors that contribute to increased mortality 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.[56]

Women with schizophrenia may have higher rates of breast cancer than women in the general population. In a meta-analysis of more than 125,000 women, this increased risk was significant in studies in which breast cancer occurred before the diagnosis of schizophrenia was excluded. However, the association between schizophrenia and breast cancer incidence was not significant in studies that did not specify the exclusion of breast cancer cases that occurred prior to the diagnosis of schizophrenia. Researchers suggest factors such as obesity, nulliparity, and potentially even increased prolactin levels may raise the risk for breast cancer. It is important to note that significant heterogeneity exists among the included studies, and it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population.[143]

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 of abstinence from alcohol and other drugs of abuse is important.

It is helpful to work with the patient so that both patient and family can learn to recognize early signs of a decompensation (eg, insomnia or increased irritability). 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.[57] Education may improve adherence to medication and may help the patient cope with the illness better in other ways.

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

People with schizophrenia have also championed self-help recovery-based approaches to care, with an emphasis on developing the personal strengths and resilience needed to combat this illness.

Much psychosocial treatment that is discussed below has an educational component.

Because other illnesses are common in schizophrenia, education about the importance of a healthy lifestyle and regular health care is helpful. Counseling with respect to sexuality, pregnancy, and sexually transmitted diseases is important for these patients.

The following resources may also be helpful:

  • Mayo Clinic -Schizophrenia

  • National Institute of Mental Health -Schizophrenia

  • Medline Plus -Schizophrenia

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

 

Presentation

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 bed wetter.[58, 59]

A noticeable change in personality and a decrease in academic, social, and interpersonal functioning often begin during middle-to-late adolescence. Usually, 1–2 years pass between the onset of these vague symptoms and the first visit to a psychiatrist.[60] 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:

  • Positive symptoms - Psychotic symptoms, such as hallucinations, which are usually auditory; delusions; and disorganized speech and behavior

  • Negative symptoms - A decrease in emotional range, poverty of speech, and loss of interests and drive; the person with schizophrenia has tremendous inertia

  • Cognitive symptoms - 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

  • Mood symptoms - Patients often seem cheerful or sad in a way that is difficult to understand; they often are depressed

Physical Examination

The findings from a general physical examination are usually noncontributory. This examination is necessary to rule out other illnesses.

It is sometimes helpful to perform a neurologic examination as a baseline before initiating antipsychotic medications, because these drugs themselves can cause some neurological signs. 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 (MSE), the following observations may be made in a severely ill patient with schizophrenia:

  • 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

  • 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’s thoughts may be disorganized, stereotyped, or perseverative

  • The patient may make odd movements (which may elated to neuroleptic medication)

  • The patient may have little insight into his or her problems (ie, anosognosia)

  • 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.

Complications

Substance abuse

Alcohol and drug abuse (especially nicotine) are common in schizophrenia, for reasons that 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.[61]

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 be associated with an earlier onset of psychosis and to correlate, in a bidirectional way, with an adverse course of psychotic symptoms in persons with schizophrenia. That is, people with more severe psychotic symptoms are more likely to use cannabis, and cannabis, in turn, seems to worsen psychotic symptoms.[62] However, other research has shown that the use of cannabis is associated with better cognitive functioning.[63]

A register-based study of more than 3000 inpatients from Scotland who experienced substance-induced psychoses showed that episodes of psychosis induced from several types of illicit substances are significantly linked to a later clinical diagnosis of schizophrenia.[64]

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

Depression

Many patients with schizophrenia report symptoms of depression. It is unclear whether such depression is an independent problem, 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 may have antidepressant properties.[65] 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.[66]

Suicide attempts are lower in people treated with clozapine than with other antipsychotic agents.[67]

Anxiety

Many patients with schizophrenia report symptoms of anxiety. It is unclear whether such anxiety is an independent problem, part of the schizophrenia, a reaction to the schizophrenia, or a complication of treatment. Some adverse effects of medications, such as akathisia, may be experienced as anxiety. Anxiety may precede the onset of schizophrenia by several years.[68]

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 (SSRIs) should be used cautiously in patients receiving clozapine; they can raise clozapine blood levels. Benzodiazepines may be helpful but carry their own risks.[69, 70]

Obsessive-compulsive symptoms

A number of patients with schizophrenia display obsessive-compulsive symptoms, such as the need to check, count, or repeat certain activities. As is similar to anxiety or depression, the connection between these symptoms and schizophrenia is not understood. Obsessive-compulsive symptoms are a known adverse effect of some antipsychotic medications, particularly clozapine. Patients with schizophrenia and obsessive-compulsive symptoms tend to do more poorly. There is no clear consensus on how to treat the obsessive-compulsive symptoms.

Violence

Most people with schizophrenia are not violent. However, a few may act violently, sometimes as a result of command hallucinations or delusions.[66] 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.[71, 72] Clozapine is sometimes recommended for treatment of patients with schizophrenia who are violent.

 

DDx

Diagnostic Considerations

Disorders 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, schizoaffective disorder is diagnosed.

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.

Substance abuse is discussed below.

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 bleeding 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.[73]

Metabolic illnesses

Wilson disease, also known as hepatolenticular degeneration, is a disorder of the metabolism of copper.

It is an autosomal recessive illness. The first psychiatric symptoms are often vague changes in behavior during adolescence. It is primarily a liver disease.

Laboratory findings include increased urinary levels of copper and low serum levels of copper and ceruloplasmin. Kayser-Fleischer rings (copper deposits around the cornea) can sometimes be seen. The diagnosis is usually confirmed by finding increased hepatic copper at biopsy.

Porphyrias are disorders of heme biosynthesis. Acute intermittent porphyria can present with 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 or hyperglycemia 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. The clinical hallmarks are decreased attention span and a waxing-and-waning type of confusion.

Endocrine disorders

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. 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 herpesviruses), 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

  • Chronic Lyme disease

  • 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 (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. Because antibodies decline during the disease, 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 infected 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. Many medications 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.

Lyme disease

A few patients with chronic Lyme disease may have problems of fatigue and difficulty thinking. There is much controversy about this diagnosis.

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 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.

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.

Alzheimer disease, the most common cause of dementia, is marked by loss of memory and personality, other cognitive, and mood changes in elderly persons. As the illness progresses the person may develop psychotic symptoms.

Dementia with Lewy bodies is the second most common type of dementia. Patients present with fluctuating mental status and prominent psychiatric symptoms, including depression and visual hallucinations. 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.[74]

Encephalitis related to paraneoplastic or autoimmune disorders can be confused with schizophrenia.

Of the several paraneoplastic neurologic syndromes, one of them, limbic encephalitis, an inflammation of the limbic system, is particularly likely to be misdiagnosed as schizophrenia. People with this disorder can experience emotional or personality changes, memory problems, hallucinations, odd motor movements, or sleep disturbances. Acuteness of onset, seizures, and EEG and MRI changes differentiate this syndrome from schizophrenia. The syndrome often develops before any evidence of malignancy and is caused by antibodies to tumor cells that cross-react with antigens within the brain.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis usually begins with a headache and or fever, and is followed by agitation, odd behavior, and impaired memory. Symptoms that differ from those seen in schizophrenia include seizures, decreased level of consciousness, dyskinesias, and autonomic instability. A variety of other neurological symptoms may develop. EEG, MRI, and CSF may be abnormal.

About one half of women with anti-NMDAR encephalitis have an ovarian teratoma. The illness may remit after removal of the tumor. Other cases of anti-NMDAR encephalitis may be associated with a viral infection, particularly the herpes simplex virus. The syndrome is caused by antibodies reacting to a subunit of the NMDAR in the brain.

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, depression, 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.[75] Anticholinergic medications can lead to delirium, especially if abused.

Vitamin deficiency

A deficiency of vitamin B-1 (thiamine) 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.[76]

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

Differential Diagnoses

 

Workup

Approach Considerations

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 all are important. This information is helpful in ruling out other causes of psychotic symptoms.

The findings from a general physical examination are usually noncontributory. This examination is necessary to rule out other illnesses.

It is sometimes helpful to perform a neurologic examination as a baseline before initiating antipsychotic medications, because these drugs themselves can cause some neurological signs. 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.

Schizophrenia is not associated with any characteristic laboratory results. The following should be performed on all patients, both at the beginning of the illness and periodically afterward, to rule out other or concomitant illnesses:

  • Complete blood cell (CBC) count

  • Liver, thyroid, and renal function tests

  • Electrolyte, glucose, vitamin B-12, serum methylmalonic acid, folate, and calcium levels

  • Pregnancy testing (if the patient is a woman of childbearing age)

  • Urine testing for drugs of abuse, such as alcohol, cocaine, opioids, cannabis

  • Urine for culture and sensitivity (to look for urinary tract infection)

  • Brain imaging to rule out subdural hematomas, vasculitis, cerebral abscesses, and tumors

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

  • Urine and serum copper and ceruloplasmin - If a strong suspicion of Wilson disease exists, consider a liver biopsy (or multiple biopsies)

  • Twenty-four-hour urine collections for porphyrins, copper, or heavy metals

  • Dexamethasone suppression test for hypercortisolism; corticotropin stimulation test for hypocortisolism, morning cortisol

  • Rapid plasma reagin (RPR) - If a strong suspicion of neurosyphilis exists, specific treponemal tests may be helpful

  • HIV antibodies

  • Lyme antibodies

  • Antinuclear antibody (ANA) for systemic lupus erythematosus

  • Chest radiography to rule out pulmonary illness or occult malignancy

  • Electroencephalography (EEG)

Some experts suggest that a lumbar puncture be performed to examine cerebrospinal fluid, especially to rule out inflammatory and infectious CNS disorders. 

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

 

Treatment

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, including some combination of the following: 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 important 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.[77]  A meta-analysis of 16 case-control studies comprising 15 samples (731 patients and 614 controls) found that individuals with first-episode schizophrenia had elevated fasting plasma glucose levels. Additionally, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, and insulin resistance (homeostatic model assessment of insulin resistance) were all significantly elevated in patients compared with controls. The results demonstrate that altered glucose homeostasis is present from illness onset, showing a direct link between schizophrenia and the development of diabetes.[78]

Antipsychotic medications (also known as neuroleptic medications or major tranquilizers) 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. Many studies have compared antipsychotic drugs with one another, but no broad 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 caused by noncompliance with pharmacotherapy, substance abuse, adverse effects or toxicity of medications, medical illness, psychosocial stress, or the waxing and waning of the illness itself. Hospitalizations are usually brief and are typically oriented towards crisis management or symptom stabilization.

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.

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 may lose these benefits—an especially problematic occurrence when, as is often the case, their job provides minimal or no health benefits. This situation is complicated and must be monitored closely by professionals with a good understanding of health benefits.

The impact of the American Affordable Care Act (ACA) on the care of schizophrenia has yet to be determined. Some parts of the ACA, such as the removal of exclusion of preexisting conditions as a barrier to getting insurance, and the removal of annual and lifetime benefit limits, will be helpful. The ACA mandates parity between care for medical and psychiatric illnesses.

However, health plans in the new exchanges might not provide all of the services that are mentioned here, such as supported employment. As well, in the states that have chosen not to expand their Medicaid programs, patients with Medicaid as their insurer may continue to have difficulty in accessing care.[#Antipsychotic]

Antipsychotic Pharmacotherapy

Before beginning antipsychotic medications, clinicians should warn patients and their families of adverse effects, and the slowness of response. The patient may be calmer and less agitated almost immediately, but alleviation of the psychosis itself often takes several weeks. Some clinicians routinely perform electrocardiography (ECG) before beginning treatment with antipsychotic medications and then as often as seems appropriate, for example if doses are increased or agents change. 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.

The first antipsychotic medications, chlorpromazine and haloperidol, were dopamine D2 antagonists. These and similar medications 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. Some of these agents (haloperidol and fluphenazine) are also available as depot preparations, meaning that a person can be given an injection of a medication every 2-4 weeks. Of the second-generation agents, risperidone is available as a long-acting injection that uses biodegradable polymers; olanzapine, paliperidone, and aripiprazole are also now available in long-acting injectable forms.[79, 80, 81, 82]

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 often more expensive than the first-generation drugs.

Comparative efficacy of agents

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

Phase 1 of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, 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 in terms of the patients choosing to stay on it, and number of hospitalizations, but also was associated with significant weight gain. Surprisingly, perphenazine performed about as well as the other 3 second-generation agents.[83]

In this and other studies the primary outcome, stopping the drug, may seem to be unusual. It is used because it reflects the “real-world” decision of the clinician and patient that the agent is either no longer tolerable or effective.

In CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study), a study from the United Kingdom, more than 200 patients who were about to change antipsychotic medication were randomly assigned to either a first-generation or a second-generation agent. In this study, the first-generation drugs seemed to perform slightly better than the newer ones, as measured by the Quality-of-Life Scale.[84]

First-episode schizophrenia

According to the results of a year-long randomized controlled trial, starting a long-acting injectable (LAI) antipsychotic after a first episode of schizophrenia is more effective than starting an oral antipsychotic. The study included 86 patients with a recent first episode of schizophrenia who were randomly assigned to receive LAI risperidone (n = 43) or oral risperidone (n = 43) for 12 months. Study data showed that the LAI formulation of risperidone proved superior to oral risperidone on measures of relapse and symptom control. The psychotic exacerbation and/or relapse rate was 5% in the LAI risperidone group vs 33% in the oral risperidone group. Treatment with LAI risperidone also provided better control of hallucinations and delusions.[85]

EUFEST (European First Episode Schizophrenia Trial) was a year-long open-label study conducted in nearly 500 patients in 13 European countries and Israel that, as did CATIE, used treatment discontinuance as the main outcome measure. The study found that 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.[86]

Similarly, the randomized, double-blind CAFE (Comparison of Atypicals for First Episode) 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, a longer sleep time with quetiapine, and menstrual irregularities in women with risperidone.[87]

The Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland recommended 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.[88]

According to a comprehensive review carried out by the Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland, early treatment with any antipsychotic medication is associated with significant symptom reduction; first- and second-generation antipsychotics may have equivalent significant short-term efficacy. However, because of the adverse adverse-effect profile of clozapine and the significant metabolic risks associated with olanzapine, PORT advised that neither drug should be considered as a first-line treatment for first-episode schizophrenia.[88]

Noting 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, PORT recommended 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.[88]

Wunderink and colleagues followed just over 100 subjects participating in a study of first episode psychosis. Subjects were randomly assigned to antipsychotic medication dose reduction or dose maintenance. At 7 years follow-up, they found that those treated with lower doses or no antipsychotics had more relapses and hospitalizations. This was not an unexpected finding. However, they also found that these lightly medicated patients overall were functioning better. They concluded that it seems that there are different responses of symptoms and functioning to medication.[89]

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.

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 because it has a high burden of adverse effects, requires regular blood work, and has not outperformed other medications in first-episode patients.[90, 91]

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.[92]

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 who were treated according to a 2003 algorithm.[93] 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.[93] 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 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 this practice lacks a compelling evidence base and does increase the complexity of the medication regimen.

Nonetheless, in one large study, discontinuance of 1 of 2 antipsychotics was followed by treatment discontinuance more often and more quickly than continuation of both antipsychotics were continued.[94] A meta-analysis of 19 studies involving more than 1200 subjects found a modest advantage for antipsychotic polypharmacy.[95]

Physicians sometimes choose what seems to be a simpler option than switching or adding medication, 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.[96]

In a recent Cochrane review, authors studied quetiapine compared with other antipsychotics.[97] Quetiapine seemed slightly less effective, but overall to have a slightly lower burden of adverse effects. Sixty percent of the patients started on quetiapine stopped taking it within a few weeks. The authors also noted that the clinical meaning of these many findings, many of them quite modest, remains unclear.

PORT provided a detailed review addressing the choice of antipsychotic medications, including recommendations and discussions regarding acute, maintenance, first-episode, and targeted intermittent treatment, as well as treatment of individual symptoms.[88]

Maximization of 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 intramuscular (IM) preparations of antipsychotic medications. A regular routine of IM medication, such as every 2-4 weeks, is preferred by some patients since it obviates the need to take medication every day. As well, it permits easier monitoring of medication adherence by the clinician. In the United States, several drugs have been approved for every 4-6 week dosing (eg, aripiprazole [Abilify Maintena, Aristada], paliperidone [Invega Sustenna]), every 2 month dosing (aripiprazole [Aristada 1064 mg dose]), and every 3 month dosing (eg, paliperidone [Invega Trinza]). IM medication is less widely used in the United States than in Europe.

Whether IM medication is superior to oral medication is not clear.

A large trial that compared long-acting injectable risperidone with 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.[98]

In a meta-analysis of 21 randomized, controlled studies involving more than 5000 patients, the long-acting injectable agents were similar to the oral antipsychotics with regard to relapse prevention.[99] However, in 10 studies using first-generation long-acting injectables, as well as studies published in or before 1991 (8 fluphenazine or long-acting injectable studies), the primary outcome with the long-acting injectable agents was superior to that with oral antipsychotics.

Adherence is usually overestimated by both patient and physician. Nonadherence can be partial or complete, but even partial adherence is associated with relapse.[100] 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.

Adverse effects

Patients tend not to be very adherent to antipsychotic medications, and this may, in part, be due to their adverse effects. Patients sometimes report they feel less like themselves, or less alert, when taking these medications. One troubling possibility is that while they are used to combat psychosis and in that sense to preserve brain functioning, these medications can actually interfere with the usual processes of the brain. Indeed, some practitioners have gone so far as to call haloperidol “neurotoxic” and suggest that it not be used. However, there may be adverse neurological effects with all of the antipsychotic medications, not just the conventional ones.

For example, in an open-label 6-month pilot study in Canada, the reduction of risperidone or olanzapine dose by 50% improved cognitive function for stable patients with schizophrenia and did not lead to worsening of psychotic symptoms.[101]

The following are adverse effects typically associated with conventional antipsychotic agents and with the atypical antipsychotic risperidone 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. It can be difficult to distinguish from anxiety or an exacerbation of psychosis.

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 an elevation of the hormone prolactin in the blood, caused by the lowering of dopamine. (Dopamine inhibits the release of prolactin from the pituitary.) It is associated with galactorrhea, gynecomastia, and osteoporosis. In women it is associated with amenorrhea, and in men it is associated with impotence.

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 consists of some combination of tremor, bradykinesia, akinesia, and rigidity.

Tardive dyskinesia (TD) consists of 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. The incidence of TD is as high as 70% in elderly patients treated with antipsychotic agents. Risk factors for TD include older age, female sex, and negative symptoms.

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 the presence or absence of TD.

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

  • Acute exacerbation of narrow- or closed-angle glaucoma (if undiagnosed or untreated)

  • 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 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. (Mesoridazine is no longer available in the United States.) Risk is increased by individual susceptibility, heart failure, bradycardias, electrolyte imbalance (especially hypokalemia), hypomagnesemia, and female gender.[102]

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.[103] 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.

Haloperidol has only a small influence on the ECG. Nevertheless, this agent has been implicated, albeit very rarely, in causing torsades de pointes, typically at high doses and when given intravenously.[104]

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.[105] 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.

A Danish study of the risk for diabetes with antipsychotics compared nearly 346,000 individuals who purchased antipsychotics and nearly 1.5 million unexposed individuals and concluded 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).[106]

Stroup et al studied 215 patients whose psychotic symptoms were stabilized on olanzapine, quetiapine, or risperidone.[107] After 24 weeks, those who switched to aripiprazole had improved 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. However, patients who switched to aripiprazole were more likely to discontinue the assigned medication: 43.9% of those who switched discontinued their medication, whereas 24.5% of those who stayed on their original medication discontinued it. They concluded patients experiencing cardiovascular or metabolic adverse effects of an antipsychotic medication may fare better if they switch to a different agent, provided they are closely monitored.

Weight gain is associated both with psychological problems (eg, decreased self-esteem) and with medical problems (eg, diabetes, coronary artery disease, and arthritis). Education about nutrition and exercise should be provided. Cognitive-behavioral therapy can be tried.

It is unclear whether weight-reducing drugs should be added to antipsychotic therapy. In one randomized, placebo-controlled study conducted in 72 patients with first-episode schizophrenia who gained more than 7% of their predrug weight, metformin (1000 mg/day) was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance.[108]

Miscellaneous adverse effects

All antipsychotic agents may be associated with esophageal dysmotility, thus increasing the risks of 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 problem 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.[109, 110]

Results from a prospective study indicated that in children and adolescents, long-term use of risperidone can negatively affect bone mass.[111]

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.[112]

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.

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); this enzyme 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 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, and 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 Pharmacotherapy

Anticholinergic agents (eg, benztropine, trihexyphenidyl, and diphenhydramine) and 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 little rigorous evidence but is widely practiced nonetheless. Medications often used include antidepressants, mood stabilizers, and anxiolytic agents. 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.[69]

Psychosocial Interventions

Psychosocial treatment is essential for people with schizophrenia and includes a number of approaches, such as social skills training, cognitive-behavioral therapy, cognitive remediation, and social cognition training.[113] PORT (see Antipsychotic Pharmacotherapy) also provides a detailed review of psychosocial interventions.[114]

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

  • To avoid hospitalization

  • 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 advantages of medication plus psychosocial intervention over medication alone.[115] In the psychosocial intervention arm, each month patients and their families received 1 day of 4 types of evidence-based interventions: psychoeducation, family intervention, skills training, and cognitive-behavioral therapy. After 1 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, vocational rehabilitation, assertive community treatment, and family intervention are reviewed.

Cognitive remediation

Cognitive impairment, a core feature of schizophrenia, is less dramatic than other symptoms of the disease (eg, hallucinations and delusions) but interferes with work, social relationships, and independent living. Cognitive impairment is not improved by medication.

Cognitive remediation is a treatment modality derived from principles of neuropsychological rehabilitation and 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 use 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.[116] These effects are durable, lasting even after the training has stopped.[117]

In a study by Grant et al, low-functioning patients with prominent negative symptoms were assigned to either recovery-oriented cognitive-behavioral therapy plus standard treatment or standard treatment; after 18 months, the authors found that both negative and positive symptoms had decreased in the group receiving the add-on cognitive therapy.[118] The study was not blinded, and the treatment was delivered by enthusiastic doctoral level therapists; thus, the findings may not be widely generalizable.

A study by Puig and colleagues also found cognitive remediation therapy to be effective. In the study, 50 patients between the ages of 12 and 18 years with early onset schizophrenia were randomized to either cognitive remediation therapy plus usual treatment or usual treatment alone. Patients in the cognitive remediation group showed significantly greater improvements than patients in the usual treatment group in verbal memory, working memory, executive function, and cognitive composite scores, at the end of treatment and at 3-month follow-up. The cognitive remediation group also had greater improvements in daily living skills, global adaptive functioning, and self-perceived family burden.[119]

Cognitive therapy may be effective as a standalone treatment for schizophrenia.[120, 121] For schizophrenic patients who cannot or will not take antipsychotic medication, cognitive therapy may be the most viable option. According to data from the first randomized trial of cognitive therapy as a standalone therapy for schizophrenia, structured treatment with a therapist significantly reduced the severity of psychiatric symptoms and improved personal and social functioning and some dimensions of delusional beliefs and voice hearing.[120, 121]

The study involved 74 individuals aged 16 to 65 years with schizophrenia spectrum disorders who had decided not to take or had stopped taking antipsychotics for at least 6 months.[120, 121] Half were randomly assigned to cognitive therapy (26 sessions during a 9-month period) plus treatment as usual and half to treatment as usual alone. After 18 months, 7 (41%) of 17 study participants receiving cognitive therapy had an improvement of more than 50% in the Positive and Negative Syndrome Scale (PANSS) total score compared with 3 (18%) of 17 receiving treatment as usual.[120, 121]

None of the antipsychotic medications currently available is 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 development of drugs that target 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.[122] 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.[123]

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 by doing the following: they 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.[124]

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, in that 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, and because of the many beneficial effects of exercise, persons with schizophrenia should be encouraged to be as physically active as possible.

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.[125]

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.[126]

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.[127]

Other Treatments

An entirely different kind of treatment for schizophrenia, still in its early stages, is transcranial magnetic stimulation (TMS). TMS involves the electromagnetic induction of an electric field in the brain. Standard TMS affects neurons within 1.5-2 cm from the scalp, and deep TMS can affect cells to a depth of 6 cm. The electric field changes the “excitability” of the neurons and seems to be safe with few adverse effects. TMS is mostly used for depression. However, early work suggests that TMS, in some cases, may decrease auditory hallucinations[128] and negative symptoms[129] in schizophrenia.

 

Medication

Medication Summary

Antipsychotic medications diminish the positive symptoms of schizophrenia and prevent relapses.

Antipsychotics, 1st Generation

Class Summary

First-generation (conventional or typical) antipsychotics, are strong dopamine D2 antagonists. However, each drug in this class has various effects on other receptors, such as serotonin type 2 (5-HT2), alpha1, histaminic, and muscarinic receptors.

First-generation antipsychotics have a high rate of extrapyramidal side effects, including rigidity, bradykinesia, dystonias, tremor, and akathisia. Tardive dyskinesia (TD)—that is, involuntary movements in the face and extremities—is another adverse effect that can occur with first-generation antipsychotics. Neuroleptic malignant syndrome (NMS) can occur with these agents.

Chlorpromazine

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

Chlorpromazine is a low-potency medication and is associated with sedation and weight gain.

Fluphenazine (Modecate, Modecate Concentrate, Moditen)

Fluphenazine is a high-potency typical antipsychotic that blocks postsynaptic dopaminergic D1 and D2 receptors. It has some alpha-adrenergic and anticholinergic effects. It is available orally and in a depot formulation (fluphenazine decanoate). A short-acting 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.

Haloperidol (Haldol, Haldol Decanoate)

Haloperidol is a dopamine 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.

Perphenazine

Perphenazine is a phenothiazine antipsychotic that blocks postsynaptic dopaminergic receptors and has 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.

Thiothixene

Thiothixene is a dopamine D2 antagonist with anticholinergic and alpha-blocking effects. It is rarely used in the United States now.

Trifluoperazine

Trifluoperazine is a piperazine phenothiazine agent that is an antagonist at the postsynaptic mesolimbic dopaminergic D2 receptors.

Loxapine inhaled (Loxitane)

Loxapine's mechanism of action is unknown but probably involves antagonism of 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.

Inhaled loxapine is a first-generation agent that may be similar to second-generation agents. In a new formulation, it can be inhaled, which may make it attractive for some patients.

Loxapine inhaled is the first noninjectable therapy to treat acute agitation associated with schizophrenia and bipolar I disorder. Approval by the US Food and Drug Administration (FDA) was based on 2 phase III studies of 658 individuals.

Antipsychotics, 2nd Generation

Class Summary

Second-generation (novel or atypical) antipsychotics, with the exception of aripiprazole, are dopamine D2 antagonists, but are associated with lower rates of extrapyramidal adverse effects and TD than the first-generation antipsychotics. However, they have higher rates of metabolic adverse effects and weight gain.

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.

Asenapine's mechanism of action is unknown. Its efficacy 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. The addition of serotonin antagonism to dopamine antagonism may improve the negative symptoms of psychoses and may reduce the incidence of extrapyramidal adverse effects when compared with typical antipsychotics.

Clozapine (Clozaril, FazaClo)

Clozapine is the oldest atypical antipsychotic agent and probably the most effective. 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 (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 an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors. It has some dopamine D2 antagonism and high D4 affinity. It carries a high adverse effect burden, including sedation, drooling, constipation, and possible cardiac effects. Because it can cause agranulocytosis, patients must have regular blood tests. It is indicated for refractory schizophrenia and for reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.

The anticholinergic adverse effects, sedation, and drooling can be burdensome. Constipation and cardiac adverse 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.

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. However, it shows high affinity for 5-HT2A, D2, and D3 receptors and low-to-moderate affinity for D1, D4, H1, 5-HT1A, 5HT6, 5-HT7, and NE alpha1 receptors. Adverse effects include dizziness, orthostatic hypotension, tachycardia, weight gain, dry mouth, and sedation. Iloperidone causes fewer extrapyramidal symptoms than do other antipsychotics.

Lurasidone (Latuda)

Lurasidone is an atypical antipsychotic whose precise mechanism of action is unknown. It is a dopamine D2 and serotonin 5-HT2A receptor antagonist. It is indicated for schizophrenia in adults and is approved by the FDA to treat schizophrenia in adolescents (aged 13-17 y)

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.

Olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv)

Olanzapine is a selective monoaminergic antagonist at serotonin, dopamine D1-4, muscarinic, histamine H1, and alpha1-adrenergic receptors. It is available as a regular tablet, a rapidly disintegrating tablet, a short-acting injectable solution, and a long-acting injectable formulation. The most common side effects of olanzapine include weight gain, sedation, akathisia, hypotension, dry mouth, and constipation. It is also approved by the FDA to treat schizophrenia in adolescents.

Paliperidone (Invega, Invega Sustenna, Invega Trinza)

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 adults and is also approved by the FDA to treat schizophrenia in adolescents. Its mechanism of action not completely understood but is thought to involve 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 and in long-term injectable IM forms (once monthly, q3mo).

Quetiapine (Seroquel, Seroquel XR)

Quetiapine may act by antagonizing dopamine and serotonin receptors. It is used for treatment of schizophrenia in adults and is also approved by the FDA to treat schizophrenia in adolescents. Quetiapine is available in immediate-release and extended-release tablets. Major adverse effects include sedation, orthostatic hypotension, akathisia, dry mouth, and weight gain.

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

Risperidone has both dopamine D2 and serotonin 5-HT2 antagonism. It is approved by the FDA to treat schizophrenia in adults and adolescents. It is available in tablets, oral disintegrating tablets, and an oral solution, as well as a long-acting form for IM injection that uses microspheres made of biodegradable polymers. It has few anticholinergic effects. Primary adverse effects of risperidone include mild sedation, hypotension, akathisia, increase in prolactin, and weight gain.

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 of acute agitation in patients with schizophrenia. Ziprasidone appears to cause less weight gain, hyperglycemia, and hyperlipidemia than other drugs in its category do.

Cariprazine (Vraylar)

The precise mechanism by which cariprazine works for schizophrenia is unknown. Efficacy could be mediated through a combination of partial agonist activity at central dopamine (D2) and serotonin 5-HT1A receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which have in vitro receptor binding profiles similar to the parent drug.

Serotonin-Dopamine Activity Modulators

Class Summary

Serotonin-dopamine activity modulators (SDAMs) act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.

Brexpiprazole (Rexulti)

Serotonin-dopamine activity modulator (SDAM) indicated for schizophrenia. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.

Aripiprazole (Abilify, Abilify Maintena, Aristada)

Aripiprazole shows high affinity for D2, D3, 5-HT1A, and 5HT2A receptors and moderate affinity for D4, 5HT2C, 5-HT7, alpha1 adrenergic, and H2 receptors and possesses moderate affinity for the serotonin reuptake transporter. It is thought to be a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, alpha1, and histamine H1 receptors. It is available in tablets, orally disintegrating tablets, and short- and long-term (once-monthly, q6wk) IM injections. The most common adverse 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. It is also approved by the FDA to treat schizophrenia in adolescents.

The IM injections are indicated for adults and may be used once monthly (Abilify Maintena, Aristada), every 6 weeks (Aristada 882 mg), or every 2 months (Aristada 1064 mg).

 

Questions & Answers

Overview

What is schizophrenia?

What are the symptoms of schizophrenia?

What are the DSM-5 criteria for schizophrenia?

How is schizophrenia managed?

How does impaired cognition affect patients with schizophrenia?

Which disorders are included in the differential diagnoses of schizophrenia?

What are the treatment options for schizophrenia?

What are the DSM-5 criteria for schizophrenia?

According to the DSM-5, how is a diagnosis of schizophrenia further specified?

Which abnormalities are found in schizophrenia?

What are neurologic findings of schizophrenia?

What is the role of the neurotransmitter system in the pathogenesis of schizophrenia?

What is the role of the immune system in the pathogenesis of schizophrenia?

What is the role of inflammation in the pathogenesis of schizophrenia?

What causes schizophrenia?

Is schizophrenia a genetic disorder?

What are the known gene variants of schizophrenia?

Which genetic loci are linked to schizophrenia?

What is the role of the COMT gene in schizophrenia?

What is the role of the RELN gene in schizophrenia?

What is the role of the NOS1AP gene in schizophrenia?

What is the role of the GRM3 gene in schizophrenia?

Which genetic structures increase the risk for schizophrenia?

Which genetic loci may increase the risk for neurologic or psychiatric disorders?

Which neurodevelopmental genes may increase the risk for schizophrenia?

What is the cause of schizophrenia when there is no family history of the disorder?

Is there evidence of a common genetic variation that causes schizophrenia?

How much of schizophrenia risk is due to genetic factors?

Which perinatal factors may increase the risk of developing schizophrenia?

Does marijuana use increase the risk of developing schizophrenia?

What is the prevalence of schizophrenia?

At what age does onset of schizophrenia usually occur?

Does the prevalence of schizophrenia differ among racial groups?

Is schizophrenia more common in men or women?

What factors affect the prognosis of schizophrenia?

Do the symptoms of schizophrenia improve over time?

What is the socioeconomic impact of schizophrenia?

Is the mortality rate increased in patients with schizophrenia?

Is breast cancer more common in women with schizophrenia?

What are the benefits of patient education in schizophrenia?

What patient education resources exist for schizophrenia?

Presentation

What should be the focus of family and medical history in suspected schizophrenia?

What personal history may indicate schizophrenia?

What are the symptoms of schizophrenia?

Are there physical exam findings that indicate schizophrenia?

What observations on a mental status exam indicate schizophrenia?

Is substance abuse a common comorbidity of schizophrenia?

Which risks are increased in comorbid substance abuse and schizophrenia?

Do drug-caused episodes of psychosis increase the risk of developing schizophrenia?

What are the treatment options for comorbid substance abuse and schizophrenia?

Are depression and schizophrenia comorbid?

Are anxiety disorders and schizophrenia comorbid?

How is anxiety treated in patients with schizophrenia?

Are obsessive-compulsive disorder (OCD) and schizophrenia comorbid?

Are patients with schizophrenia at increased risk for violence?

DDX

Which disorders should be considered in the differential diagnoses of schizophrenia?

How is schizophrenia differentiated from bipolar affective disorder (manic-depressive illness)?

How is schizophrenia differentiated from delusional disorder?

How is schizophrenia differentiated from schizotypal personality disorders?

How is schizophrenia differentiated from paranoid personality disorder?

How is schizophrenia differentiated from brain tumors?

How is schizophrenia differentiated from subdural hematomas?

How is schizophrenia differentiated from idiopathic calcification of the basal ganglia?

How is schizophrenia differentiated from Wilson disease (hepatolenticular degeneration)?

How is schizophrenia differentiated from porphyrias?

Which metabolic or endocrine disorders should be included in the differential diagnoses of schizophrenia?

Which infectious diseases should be included in the differential diagnoses of schizophrenia?

How is neurosyphilis differentiated from schizophrenia?

How is HIV infection differentiated from schizophrenia?

Can cerebral abscesses cause psychotic symptoms?

Can chronic Lyme disease cause psychotic symptoms?

Should Creutzfeldt-Jakob disease be included in the differential diagnoses of schizophrenia?

Should multiple sclerosis be considered in the differential diagnoses of schizophrenia?

Should Huntington disease be considered in the differential diagnoses of schizophrenia?

Should Alzheimer disease be considered in the differential diagnoses of schizophrenia?

Should dementia with Lewy bodies be considered in the differential diagnoses of schizophrenia?

Should lipid storage disorders be considered in the differential diagnoses of schizophrenia?

How is encephalitis differentiated from schizophrenia?

Which seizure disorders might be considered in the differential diagnoses of schizophrenia?

How is schizophrenia differentiated from systemic lupus erythematosus (SLE)?

How is schizophrenia differentiated from systemic vasculitides?

Should heavy metal toxicity be included in the differential diagnoses of schizophrenia?

Which drugs are associated with mental status changes?

Which vitamin deficiencies may cause mental status changes?

What are the differential diagnoses for Schizophrenia?

Workup

What history details should be considered in the diagnosis of schizophrenia?

Are physical exam findings helpful in the diagnosis of schizophrenia?

What is the role of neurologic exam in the management of schizophrenia?

What is the role of lab testing in the diagnosis and management of schizophrenia?

Treatment

How is schizophrenia treated?

What is the role of medical care in the management of schizophrenia?

What is the effect of antipsychotic (neuroleptic) medications on schizophrenia?

What factors should be considered in the selection of medications for the management of schizophrenia?

When is hospitalization (in-patient treatment) indicated in the treatment of schizophrenia?

Are patients with schizophrenia able to provide informed consent?

Are patients with schizophrenia eligible for Medicare and Medicaid?

What is the impact of the American Affordable Care Act (ACA) on the care of schizophrenia?

What warnings should be given prior to treatment with antipsychotic medications for schizophrenia?

What are first- and second-generation antipsychotics used in the management of schizophrenia?

How are antipsychotic agents administered in the treatment of schizophrenia?

What are the adverse effects of antipsychotic drugs used to manage schizophrenia?

Are certain antipsychotic drugs more effective in managing the symptoms of schizophrenia?

Is injectable or oral administration of antipsychotic agents more effective for schizophrenia?

Which antipsychotic agents are patients with schizophrenia most likely to stop taking?

Is olanzapine, quetiapine, or risperidone more effective for treatment of schizophrenia?

What are The Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland recommendations for the initial treatment of schizophrenia?

Does early treatment of schizophrenia prevent long-term disability?

Which is the antipsychotic drug of choice for schizophrenia?

Is using an algorithm for the treatment of schizophrenia effective?

Is multidrug therapy safe in the treatment of schizophrenia?

How effective is quetiapine in the treatment of schizophrenia?

What recommendations have been provided by The Schizophrenia Patient Outcomes Research Team (PORT) of the University of Maryland?

How is medication compliance optimized for schizophrenia?

What are the possible adverse effects of antipsychotic therapy in the treatment of schizophrenia?

Is akathisia a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

Is dystonia a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

Is hyperprolactinemia a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

Is neuroleptic malignant syndrome (NMS) a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

Is parkinsonism a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

Is tardive dyskinesia (TD) a possible adverse effect of antipsychotic therapy in the treatment of schizophrenia?

What are the anticholinergic side effects of antipsychotics used to manage schizophrenia?

How do antipsychotic agents affect the QT interval in patients with schizophrenia?

Which antipsychotic agents cause altered glucose, lipid metabolism, and weight gain in patients with schizophrenia?

How do antipsychotic agents affect glucose, lipid metabolism, and weight gain in patients with schizophrenia?

Can antipsychotic agents cause esophageal dysmotility and orthostatic hypotension in patients with schizophrenia?

Can antipsychotic agents cause venous thromboembolism in patients with schizophrenia?

What are the risks of risperidone in children and adolescents with schizophrenia?

What are neurotoxic effects of antipsychotic therapy in patients with schizophrenia?

How is monitoring of blood medication levels useful in the management of schizophrenia?

When are anticholinergic agents used in the treatment of schizophrenia?

Which medications are used as adjunct therapy for schizophrenia?

Are psychosocial interventions used in the management of schizophrenia?

What are the goals of psychosocial treatment for schizophrenia?

Is psychosocial treatment for schizophrenia effective?

What is cognitive remediation for schizophrenia?

What are the cognitive remediation models used for schizophrenia?

When is cognitive remediation most effective in patients with schizophrenia?

Is cognitive remediation therapy effective for schizophrenia?

Is cognitive therapy effective as standalone treatment for schizophrenia?

What is Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)?

How effective is vocational rehabilitation for schizophrenia?

What is assertive community treatment for schizophrenia?

What are the benefits of family interventions for schizophrenia?

Should patients with schizophrenia be encouraged to stop smoking?

What is the role of diet and exercise in the treatment of schizophrenia?

Does the prognosis of schizophrenia improve with early detection and intervention?

What is the role of transcranial magnetic stimulation (TMS) in the treatment of schizophrenia?

Medications

What is the role of antipsychotic medications in the treatment of schizophrenia?

Which medications in the drug class Antipsychotics, 1st Generation are used in the treatment of Schizophrenia?

Which medications in the drug class Antipsychotics, 2nd Generation are used in the treatment of Schizophrenia?

Which medications in the drug class Serotonin-Dopamine Activity Modulators are used in the treatment of Schizophrenia?