medicine

NAME: _____________________________ PERIOD ____________

NEUROLOGICAL or PSYCHOLOGICAL DISORDER PROJECT

NEUROLOGICAL DISORDER PROJECT TOPIC: ___________________________________ TEACHER APPROVAL ________ DUE DATE: ___March 26__

PURPOSE: The purpose of this assignment is to have you look at the human body from a different angle. It is almost impossible to open the newspaper or

watch the news on TV without hearing about human disorders and diseases, new

cures, and the state of our health care system. The body is susceptible to

malfunction and diseases and Americans are worried about how they are going to

pay the costs of their health care if they become sick. In this project, we will focus

on neurological, neuromuscular, and psychological disorders as a way to learn

more about the way the body works stemming from the nervous system.

PROCEDURE:

1) Choose a disorder or serious physical problem to focus on for your project. Your project will have more meaning for you if you choose a disease that affects someone in your family or "extended" family such as aunts, uncles, cousins, or a friend etc. Careful choice of a disease will make this project more interesting for you. (Note that no two students can do the same project.)

2) Find out all you can about the disorder/disease you chose for your project. The following are resources you should consult about the disease: Books, the Internet, magazines or journals, professionals in the health field, special interest organizations, and last but not least persons who are affected by the disease you have chosen.

MAKE SURE YOUR REPORT INCLUDES THE FOLLOWING INFORMATION:

a) UNDERSTANDING THE DISEASE/DISORDER i) Background and/or history

(1) Who discovered (2) How was it named (3) Associated disorders- (similar to the disease) (4) Type of Disorder- if it is inherited include Genetics of the disorder

ii) Environmental Effects (1) Transmission or spreading (2) Behavioral risk factors (3) Seasonal or Climate

iii) Demographics (1) The age one normally gets this disease (2) Statistics of numbers with disease, and in what countries

b) HOW THE DISEASE AFFECTS THE BODY i) Biochemical changes that cause the disease ii) How the disease affects normal cellular function Pathology

(1) Structural and Functional Abnormalities (2) Description of organ system(s) involved

iii) How a person's daily life is affected by the disease iv) The symptoms of the disease

c) TREATMENTS FOR THE DISEASE i) Tests a health care provider would run to help diagnose the disease ii) Medications to treat the disorder and how they work iii) Current research to find a cure or better treatment for the disease; include a copy of that article and

a summary of what you understood about it. iv) Information on the cost of having the disease, treatment, medications, hospitalization, etc.

Schizophrenia

Alex Shah

d) CONCLUSION PARAGRAPH. i) Write about why you chose this disease? ii) What was the most interesting fact that you learned from doing the project? iii) What was the most important source of information that you used to write your report? iv) What questions would you still like answered about this disease? v) What do you feel that everyone should learn from your project?

3) BIBLIOGRAPHY Include at the end of your report a bibliography of sources to produce your presentation. (MLA or APA format with the exact URL address) There is a requirement of at least 5 reliable sources with at least 2 of the 5 coming from a journal article (Google PNAS)

4) PRESENTATION Your presentation will be held to 5 minutes maximum! Please know and internalize the important information….don’t read off the screen or computer! Your research project is to design a presentation and load it to Google Classroom.

a) The presentation should include at least one graphic per slide i) Points will be given for neatness and clarity ii) Make sure the image serves a purpose to your topic in the slide.

b) Your paper will be submitted to an electronic website to check for originality. c) Use note cards only to assist in the organization of your project (it is not necessary)

i) Points will be taken off for reading directly from the note cards. d) Students should be prepared to answer a minimum of 2 questions that the teacher or students have

about the disorder. e) PowerPoints must be in your Google Classroom.

Grade Breakdown: � 50 points possible for the paper � 15 points possible for the PPT � 35 points possible for the presentation and Q&A session

Deadline - Neurological Disorder- Approved by the teacher before Feb. 15 (Neurological disorder must be first

approved by the teacher before starting the research). - Research Paper March 26 - PowerPoint or other approved presentation program- March 26 - Oral presentation starts- March 26 (volunteers first then random)

Evaluation- Neurological or Psychological Condition

- Not clearly defined

1- Listed a part of what is required

2- Somewhat defined

3- Listed most of what is required

4- Listed everything of what is required and clearly defined.

5- Listed all that is required and clearly defined in an organized/cohesive manner

Research Report (50 points)

Understanding the disorder (x 2)

0 1 2 3 4 5

How the disorder affects the body (x 2)

0 1 2 3 4 5

Treatment of the disorder (x 2)

0 1 2 3 4 5

Conclusion (x 2)

0 1 2 3 4 5

Bibliography (x 2)

0 1 2 3 4 5

Visual Presentation (15 points- x 3)

0 1 2 3 4 5

Oral Presentation (35 points)

Subject Knowledge (x 3)

0 1 2 3 4 5

Enthusiasm

0 1 2 3 4 5

Response to Questions

0 1 2 3 4 5

Eye Contact and Body Language

0 1 2 3 4 5

Elocution

0 1 2 3 4 5

Final Grade: __________

Comments:

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 1 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…search_result&selectedTitle=3~150&usage_type=default&display_rank=3

Official reprint from UpToDate www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Schizophrenia in adults: Epidemiology and pathogenesis

Authors: Bernard A Fischer, MD, Robert W Buchanan, MD Section Editor: Stephen Marder, MD Deputy Editor: Richard Hermann, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2018. | This topic last updated: Jan 26, 2018.

INTRODUCTION — Schizophrenia is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [1].

Characteristics of schizophrenia typically include positive symptoms, such as hallucinations or delusions; disorganized speech; negative symptoms, such as a flat affect or poverty of speech; and impairments in cognition, including attention, memory, and executive functions. The illness is commonly associated with impairments in social and occupational functioning [2]. Antipsychotic medications are the first-line treatment for schizophrenia. Evidence-based psychosocial interventions in conjunction with pharmacotherapy can help patients achieve recovery.

This topic discusses the epidemiology and pathogenesis of schizophrenia. Clinical manifestations, assessment, diagnosis, and course of schizophrenia are discussed separately. Anxiety and depression in schizophrenia are discussed separately. Psychosocial and pharmacologic treatments for schizophrenia are discussed separately, including long-acting antipsychotics, clozapine, and management of antipsychotic side effects. Evaluation and management of treatment resistant schizophrenia are also reviewed separately. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect management" and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Psychosocial interventions for schizophrenia" and "Depression in schizophrenia" and "Anxiety in schizophrenia" and "Evaluation and management of treatment-resistant schizophrenia".)

EPIDEMIOLOGY — Schizophrenia occurs throughout the world. The prevalence of schizophrenia (ie, the number of cases in a population at any one time point) approaches 1 percent internationally. The incidence (the number of new cases annually) is about 1.5 per 10,000 people [3]. Age of onset is typically during adolescence; childhood and late-life onset (over 45 years) are rare. Slightly more men are diagnosed with schizophrenia than women (on the order of 1.4:1) [4], and women tend to be diagnosed later in life than men. Modal age of onset is between 18 and 25 for men and between 25 and 35 for women, with a second peak occurring around menopause [5]. There is also some indication that the prognosis is worse in men [6,7].

®

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 2 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

Co-occurring conditions — People with schizophrenia have higher rates of several psychiatric disorders than people without schizophrenia, including:

People with schizophrenia are also at greater risk for co-occurring conditions, such as metabolic and neurological problems. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Associated physical manifestations'.)

The rate of suicide among people with schizophrenia is much higher than in the general population. Approximately 5 percent of people with schizophrenia commit suicide over their lifetime [8]. About 10 percent of all completed suicides are among people with schizophrenia [9,10].

Risk factors — A number of epidemiologic risk factors have been associated with the development of schizophrenia, including:

Environmental risk factors for schizophrenia are discussed below. (See 'Environmental risk factors' below.)

Cost — The cost of schizophrenia is staggering. The overall cost of schizophrenia in the United States in 2002 was estimated at about $63 billion [18]. This figure includes direct healthcare costs and indirect costs associated with loss of productivity. A study comparing the cost of schizophrenia in India in 2001 with the cost in the same catchment area in 2011 found that the cost had doubled in those 10 years, mainly related to increases in indirect costs [19]. A study examining United States insurance claims found that the annual health-related expenses of someone with chronic schizophrenia averaged more than $15,000 [20]. The cost of schizophrenia treatment from 2004 to 2009 to Medicare in the United States increased from $9.4 billion to $11.5 billion [21].

Deficit schizophrenia — Deficit schizophrenia, characterized by primary, enduring negative symptoms, seems to be a specific disease process within the larger syndrome of schizophrenia. Approximately 15 to 20 percent of the total schizophrenia population has the deficit form of schizophrenia [22-25]. They are more likely to be male and more likely to have relatives with schizophrenia than people with nondeficit schizophrenia [26-30]. As

Depressive disorders (see "Depression in schizophrenia")●

Anxiety disorders: social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (see "Anxiety in schizophrenia")

●

Alcohol and other substance use disorders (see "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis")

●

Living in an urban area [11,12]●

Immigration [13,14]●

Obstetrical complications [15]●

Late winter-early spring birth – Perhaps reflecting exposure to influenza virus during neural development●

Advanced paternal age at conception [16] – May be associated with an increased risk of de novo mutations [17]

●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 3 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

opposed to the excess of late winter-early spring births observed in schizophrenia in general, there is a disproportionate rate of summer births in the deficit group [22,31]. Examples of negative symptoms include decreased expressiveness, apathy, flat affect, and a lack of energy. People with deficit schizophrenia are less likely to have addictions, depression, suicidality, or delusions with high emotional content (such as jealous delusions) compared to nondeficit schizophrenia [32-34]. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Deficit schizophrenia'.)

PATHOGENESIS — Although the pathogenesis of the disorder is unknown, it is almost certain that schizophrenia represents a syndrome comprised of multiple diseases that present with similar signs and symptoms [35]. This heterogeneity complicates the elucidation of the etiological and pathophysiological factors that underlie the group of disorders. Schizophrenia appears to be a uniquely human condition, which limits the utility of animal models [36]. There is little doubt that schizophrenia proceeds from a complex interaction between genes and the environment, but even the attempt to differentiate genetic from environmental risk factors may be artificial, since environmental factors can influence gene expression just as a person’s genetic make-up can influence response to environmental stressors.

Research studies have found the following genetic and environmental risk factors in schizophrenia, which may act through disrupted neurotransmitter system function.

Genetic risk factors — Twin studies have been conducted in monozygotic and dizygotic twins to examine concordance rates of schizophrenia within the twin pairs. The observed concordance rate in monozygotic twins, who share 100 percent of their genes, is about 40 to 50 percent, whereas the observed concordance rate in dizygotic twins, who share 50 percent of their genes, is about 10 to 15 percent. [37-39]. The increased concordance rate of schizophrenia in monozygotic compared to dizygotic twins suggests a strong genetic component to schizophrenia. The offspring of the unaffected monozygotic twins are at increased risk of schizophrenia, which further supports the existence of a genetic predisposition for the illness. The fact that the monozygotic twin concordance rate is less than 100 percent, however, suggests that nongenetic, environmental factors are also involved in the development of the illness [37-39]. Adoption studies have provided further evidence for the presence of genetic risk factors.

Although there is abundant evidence for genetic risk factors, the specific genes involved in the etiology of schizophrenia have not been identified. Initial studies have used genetic linkage or candidate gene approaches to identify several specific genes as candidates for a role in the development of schizophrenia (table 1).

The mapping of the human genome has allowed for the study of associations between gene variants and risk or occurrence of diseases, ie, genome-wide association studies (GWAS). The results of GWAS of schizophrenia support a polygenic model, in which multiple genes with additive small effects lead to the disorder. As many as 500,000 single nucleotide polymorphisms (SNPs) have been tested in GWAS for association with schizophrenia. In a study of over 35,000 cases and 110,00 controls, 108 SNPs were found to have a significant association with schizophrenia [40]. The identified genetic loci supported the involvement of the dopaminergic and glutamatergic neurotransmitter systems in the pathophysiology of schizophrenia. The study also replicated previous studies that have shown an association between genes of the major histocompatibility complex (MHC), which support immune functions, and schizophrenia. A 2016 study of the MHC locus demonstrated that expression of complement component 4 allele A (C4A) was proportional to the risk of having schizophrenia [41]. C4 expression

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 4 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

and activity were then tested in mouse models and shown to be related to adolescent pruning of brain synapses. These findings are consistent with decreased “neuropil,” or dendritic density, which has been reliably observed in people with schizophrenia [42]. (See "Genetic association studies: Principles and applications".)

Another attempt to delineate the genetics of schizophrenia is the evaluation of copy number variants (CNVs), which are genes that have been duplicated or deleted. People with schizophrenia have been found to have higher rates of CNVs. The most frequent CNV associated with schizophrenia is a deletion on the long arm of chromosome 22 (22q11) [43]. (See "Genetic association studies: Principles and applications".)

Environmental risk factors

Obstetrical complications — Various perinatal problems, grouped together for analysis as “obstetrical complications,” increase the risk of later development of schizophrenia two-fold [15]. These perinatal problems include:

The accuracy of these data, based on maternal recall many years after childbirth, has been questioned, but studies suggest that the risk does not appear to be influenced by inaccurate memories [44,45]. The association between obstetrical complications and the development of schizophrenia has also been observed in data from medical records, which do not rely on recall [15].

In studies based on subsequent hospital records, pregnancy during famines in the Netherlands (1944 through 1945) [46] and in China (1959 through 1961) [47,48] has been associated with a two-fold risk of schizophrenia in the offspring. The results of these studies indicate that maternal nutrition is a factor in the development of schizophrenia. Other, related factors associated with an increased risk of subsequently developing schizophrenia include being the product of an unwanted pregnancy [49] and the prenatal death of the father [50].

Increased prenatal maternal stress has been proposed as the common pathophysiological mechanism underlying risk factors, such as famine, bereavement, and antenatal infection. An animal model provides some support for this theory [51].

Infections — Several epidemiologic findings have suggested a possible role of certain infectious agents as potential risk factors for the development of schizophrenia:

Hemorrhage●

Preterm labor●

Blood-group incompatibilities●

Fetal hypoxia●

Maternal infection (see 'Infections' below)●

Numerous epidemiological studies have found an increase in schizophrenia prevalence in cohorts born during influenza epidemics [52].

●

The increased risk for schizophrenia among those born in the late winter-early spring could possibly•

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 5 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

The mechanism by which infections increase the risk of schizophrenia is unclear. There is little evidence to suggest that the risk is associated with direct damage by the infectious agent to the central nervous system (CNS). A study comparing individuals hospitalized for meningitis as children to a control group who were hospitalized with gastroenteritis as children found no difference in the risk of later hospitalization for schizophrenia [62]. A more likely explanation is that infection by certain agents triggers an immune response in a mother that is passed through the placenta to the developing fetus, which compromises the blood brain barrier and allows antibodies, which cross-react with CNS proteins, to enter into the developing nervous system [63]. Early childhood infections could also initiate an immune response and lead to a general state of increased inflammation. (See 'Inflammation' below.)

Inflammation — Increased immune system activation leads to higher levels of circulating pro-inflammatory cytokines. Increased pro-inflammatory cytokine levels have been frequently observed in schizophrenia [64]. Cytokines can alter the blood-brain barrier, or be produced locally in the CNS by activated microglia, and may be responsible for psychosis, its exacerbation, or cognitive impairments [65]. The actions of antipsychotic drugs may be partially mediated by the anti-inflammatory effects of these agents [66].

In addition to associations between schizophrenia and some infections, there is other evidence for abnormal immune activation in people with schizophrenia. (See 'Infections' above.)

Autoimmune disorders that have been associated with a higher prevalence of schizophrenia include [67,68]:

reflect increased maternal exposure to influenza virus during prenatal neural development.

High maternal IgG antibodies to the parasite toxoplasma gondii have been found to increase the relative risk of developing schizophrenia in offspring by about 60 to 70 percent [53,54].

●

Studies have varied on whether herpes simplex virus type 2 maternal infection increases the risk for schizophrenia; some studies have found increased risks between 60 percent to more than 400 percent [55,56], while other studies have found no increased risk [57].

●

Other infectious agents associated with schizophrenia appear to have an influence outside the model of perinatal exposure of the affected individual. As examples:

●

Higher maternal levels of IgG to toxoplasma gondii are related to the later development of schizophrenia in the mother herself [58].

•

Measles antibodies are higher in people with schizophrenia, especially in those with recent-onset of psychosis, than controls [59].

•

Bacterial infections during childhood, which lead to hospitalization, are related to an increased risk for developing schizophrenia [60,61].

•

Acquired hemolytic anemia●

Bullous pemphigoid●

Celiac disease●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 6 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

(A notable exception is rheumatoid arthritis, in which schizophrenia rates are lower than expected based on rates in the general population [69]. People with schizophrenia are also more likely to have circulating antibodies to proteins common in most Western diets, such as gluten [70,71] and casein [72,73].)

Clinical trials of anti-inflammatory agents for psychosis have been spurred, in part, by these findings. (See "Evaluation and management of treatment-resistant schizophrenia", section on 'Other adjunctive medications'.)

Inflammation in people with schizophrenia may also be responsible for some of the disorder’s associated conditions such as heart disease (through decreased elasticity of inflamed blood vessels) and diabetes (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Metabolic disturbances'.)

Cannabis use — Epidemiological studies suggest that cannabis use is a risk factor for the development of psychosis [74-76]. Initial findings from retrospective studies were inconclusive because people with psychotic disorders, even before they were diagnosed, could be using cannabis. This would indicate that psychosis was a risk factor for using cannabis rather than the reverse. Well-controlled, prospective studies following hundreds of people have subsequently supported the hypothesis that cannabis use is the risk factor and psychosis the result [77,78]. The increased risk posed by cannabis use depends on other risk factors, such as family history, but is generally reported with odds ratios of 2.2 to 2.8 [75,77,78]. Acute infusions of delta-9-tetrahydrocannabinol have provoked psychotic-like symptoms in people with and without schizophrenia [79,80], providing further evidence for cannabis as a risk factor for psychosis. (See "Cannabis use and disorder: Epidemiology, comorbidity, health consequences, and medico-legal status".)

Cigarette smoking — Studies of the effect of cigarette smoking during pregnancy on the risk for the development of schizophrenia have been mixed. The first study to use serum cotinine as a biomarker for smoking, however, found cigarette smoking during pregnancy significantly increases the odds of schizophrenia in the offspring (odds ratio = 3.41, 95% CI 1.86-6.24). This study was based on a Finnish national health registry and included 977 cases of schizophrenia [81].

Although this finding could be related to nicotinic acetylcholine perturbations during development or fetal hypoxia, it may simply reflect genetic risk. It is well known that first-degree relatives of people with schizophrenia have higher rates of smoking compared with the relatives of healthy controls [82].

Immigration — Numerous studies in multiple countries have observed a higher prevalence of schizophrenia in immigrant populations compared with native-born populations [13,14]. This increased relative risk can be as high as four-fold, depending on the study. An increased risk appears to extend to second-generation immigrants as well [14].

Several possible explanations for the association between immigrants and schizophrenia have been proposed:

Interstitial cystitis●

Thyrotoxicosis●

Schizophrenia may be overdiagnosed in immigrant populations; however, further research suggests that this cannot entirely explain the increase in risk observed [83].

●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 7 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…search_result&selectedTitle=3~150&usage_type=default&display_rank=3

Neurotransmitters

Dopamine — All drugs with antipsychotic properties block the dopaminergic D2 receptor, a finding that has led to the dopamine hypothesis of schizophrenia, in which excess dopamine in the mesolimbic tract has been hypothesized to cause positive psychotic symptoms. However, if dopamine were the sole neurotransmitter disrupted in schizophrenia, then antipsychotics would be universally and completely effective for these symptoms. However, despite adequate antipsychotic treatment, many people with schizophrenia continue to exhibit positive symptoms. Therefore, it is likely that dysfunction in other neurotransmitter systems is required to explain why many people with the illness exhibit only a partial reduction in positive symptoms, and why clozapine, the most efficacious antipsychotic in schizophrenia, is a weak D2 antagonist.

Decreased dopamine in the prefrontal cortex (largely affecting the D1 receptor) may be responsible for some of the cognitive and negative symptoms observed in schizophrenia [87,88]. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Clinical manifestations'.)

Glutamate — Glutamate is the major CNS excitatory neurotransmitter. Hypofunction of the N-methyl-D- aspartate (NMDA) glutamate receptor has been hypothesized to contribute to the pathology of schizophrenia [89]. Evidence comes from:

In people with either a genetic or neurodevelopmental biological risk for schizophrenia, stress can play a role in the ultimate development of the disorder. In this way, the stress of immigration, becoming part of an outsider group, may contribute to the development of schizophrenia. Studies have found associations between the amount of social discrimination experienced by immigrant groups and the rates of schizophrenia in the group; that is, immigrant groups experiencing more discrimination have higher rates of schizophrenia than immigrant groups experiencing lower rates of social discrimination. This finding has been observed in several immigrant groups in several countries:

●

Ethiopian immigrants to Israel [84]•

Moroccan immigrants to Holland [14]•

Caribbean immigrants to the United Kingdom [85]•

The increased risk of schizophrenia in immigrants may be related to vitamin D deficiency, especially among individuals who move to more northern latitudes [86].

●

Clinical observations of people who have misused phencyclidine (a NMDA receptor antagonist)●

Challenge studies using ketamine (a NMDA receptor antagonist) [90-92]●

Genetic findings [89]●

Post-mortem studies [93]●

Studies measuring the level of endogenous NMDA receptor antagonists in the CNS of people with schizophrenia [94,95]

●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 8 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

Clinical trials with agents that enhance glutamatergic neurotransmission have had varied results depending on the mechanism of the agent used [96,97]. (See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment".)

Gamma-amino-butyric acid — Gamma-amino-butyric acid (GABA) is the major CNS inhibitory neurotransmitter. GABAergic interneurons are important for regulation of prefrontal cortical function, through their modulation of glutamatergic pyramidal cells. Several lines of evidence suggest that these interneurons are dysfunctional in people with schizophrenia [98-103].

Acetylcholine — The increased smoking behaviors observed in people with schizophrenia [105-108] has led to the hypothesis that nicotine, which stimulates a subset of acetylcholine receptors, is correcting a fundamental neurochemical problem in schizophrenia. Treatment with nicotine or a nicotinic cholinergic drug can normalize some eye-tracking and EEG abnormalities observed in people with schizophrenia [109-113] and may acutely improve some aspects of cognition [114,115]. However, nicotinic acetylcholine receptors can affect many other neurotransmitter systems (for example, nicotine can enhance current mediated by glutamate receptors in dopamine neurons of the rat ventral tegmentum [116,117]), and so it is not clear whether the cholinergic system is primarily disrupted in schizophrenia or the disruption is secondary to other pathological characteristics of the illness.

SUMMARY AND RECOMMENDATIONS

Postmortem studies in people with schizophrenia have found decreased levels of glutamic acid decarboxylase (GAD67) mRNA expression in the prefrontal cortex [104].

●

In people with schizophrenia with decreased GAD67, there is a decrease in the density of chandelier cell connections with the pyramidal cell axon initial segment [104] and in the immunoreactivity of the GABA plasma membrane transporter-1 in chandelier cell axon terminals [104].

●

There appears to be a decrease in GABA reuptake transporter mRNA levels [104] and an increase in GABAA alpha-2 subunit density on the axon initial segment [104], both of which may be compensatory shifts.

●

Schizophrenia has a worldwide prevalence approaching 1 percent, with an incidence of about 1.5 new cases annually per 10,000 people. (See 'Epidemiology' above.)

●

People with schizophrenia have higher rates of depression, several anxiety disorders, substance use disorders, and suicide compared to people without schizophrenia. (See 'Co-occurring conditions' above.)

●

Approximately 15 to 20 percent of patients with schizophrenia have the deficit form of schizophrenia, characterized by primary, enduring negative symptoms such as decreased expressiveness, apathy, flat affect, and a lack of energy. (See 'Deficit schizophrenia' above and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Deficit schizophrenia'.)

●

Although the pathogenesis of the disorder is unknown, schizophrenia is likely a syndrome comprised of multiple diseases that present with similar signs and symptoms. The disorder appears to proceed from a complex interaction between genes and the environment. (See 'Pathogenesis' above.)

●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 9 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Murray CJL, Lopez AD. The Global Burden of Disease, Harvard University Press, Cambridge, MA 1996. p. 21.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DS M-5), American Psychiatric Association, Arlington 2013.

3. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008; 30:67.

4. Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry 2010; 22:417.

5. American Psychiatric Association. Diagnostic and Statistical Manual, Fourth Edition Text Revision (DSM-IV TR), American Psychiatric Publishing, Arlington 2000.

6. Grossman LS, Harrow M, Rosen C, et al. Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery. Compr Psychiatry 2008; 49:523.

7. Usall J, Ochoa S, Araya S, et al. Gender differences and outcome in schizophrenia: a 2-year follow-up study in a large community sample. Eur Psychiatry 2003; 18:282.

8. Hor K, Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010; 24:81.

9. Arsenault-Lapierre G, Kim C, Turecki G. Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry 2004; 4:37.

10. Suominen K, Isometsä E, Heilä H, et al. General hospital suicides--a psychological autopsy study in Finland. Gen Hosp Psychiatry 2002; 24:412.

11. Krabbendam L, van Os J. Schizophrenia and urbanicity: a major environmental influence--conditional on genetic risk. Schizophr Bull 2005; 31:795.

12. Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry 2001; 58:1039.

13. Werbeloff N, Levine SZ, Rabinowitz J. Elaboration on the association between immigration and schizophrenia: a population-based national study disaggregating annual trends, country of origin and sex over 15 years. Soc Psychiatry Psychiatr Epidemiol 2012; 47:303.

14. Bourque F, van der Ven E, Malla A. A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med 2011; 41:897.

15. Clarke MC, Harley M, Cannon M. The role of obstetric events in schizophrenia. Schizophr Bull 2006; 32:3.

16. Miller B, Messias E, Miettunen J, et al. Meta-analysis of paternal age and schizophrenia risk in male versus

Several neurotransmitter systems are involved in the pathology of schizophrenia including dopamine, glutamate, GABA, and acetylcholine. These represent the current best targets for pharmacological intervention in the disorder. (See 'Neurotransmitters' above and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment".)

●

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 10 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

female offspring. Schizophr Bull 2011; 37:1039.

17. Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 2012; 488:471.

18. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry 2005; 66:1122.

19. Somaiya M, Grover S, Avasthi A, Chakrabarti S. Changes in cost of treating schizophrenia: comparison of two studies done a decade apart. Psychiatry Res 2014; 215:547.

20. Nicholl D, Akhras KS, Diels J, Schadrack J. Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective. Curr Med Res Opin 2010; 26:943.

21. Feldman R, Bailey RA, Muller J, et al. Cost of schizophrenia in the Medicare program. Popul Health Manag 2014; 17:190.

22. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 2001; 58:165.

23. Kirkpatrick B, Buchanan RW, Breier A, Carpenter WT Jr. Case identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res 1993; 47:47.

24. Amador XF, Kirkpatrick B, Buchanan RW, et al. Stability of the diagnosis of deficit syndrome in schizophrenia. Am J Psychiatry 1999; 156:637.

25. Carpenter WT Jr, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 1988; 145:578.

26. Kirkpatrick B, Mitchell BD, DeLisi LE. Concordance of the deficit/nondeficit categorization in affected siblings. Schizophr Bull 2007; 33:282.

27. Kirkpatrick B, Castle D, Murray RM, Carpenter WT Jr. Risk factors for the deficit syndrome of schizophrenia. Schizophr Bull 2000; 26:233.

28. Dollfus S, Ribeyre JM, Petit M. Family history and deficit form in schizophrenia. Eur Psychiatry 1996; 11:260.

29. Kirkpatrick B, Ross DE, Walsh D, et al. Family characteristics of deficit and nondeficit schizophrenia in the Roscommon Family Study. Schizophr Res 2000; 45:57.

30. Ross DE, Kirkpatrick B, Karkowski LM, et al. Sibling correlation of deficit syndrome in the Irish study of high-density schizophrenia families. Am J Psychiatry 2000; 157:1071.

31. Messias E, Kirkpatrick B, Bromet E, et al. Summer birth and deficit schizophrenia: a pooled analysis from 6 countries. Arch Gen Psychiatry 2004; 61:985.

32. Fenton WS, McGlashan TH. Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia. Am J Psychiatry 1994; 151:351.

33. Kirkpatrick B, Amador XF, Flaum M, et al. The deficit syndrome in the DSM-IV Field Trial: I. Alcohol and other drug abuse. Schizophr Res 1996; 20:69.

34. Kirkpatrick B, Buchanan RW, Breier A, Carpenter WT Jr. Depressive symptoms and the deficit syndrome of schizophrenia. J Nerv Ment Dis 1994; 182:452.

35. Fischer BA, Carpenter WT Jr. Will the Kraepelinian dichotomy survive DSM-V? Neuropsychopharmacology 2009; 34:2081.

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 11 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

36. Taylor A, Taylor S, Markham J, Koenig J. Schizophrenia Research Forum: Animal Models of Schizophrenia. [pdf] 2009. http://www.schizophreniaforum.org/res/models/Animal_Models_04_09.pdf (Accessed on Septe mber 29, 2011).

37. Kringlen E. Twin studies in schizophrenia with special emphasis on concordance figures. Am J Med Genet 2000; 97:4.

38. Cardno AG, Marshall EJ, Coid B, et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56:162.

39. Cannon TD, Kaprio J, Lönnqvist J, et al. The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. Arch Gen Psychiatry 1998; 55:67.

40. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511:421.

41. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016; 530:177.

42. Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience 2013; 251:90.

43. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455:232.

44. Buka SL, Goldstein JM, Seidman LJ, Tsuang MT. Maternal recall of pregnancy history: accuracy and bias in schizophrenia research. Schizophr Bull 2000; 26:335.

45. Walshe M, McDonald C, Boydell J, et al. Long-term maternal recall of obstetric complications in schizophrenia research. Psychiatry Res 2011; 187:335.

46. Susser E, Neugebauer R, Hoek HW, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry 1996; 53:25.

47. St Clair D, Xu M, Wang P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA 2005; 294:557.

48. Xu MQ, Sun WS, Liu BX, et al. Prenatal malnutrition and adult schizophrenia: further evidence from the 1959-1961 Chinese famine. Schizophr Bull 2009; 35:568.

49. Myhrman A, Rantakallio P, Isohanni M, et al. Unwantedness of a pregnancy and schizophrenia in the child. Br J Psychiatry 1996; 169:637.

50. Huttunen MO, Niskanen P. Prenatal loss of father and psychiatric disorders. Arch Gen Psychiatry 1978; 35:429.

51. Koenig JI, Elmer GI, Shepard PD, et al. Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. Behav Brain Res 2005; 156:251.

52. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010; 167:261.

53. Mortensen PB, Nørgaard-Pedersen B, Waltoft BL, et al. Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biol Psychiatry 2007; 61:688.

54. Brown AS, Schaefer CA, Quesenberry CP Jr, et al. Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 2005; 162:767.

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 12 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

55. Buka SL, Cannon TD, Torrey EF, et al. Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry 2008; 63:809.

56. Buka SL, Tsuang MT, Torrey EF, et al. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001; 58:1032.

57. Brown AS, Schaefer CA, Quesenberry CP Jr, et al. No evidence of relation between maternal exposure to herpes simplex virus type 2 and risk of schizophrenia? Am J Psychiatry 2006; 163:2178.

58. Pedersen MG, Stevens H, Pedersen CB, et al. Toxoplasma infection and later development of schizophrenia in mothers. Am J Psychiatry 2011; 168:814.

59. Dickerson F, Stallings C, Origoni A, et al. Antibodies to measles in individuals with recent onset psychosis. Schizophr Res 2010; 119:89.

60. Blomström Å, Karlsson H, Svensson A, et al. Hospital admission with infection during childhood and risk for psychotic illness--a population-based cohort study. Schizophr Bull 2014; 40:1518.

61. Nielsen PR, Benros ME, Mortensen PB. Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers. Schizophr Bull 2014; 40:1526.

62. Weiser M, Werbeloff N, Levine A, et al. CNS infection in childhood does not confer risk for later schizophrenia: a case-control study. Schizophr Res 2010; 124:231.

63. Benros ME, Nielsen PR, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011; 168:1303.

64. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011; 70:663.

65. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 2009; 63:257.

66. Kato TA, Monji A, Mizoguchi Y, et al. Anti-Inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a 'fire extinguisher' in the brain of schizophrenia? Mini Rev Med Chem 2011; 11:565.

67. Chen YJ, Wu CY, Lin MW, et al. Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study. Br J Dermatol 2011; 165:593.

68. Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163:521.

69. Eaton WW, Hayward C, Ram R. Schizophrenia and rheumatoid arthritis: a review. Schizophr Res 1992; 6:181.

70. Dickerson F, Stallings C, Origoni A, et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry 2010; 68:100.

71. Samaroo D, Dickerson F, Kasarda DD, et al. Novel immune response to gluten in individuals with schizophrenia. Schizophr Res 2010; 118:248.

72. Severance EG, Dickerson FB, Halling M, et al. Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res 2010; 118:240.

73. Severance EG, Lin J, Sampson HA, et al. Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia. Schizophr Res 2011; 126:43.

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 13 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

74. Andréasson S, Allebeck P, Engström A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 1987; 2:1483.

75. van Os J, Bak M, Hanssen M, et al. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156:319.

76. Kristensen K, Cadenhead KS. Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res 2007; 151:151.

77. Kuepper R, van Os J, Lieb R, et al. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ 2011; 342:d738.

78. McGrath J, Welham J, Scott J, et al. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry 2010; 67:440.

79. D'Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9- tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004; 29:1558.

80. D'Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry 2005; 57:594.

81. Niemelä S, Sourander A, Surcel HM, et al. Prenatal Nicotine Exposure and Risk of Schizophrenia Among Offspring in a National Birth Cohort. Am J Psychiatry 2016; 173:799.

82. Ferchiou A, Szöke A, Laguerre A, et al. Exploring the relationships between tobacco smoking and schizophrenia in first-degree relatives. Psychiatry Res 2012; 200:674.

83. Selten JP, Hoek HW. Does misdiagnosis explain the schizophrenia epidemic among immigrants from developing countries to Western Europe? Soc Psychiatry Psychiatr Epidemiol 2008; 43:937.

84. Youngmann R, Pugachova I, Zilber N. Patterns of psychiatric hospitalization among ethiopian and former soviet union immigrants and persons born in Israel. Psychiatr Serv 2009; 60:1656.

85. Coid JW, Kirkbride JB, Barker D, et al. Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Arch Gen Psychiatry 2008; 65:1250.

86. McGrath JJ, Eyles DW, Pedersen CB, et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry 2010; 67:889.

87. Fischer BA, Kirkpatrick B, Carpenter WT. The neurobiology of negative symptoms and the deficit syndrome . In: The Handbook of Neurochemistry and Molecular Neurobiology: Schizophrenia, 3rd ed, Javitt DC, Kantr owitz JT (Eds), Springer Science and Business Media LLC, New York 2009. Vol 27, p.507.

88. Goldman-Rakic PS, Castner SA, Svensson TH, et al. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 2004; 174:3.

89. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148:1301.

90. Lahti AC, Weiler MA, Tamara Michaelidis BA, et al. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 2001; 25:455.

91. Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 1999; 20:106.

92. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist,

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 14 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51:199.

93. Geddes AE, Huang XF, Newell KA. Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:896.

94. Schwarcz R, Rassoulpour A, Wu HQ, et al. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 2001; 50:521.

95. Erhardt S, Schwieler L, Nilsson L, et al. The kynurenic acid hypothesis of schizophrenia. Physiol Behav 2007; 92:203.

96. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007; 164:1593.

97. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007; 13:1102.

98. Hashimoto T, Volk DW, Eggan SM, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23:6315.

99. Guidotti A, Auta J, Davis JM, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57:1061.

100. Pierri JN, Chaudry AS, Woo TU, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry 1999; 156:1709.

101. Woo TU, Whitehead RE, Melchitzky DS, Lewis DA. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci U S A 1998; 95:5341.

102. Volk D, Austin M, Pierri J, et al. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am J Psychiatry 2001; 158:256.

103. Volk DW, Pierri JN, Fritschy JM, et al. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex 2002; 12:1063.

104. Kinon BJ, Zhang L, Millen BA, et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31:349.

105. Uçok A, Polat A, Bozkurt O, Meteris H. Cigarette smoking among patients with schizophrenia and bipolar disorders. Psychiatry Clin Neurosci 2004; 58:434.

106. de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res 2005; 76:135.

107. Williams JM, Gandhi KK, Lu SE, et al. Higher nicotine levels in schizophrenia compared with controls after smoking a single cigarette. Nicotine Tob Res 2010; 12:855.

108. Olincy A, Young DA, Freedman R. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry 1997; 42:1.

109. Avila MT, Sherr JD, Hong E, et al. Effects of nicotine on leading saccades during smooth pursuit eye movements in smokers and nonsmokers with schizophrenia. Neuropsychopharmacology 2003; 28:2184.

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 15 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

110. Olincy A, Johnson LL, Ross RG. Differential effects of cigarette smoking on performance of a smooth pursuit and a saccadic eye movement task in schizophrenia. Psychiatry Res 2003; 117:223.

111. Sherr JD, Myers C, Avila MT, et al. The effects of nicotine on specific eye tracking measures in schizophrenia. Biol Psychiatry 2002; 52:721.

112. Adler LE, Hoffer LD, Wiser A, Freedman R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993; 150:1856.

113. Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006; 63:630.

114. Hong LE, Schroeder M, Ross TJ, et al. Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia. Schizophr Bull 2011; 37:416.

115. Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 2008; 165:1040.

116. Mao D, Gallagher K, McGehee DS. Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. J Neurosci 2011; 31:6710.

117. Jin Y, Yang K, Wang H, Wu J. Exposure of nicotine to ventral tegmental area slices induces glutamatergic synaptic plasticity on dopamine neurons. Synapse 2011; 65:332.

Topic 14804 Version 16.0

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 16 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

GRAPHICS

Some genes of interest in schizophrenia

Gene name or product

Gene Hypothesized

function Notes

Catechol-O-methyl transferase

COMT Catecholamine (including dopamine) metabolism

At position 158 in the resulting protein: a VAL/VAL allele is more active than a VAL/MET or MET/MET allele.

The VAL/VAL allele is associated with greater risk of psychosis in cannabis users . Position 22q11.

D-amino acid oxidase activator/D- amino acid oxidase

DAOA/G30 and DAO DAO breaks down D- serine, which is an NMDA receptor cofactor

DAOA/G30 and DAO are an interacting pair of genes ​.

Disrupted in schizophrenia 1

DISC1 Wide array of hypothesized functions from cell migration during development to dendritic outgrowths and cell adhesion

Discovered from studying a Scottish family with many members having a severe mental disorder and also a translocation disrupting the expression of the gene. Position 1q42.

Dystrobrevin binding protein 1 (dysbindin)

DTNBP1 Axon stability Also associated with skeletal muscle. Position 6p22.

Gamma- aminobutyric acid (GABA) A receptor subunit beta 2

GABRB2 Inhibitory neurotransmission

There is evidence of GABA signaling system abnormalities in schizophrenia. Position 5q34.

Neuregulin 1 NRG1 Signal transduction related to cell growth and differentiation

NRG1 undergoes alternative splicing into several proteins. Position 8p12-21.

Zinc finger protein 804A

ZNF804A Unknown (may be transcription factor)

Identified in GWAS study .

Also associated with bipolar disorders.

Examination of rare alleles of the gene found no difference in rates in schizophrenia compared to controls .

References: ​ 1. Henquet C, Rosa A, Krabbendam L, et al. An experimental study of catechol-O-methyltransferase Val158Met

moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 2006; 31:2748.

2. Corvin A, McGhee KA, Murphy K, et al. Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:949.

3. O'Donovan MC, Craddock N, Norton N, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 4:1053.

[1]

[2]

[3]

[4]

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 17 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

4. Dwyer S, Williams H, Holmans P, et al. No evidence that rare coding variants in ZNF804A confer risk of schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2010; 153B:1411.

Graphic 69865 Version 3.0

3/24/18, 10*44 AMSchizophrenia in adults: Epidemiology and pathogenesis - UpToDate

Page 18 of 18https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiol…earch_result&selectedTitle=3~150&usage_type=default&display_rank=3

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 1 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Official reprint from UpToDate www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis

Authors: Bernard A Fischer, MD, Robert W Buchanan, MD Section Editor: Stephen Marder, MD Deputy Editor: Richard Hermann, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2018. | This topic last updated: Jan 26, 2018.

INTRODUCTION — Schizophrenia is a psychiatric disorder involving chronic or recurrent psychosis. It is commonly associated with impairments in social and occupational functioning [1]. It is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [2].

Characteristics of schizophrenia typically include positive symptoms, such as hallucinations or delusions, disorganized speech; negative symptoms, such as a flat affect or poverty of speech; and impairments in cognition, including attention, memory and executive functions. A diagnosis of schizophrenia is based on the presence of such symptoms, coupled with social or occupational dysfunction, for at least six months in the absence of another diagnosis that would better account for the presentation.

This topic discusses clinical manifestations, assessment, diagnosis, and course of schizophrenia. The epidemiology and pathogenesis of schizophrenia are discussed separately. Anxiety, depression, and substance abuse in schizophrenia are discussed separately. The treatments for schizophrenia are discussed separately, as are other psychotic disorders. Schizophrenia in children is also reviewed separately. (See "Schizophrenia in adults: Epidemiology and pathogenesis" and "Depression in schizophrenia" and "Anxiety in schizophrenia" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect management" and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis" and "Psychosocial interventions for schizophrenia" and "Schizophrenia in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents".)

CLINICAL MANIFESTATIONS — Schizophrenia is a syndrome. People with schizophrenia generally present with several symptom domains (ie, areas of distinct psychopathology):

Positive symptoms — This group of symptoms includes the reality distortion symptoms of hallucinations and delusions, as well as disorganized thoughts and behavior [3-5].

Hallucinations — Hallucinations are defined as the perception of a sensory process in the absence of an external source. They can be auditory, visual, somatic, olfactory, or gustatory.

®

Positive symptoms●

Negative symptoms●

Cognitive impairment●

Mood and anxiety symptoms●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 2 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Delusions — Delusions, defined as a fixed (ie, resistant to change, even in the face of overwhelming contradictory evidence), false belief, are present in approximately 80 percent of people with schizophrenia [7]. Because insight into their illness may be impaired, people with schizophrenia often have delusional explanations for their hallucinations. Delusions are broadly categorized as bizarre or non-bizarre although the distinction is less important in the current diagnostic rubric.

The content of delusions can often be categorized as ideas of reference, grandiose, paranoid, nihilistic, and erotomanic.

Disorganization — Schizophrenia is a thought disorder. People with schizophrenia typically display some disorganization in behavior and/or thinking. Disorganized behaviors are directly observed while disorganized thoughts must be inferred from the speech of the person. Disjointed, disconnected speech patterns reflect a disruption in the organization of person’s thoughts. The most commonly observed forms of abnormal speech are tangentiality and circumstantiality, while more severe thought disorder includes derailment, neologisms, and word salad. The symptoms of disorganization are independent of the severity of hallucinations or [10].

Auditory hallucinations are the most common form of hallucination, with prevalence estimates between 40 and 80 percent in people with schizophrenia [6,7]. Although auditory hallucinations are frequently voices, they can also take the form of other sounds such as music, body noises, or machinery. Some people with schizophrenia describe the sounds as coming from inside their head, whereas others can point to a specific external location from which they emanate. Auditory hallucinations are often the manifestation of the illness most responsive to antipsychotic medication. Many people with schizophrenia report antipsychotics “turn down the volume” of these hallucinations such that they can cope with them better.

●

Visual hallucinations are often unformed, such as glowing orbs or flashes of color. However, some people with schizophrenia describe fully formed human figures, faces, or body parts.

●

Somatic hallucinations can include feelings of being touched, of sexual intercourse, or of pain.●

Olfactory and gustatory hallucinations have not been systematically studied, but occasional patients will report a strange taste or smell.

●

Bizarre delusions are clearly implausible, ie, they have no possibility of being true (eg, contradict the laws of physics). Their content is not understandable [8]. Basic concepts may be described in an unusual way, eg, how the person experiences time, space, the self, or causality [9]. An example of a bizarre delusion is the belief that aliens have cloned a perfect body for the patient, but he must find a way to take off his head so that his spirit can flow into the new body.

●

A non-bizarre delusion is one that while not true is understandable and has the possibility of being true. An example is that the IRS is after the patient for not paying taxes.

●

Ideas/delusions of reference are beliefs that random or neutral events are not random or neutral, but include the individual in a special way. Common ideas of reference include believing that occurrences on the television or radio (certain words said or songs played) are meant to deliver a special message to the individual.

●

Grandiose delusions form around the belief that the person has some special significance or power.●

Paranoid delusions are clinically important, because they may prevent the individual from cooperating with evaluation or treatment, and because they may increase the likelihood of problems, such as homelessness, as the person goes “off the grid.”

●

Nihilistic delusions are uncommon, bizarre beliefs that one is dead or one’s body is breaking down or that one does not exist.●

In erotomanic delusions, the person erroneously believes that he/she has a special relationship with someone. These delusions can lead to legal problems, such as restraining orders and trespass charges.

●

Tangential speech – The person gets increasingly further off the topic without appropriately answering a question.●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 3 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Negative symptoms — While positive symptoms represent an exaggeration of normal processes, negative symptoms are conceptualized as an absence or diminution of normal processes. Negative symptoms may be primary or secondary.

Primary, enduring negative symptoms represent a core feature of schizophrenia; they are also referred to as deficit symptoms. Examples of negative symptoms include decreased expressiveness, apathy, flat affect, and a lack of energy. Independent of the primary/secondary distinction, negative symptoms appear to cluster into two components: a diminished expression symptom cluster and an avolition-apathy cluster [11,12]. The recognition of the existence of these two clusters may facilitate the delineation of the pathophysiology of this illness component and lead to the development of novel therapeutics. A table lists negative symptoms (table 1).

Primary negative symptoms are very resistant to treatment [13-15] and closely related to functional outcome [16,17]. The severity of negative symptoms is independent of the reality distortion positive symptoms (ie, hallucinations and delusions) [18]. A person may simultaneously have deficit symptoms and be quite psychotic, or have deficit symptoms in the absence of positive symptoms.

Alternatively, negative symptoms may be secondary to other manifestations of the illness or its treatment. As examples, paranoia may lead to social isolation, and depression may lead to anergy. An unchanging facial expression may be due to extrapyramidal side effects of an antipsychotic medication.

Deficit schizophrenia — While not a recognized DSM-5 subtype of schizophrenia, people with schizophrenia who have prominent negative (or deficit) symptoms appear to represent a distinct subgroup [18]. People with deficit schizophrenia are less likely to have delusions with high emotional content (eg, jealous delusions), to have a depressive disorder, or to have a substance use disorder compared with nondeficit schizophrenia [17,19,20]. People categorized as deficit are least likely to show improvement and recovery over the course of the illness. (See "Schizophrenia in adults: Epidemiology and pathogenesis", section on 'Deficit schizophrenia'.)

Cognitive impairment — Areas of cognition that seem to be the most affected in schizophrenia are described below [21]. It is not known whether these areas reflect multiple unique impairments, or a generalized impairment that affects multiple areas of cognition [22,23].

These impairments are reflected in the performance on neuropsychological tests among people with schizophrenia. On average, the neuropsychological test performance of someone with schizophrenia is one to two standard deviations lower than the

Circumstantial speech – The person will eventually answer a question, but in a markedly roundabout manner.●

Derailment – The person suddenly switches topic without any logic or segue.●

Neologisms – The creation of new, idiosyncratic words.●

Word salad – Words are thrown together without any sensible meaning.●

Processing speed●

Attention●

Working memory●

Verbal learning and memory●

Visual learning and memory●

Reasoning/executive functioning●

Verbal comprehension●

Social cognition●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 4 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

performance of healthy controls [22,24]. If an individual tests within the normal range on any given neuropsychological battery, then his or her pre-morbid performance was very likely to have been above average. People with schizophrenia who appear to lack cognitive impairment, when matched to healthy controls on age, education, and intelligence quotient (IQ), may actually show a unique pattern of performance impairments in memory and processing speed [25,26].

Cognitive impairments usually precede the onset of positive symptoms [27]. Impairment in the performance of cognitive tasks in people with first-episode schizophrenia is usually of a similar magnitude as that seen in people with multiple episodes [28]. The same pattern of cognitive impairment is observed in the family members of people with schizophrenia, though the magnitude of impairment is less [29]. In a study of monozygotic twins discordant for the disorder, affected twins performed worse on tests of memory and vigilance than the unaffected siblings [30].

Although antipsychotic and anticholinergic medications can impair cognition [31,32], reports of memory disturbances in schizophrenia frequently predate the advent of pharmacologic treatment [33]. The same pattern of cognitive dysfunction in people with schizophrenia is seen in both treated groups and those who have never been exposed to antipsychotics [34].

Mood and anxiety symptoms — Mood and anxiety symptoms are common in schizophrenia; mood and anxiety disorders appear to occur at a higher rate than in the general population. The epidemiology, clinical manifestations, diagnosis, and treatment of mood and anxiety symptoms in schizophrenia are discussed separately. (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)

Stigma — In the course of assessment and ongoing clinical care, the clinician can be an important source of compassion and education for the patient and family. Along with treatment for symptoms and medication side effects, the patient may need help coping with disabilities, associated losses, and the stigma associated with the diagnosis of schizophrenia. The experience of stigmatizing attitudes towards people with schizophrenia is common [35] and may be internalized, leading to “self-stigma” [36]. Internalized stigma can be as damaging as the direct effects of the illness. In a five-month longitudinal study of 78 people with schizophrenia, internalized stigma was associated with poorer response to vocational rehabilitation [37]. A discriminant function analysis of 105 people with schizophrenia found that self-stigma was a predictor of decreased treatment adherence [38,39].

Associated physical manifestations — There are several physical manifestations associated with schizophrenia, including neurological disturbances, catatonia, and metabolic disturbances.

Neurological disturbances — Neurological “soft signs” involve subtle impairments of sensory integration, motor coordination, and sequencing [40]. Examples of neurological soft signs are right-left confusion, agraphesthesia (the inability to recognize letters or numbers traced on the skin, usually on the palm of the hand), and astereognosia (the inability to identify familiar objects by touch alone). These neurological soft signs are observed in schizophrenia, are relatively stable, and are largely unrelated to medication [40-43].

Research findings have linked certain symptom domains to neurological signs, ie, sensory integration problems have been correlated with deficit symptoms, disorganization, and cognitive impairment, while impaired sequencing of complex motor behaviors has been correlated with disorganization [42,43].

Most neurological disturbances readily observed in people with schizophrenia are likely medication-induced. Antipsychotic dopamine blockade can cause extrapyramidal symptoms (EPS), such as tremor and bradykinesia, acute dystonias, akathisia (a subjective sense of restlessness or actual restlessness), or tardive (meaning ‘late’) dyskinesia (which includes abnormal peri-oral and other movements). However, descriptions of movement disorders including signs of pseudoparkinsonism, choreiform movements, and myoclonic jerking are common in the descriptions of schizophrenia that predate the development of antipsychotics [34]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Tardive dyskinesia: Etiology and epidemiology" and "Pharmacotherapy for schizophrenia: Side effect management".)

Catatonia — Catatonia can present in schizophrenia as either extreme negativism, eg, motiveless motor resistance to instruction or attempts to move the person or mutism, or catatonic excitement, eg, excessive, purposeless motor activity.

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 5 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Catatonia is reviewed in more detail separately (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)

Metabolic disturbances — Schizophrenia is associated with diabetes, hyperlipidemia, and hypertension. Although many antipsychotic medications cause metabolic disturbances, including weight gain and diabetes, people with schizophrenia often have other risk factors for these conditions, including a sedentary lifestyle and smoking. The life expectancy of people with schizophrenia is reduced by more than a decade compared with the general population. This excess medical mortality is largely mediated by heart disease [44]. (See "Pharmacotherapy for schizophrenia: Side effect management".)

Schizophrenia, independent of treatment with antipsychotic medication, is associated with altered glucose homeostasis, indicating an increased risk of diabetes. A meta-analysis examined 16 case-control studies of glucose homeostasis in 731 antipsychotic- naive individuals with first-episode schizophrenia compared with 614 healthy controls [45]. Higher levels of fasting plasma glucose (Hedges g = 0.20; 95% CI 0.02-0.38) and fasting plasma insulin (0.41; 95% CI 0.09-0.72) were seen as well as lower glucose tolerance (0.61; 95% CI 0.16-1.05) and greater insulin resistance (0.35; 95% CI 0.14-0.55) in people with schizophrenia compared with controls. Hemoglobin A1c levels did not differ between the two groups.

There is also evidence from the pre-antipsychotic era and insulin coma treatments that schizophrenia itself is associated with insulin resistance [46].

COURSE — Although earlier descriptions of schizophrenia suggested that the course was quite poor, the course actually shows considerable heterogeneity. One of the first and most influential longitudinal studies of the course of schizophrenia described eight course types, which differ in several ways [47]:

Most people with schizophrenia in the study had an acute onset, intermittent symptoms, and later had no or only mild symptoms. Only about 20 percent had the stereotypical insidious onset, continuous symptoms, and poor outcome. In a re-examination of these data, participants were re-diagnosed with more stringent DSM-IV and ICD criteria, and the results among those retaining a schizophrenia diagnosis were largely unchanged from the original course observations [48].

Other influential longitudinal studies of schizophrenia demonstrate that the course of schizophrenia is not uniform and that there are subsets of individuals with fairly good outcome [49-51]. A 15- to 25-year follow-up of 644 participants with schizophrenia who participated in World Health Organization studies (including the International Pilot Study of Schizophrenia and the Determinants of Outcome of Severe Mental Disorders study) found that about half had favorable outcomes (minimal or no symptoms, employment, Global Assessment of Functioning (GAF) scores greater than 60) [51,52].

In general, people with the deficit form of schizophrenia seem to have a more consistently poor prognosis compared with their nondeficit peers [16,17].

Earlier in the illness, functional recovery is rarer. In a medication algorithm study, only about 14 percent of 118 people with a first episode of schizophrenia or schizoaffective disorder met recovery criteria for two or more years during the first five years of the illness [53]. Recovery in this study was defined as no more than mild psychotic symptoms, no more than moderate negative symptoms, adequate role function (student, employment, homemaker), attention to hygiene, and independence in daily chores.

Timely, intensive treatment can impact functional recovery early in the illness. As an example, a clinical trial randomized 34 community mental health centers in 21 US states to offer people with newly-diagnosed, nonaffective psychosis either standard care (181 patients) or a program of intensive treatment (computerized, algorithm-assisted medication management; family psychoeducation; resiliency-focused individual psychotherapy; and supported education/employment; 223 patients) [54]. After two years, people receiving the intensive intervention had greater improvement in quality of life, more involvement in school/work, and

Onset – Abrupt versus insidious●

Symptom presentation – Continuous versus intermittent●

Outcome – Poor versus non-poor●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 6 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

less psychopathology. Rates of hospitalization did not differ between groups.

The DSM-5 has several specifiers that can be applied to describe the course of illness after one year following the patient’s diagnosis [1]. (See 'Specifiers for schizophrenia in DSM-5' below.)

Remission of schizophrenia refers to a state in which the individual has no symptoms, or minimal symptoms that do not interfere with behavior, for a period of at least six months [55,56].

Over the past decade, consumer advocacy has drawn attention to the concept of recovery from schizophrenia. The model of recovery that has emerged differs from a strictly clinical model of recovery (eg, no or mild symptoms, restored functioning). The consumer-driven model is a blend of function, life-satisfaction, and independence. Despite scientific efforts to capture this outcome, there are no currently accepted scales to measure recovery [57].

ASSESSMENT — The differential diagnosis of psychosis, and the medical workup to identify/exclude psychoses secondary to medical conditions, are described separately. (See "Clinical manifestations, differential diagnosis, and initial management of psychosis in adults".)

The diagnosis of schizophrenia is often one of exclusion. No symptom or group of symptoms is pathognomonic for schizophrenia; however, there are specific hallucinations and delusions that are characteristic of the illness, known as “first-rank symptoms” [58] (table 2). Although upwards of 85 percent of people with schizophrenia endorse these symptoms, up to 25 percent of manic bipolar patients endorse first-rank symptoms in cross-sectional studies [7], and about 45 percent endorse these symptoms in longitudinal studies [59], which suggests that these symptoms are not specific to schizophrenia [59,60]. There are no laboratory or physical examination findings or other biomarkers that are useful in making the diagnosis.

The patient assessment is based on the diagnostic interview supplemented by collateral information. Family members or caregivers are often a good source of information about a patient’s clinical presentation outside the office or hospital. Medical records, especially from the initial presentation of the illness and most recent hospitalization, can give additional information.

Working with patients who are uncooperative, whether from paranoia or for other reasons, can be challenging. Even if a person denies hearing voices, it is sometimes observed that he or she seems to be responding to internal stimulation (by smiling inappropriately, looking in the direction from where they hear a voice, or seeming distracted during an interview). Although there are other reasons a person might act this way, and diagnosis should not be based solely on these observations, the behaviors of a person may provide useful information as to their ongoing internal experiences.

The severity of symptoms should be assessed in each domain affected by the illness, ie, psychosis/thought disorder, negative symptoms, cognitive impairment, mood/anxiety.

Assessment of someone with schizophrenia should include evaluations of health, including cholesterol, blood glucose, weight and BMI, prolactin, evaluation of motor disturbances, and a urine drug screen.

DIAGNOSIS — The diagnosis of schizophrenia requires the presence of “characteristic symptoms” of the disorder (delusions, hallucinations, disorganized speech or behavior, and/or negative symptoms) coupled with social and/or occupational dysfunction for at least six months in the absence of another diagnosis that would better account for the presentation.

DSM-5 diagnostic criteria for schizophrenia are described in more detail below [1].

A. Two or more of the characteristic symptoms below are present for a significant portion of time during a one-month period (or less if successfully treated):

●

1. Delusions•

2. Hallucinations•

3. Disorganized speech (eg, frequent derailment or incoherence)•

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 7 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Specifiers for schizophrenia in DSM-5 — The following course specifiers can be applied only after at least 1 year has elapsed since the initial onset of the disorder.

Specify if:

Specify if: with catatonia

Specify current severity: Each of the following symptoms may be rated for its highest severity in the last seven days. A five-point scale is used: from 0 (not present) to 4 (present and severe).

4. Grossly disorganized or catatonic behavior•

5. Negative symptoms, ie, affective flattening, alogia, or avolition•

B. For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset. When the onset is in childhood or adolescence: failure to achieve expected level of interpersonal, academic, or occupational achievement.

●

C. Continuous signs of the disturbance persist for at least six months. The six-month period must include at least one month of symptoms (or less if successfully treated) that meet Criterion A (ie, active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A that present in an attenuated form (eg, odd beliefs, unusual perceptual experiences).

●

D. Schizoaffective disorder and mood 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) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.

●

E. The disturbance is not due to the direct physiological effects of a substance (eg, a drug of abuse or medication) or a general medical condition.

●

F. If the patient has a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).

●

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●

Delusions●

Hallucinations●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 8 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Changes to the diagnostic criteria for schizophrenia from DSM-IV to DSM-5 included [1]:

Differential diagnosis — In the differential diagnosis of schizophrenia, the most common psychiatric disorders include schizophreniform disorder, schizoaffective disorder, bipolar disorder, and major depression with psychotic features, and substance-induced psychotic disorders. Characteristics of psychiatric disorders informing the differential diagnosis of schizophrenia are described below. An algorithm describes the differential diagnosis of delusions (algorithm 1).

Disorganized speech●

Abnormal psychomotor behavior●

Negative symptoms●

At least two of the five A-criteria symptoms must be present, and at least one must be delusions, hallucinations, or disorganized speech in DSM-5. One symptom was sufficient in certain circumstances in DSM-IV.

●

A specifier to document the presence of catatonia was added in DSM-5; the DSM-IV specifier, with prominent negative symptoms, was omitted from DSM-5. (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)

●

DSM-5 included new specifiers for rating the severity of A-criteria symptoms and for describing the patient’s course of illness.●

DSM-5 excluded the five subtypes of schizophrenia that were included in previous versions of the manual. There was little evidence that these subtypes were stable [61], clustered in families [62], or provided clinical utility beyond a description of the patient’s presentation at the time of diagnosis.

●

In schizophreniform disorder all the criteria for schizophrenia are met, but the total duration of the disorder is less than six months.

●

Schizoaffective disorder, bipolar disorder, and major depression with psychotic features all differ from schizophrenia in that there is a prominent mood component to the patient’s presentation. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis" and "Bipolar disorder in adults: Clinical features".)

●

Schizoaffective disorder is essentially schizophrenia with manic episodes or a significant depressive component. The validity and reliability of schizoaffective disorder remains unresolved [63].

●

The difference between mood disorders with psychosis and schizoaffective disorder is the timing of symptoms.●

In schizoaffective disorder, psychosis can and does occur in the absence of a mood episode.

In psychotic mood disorders the psychosis is only observed in the presence of a mood episode. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)

In substance-induced psychotic disorders the symptoms are a manifestation of intoxication or acute withdrawal and do not persist after the individual is sober.

●

Psychosis due to a general medical condition should be ruled out. Conditions, such as previous CVA or TBI, Wilson’s disease, porphyria, syphilis infection, and others, can present with psychotic symptoms.

●

Delusional disorder is present if the individual has a delusion, but criteria from schizophrenia have never been met. An exception to this is that the person may have olfactory or tactile hallucinations consistent with the delusion, but not auditory hallucinations.

●

Schizotypal personality disorder is a long-standing pattern of odd or eccentric beliefs and/or perceptual disturbances that do not rise to the level of delusions or hallucinations. People with this presentation may eventually transition to a psychotic disorder, but many do not [64].

●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 9 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-m…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

The diagnoses of schizophreniform disorder, schizophrenia, schizoaffective disorder, schizotypal personality disorder, and schizoid personality disorder are described collectively as ‘schizophrenia spectrum’ disorders. Although most researchers believe schizophrenia is likely a syndrome of distinct disease entities, the concept of schizophrenia spectrum disorders is useful for epidemiological research.

In many cases, repeated assessment longitudinally is necessary to definitively diagnose a patient presenting with a schizophrenia spectrum disorder.

ICD-10 diagnosis – The World Health Organization’s International Statistical Classification of Disease and Related Health Problems, 10 Revision (ICD-10) is primarily a coding source text and not a diagnostic manual, ie, there is minimal guidance on making a diagnosis [65]. Psychiatric diseases are listed with a short, prototypical description. The schizophrenia section describes first-rank and negative symptoms as characteristic and includes information on the variable course that can be seen in the illness.

ICD-10 includes the following subtypes of schizophrenia, many of which are similar to the subtypes found in DSM-IV, but no longer present in DSM-5:

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Schizoid personality disorder is a long-standing pattern of little interest in social relationships or intimacy. There is overlap with the negative symptoms seen in schizoid personality disorder and schizophrenia, but schizoid personality disorder does not present with psychosis.

●

Pervasive developmental disorders may present with psychosis or negative symptoms. An additional diagnosis of schizophrenia should only be made in a patient with autism if psychotic symptoms last more than one month.

●

th

Paranoid – Prominent delusions and hallucinations with little disturbance in affect or speech.●

Hebephrenic – Similar to the DSM-IV disorganized schizophrenia, “affective changes are prominent… mood is shallow and inappropriate… should normally only be diagnosed in adolescents and young adults.”

●

Catatonic. (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)●

Post-schizophrenic depression – Although listed with the subtypes of the illness, this diagnosis refers to a period of depressed mood occurring after the resolution of an acute psychotic exacerbation in someone with schizophrenia.

●

Residual – Described as a “chronic stage… in which there has been a clear progression from an early stage to a later stage characterized by long-term… negative symptoms.”

●

Simple – The picture of residual schizophrenia without having previously experienced any explicit psychosis.●

Undifferentiated – Schizophrenia that does not fit a subtype.●

th th

th th

Basics topics (see "Patient education: Schizophrenia (The Basics)")●

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 10 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American P sychiatric Association, Arlington, VA 2013.

2. Murray CJL, Lopez AD. The Global Burden of Disease, Harvard University Press, Cambridge, MA 1996. p.21.

3. Carpenter WT Jr, Strauss JS, Bartko JJ. The diagnosis and understanding of schizophrenia. Part I. Use of signs and symptoms for the identification of schizophrenic patients. Schizophr Bull 1974; :37.

4. Bartko JJ, Strauss JS, Carpenter WT Jr. The diagnosis and understanding of schizophrenia. Part II. Expanded perspectives for describing and comparing schizophrenic patients. Schizophr Bull 1974; :50.

5. Strauss JS, Carpenter WT Jr, Bartko JJ. The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 1974; :61.

6. Thomas P, Mathur P, Gottesman II, et al. Correlates of hallucinations in schizophrenia: A cross-cultural evaluation. Schizophr

Clinical manifestations of schizophrenia include positive and negative symptoms, cognitive impairment, and mood or anxiety symptoms. Positive symptoms include hallucinations, delusions, and disorganization. (See 'Positive symptoms' above.)

●

Hallucinations are defined as the perception of a sensory process in the absence of an external source. They can be auditory, visual, somatic, olfactory, or gustatory.

•

Delusions are defined as a fixed, false belief. They can be bizarre or non-bizarre. Their content can often be categorized as grandiose, paranoid, nihilistic, or erotomanic.

•

Disorganization can typically be seen in both behavior and speech. The most commonly observed forms of abnormal speech are tangentiality and circumstantiality, while more severe thought disorder includes derailment, neologisms, and word salad.

•

Primary, enduring negative symptoms represent a core feature of schizophrenia; they are also referred to as deficit symptoms. Examples of negative symptoms include a flat affect, poverty of speech, and a lack of interest or energy. A table lists other negative symptoms (table 1). Secondary negative symptoms can be caused by antipsychotic medications. (See 'Negative symptoms' above.)

●

Physical manifestations of schizophrenia include neurological “soft signs,” catatonia, and metabolic disturbances. Metabolic abnormalities and movement disorders can be caused by schizophrenia itself as well as by antipsychotic medications. (See 'Associated physical manifestations' above.)

●

The diagnosis of schizophrenia (table 3) requires the presence of two of the five characteristic symptoms below coupled with social and/or occupational dysfunction for at least six months, and the absence of another diagnosis that would better account for the presentation (such as drug use, certain medical conditions, or psychotic mood disorders). (See 'Diagnosis' above.)

●

Delusions•

Hallucinations•

Disorganized speech•

Disorganized or catatonic behavior•

Negative symptoms•

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 11 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Res 2007; 92:41.

7. Andreasen NC, Flaum M. Schizophrenia: the characteristic symptoms. Schizophr Bull 1991; 17:27.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Ame rican Psychiatric Association, Washington DC 2000.

9. Cermolacce M, Sass L, Parnas J. What is bizarre in bizarre delusions? A critical review. Schizophr Bull 2010; 36:667.

10. Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry 1982; 39:789.

11. Strauss GP, Horan WP, Kirkpatrick B, et al. Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome. J Psychiatr Res 2013; 47:783.

12. Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull 2006; 32:238.

13. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71.

14. Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32:214.

15. Kirkpatrick B, Kopelowicz A, Buchanan RW, Carpenter WT Jr. Assessing the efficacy of treatments for the deficit syndrome of schizophrenia. Neuropsychopharmacology 2000; 22:303.

16. Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of recovery in deficit syndrome schizophrenia: a 20-year multi- follow-up longitudinal study. Schizophr Bull 2010; 36:788.

17. Fenton WS, McGlashan TH. Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia. Am J Psychiatry 1994; 151:351.

18. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 2001; 58:165.

19. Kirkpatrick B, Amador XF, Flaum M, et al. The deficit syndrome in the DSM-IV Field Trial: I. Alcohol and other drug abuse. Schizophr Res 1996; 20:69.

20. Kirkpatrick B, Buchanan RW, Breier A, Carpenter WT Jr. Depressive symptoms and the deficit syndrome of schizophrenia. J Nerv Ment Dis 1994; 182:452.

21. Nuechterlein KH, Barch DM, Gold JM, et al. Identification of separable cognitive factors in schizophrenia. Schizophr Res 2004; 72:29.

22. Gold JM, Hahn B, Strauss GP, Waltz JA. Turning it upside down: areas of preserved cognitive function in schizophrenia. Neuropsychol Rev 2009; 19:294.

23. Dickinson D, Iannone VN, Wilk CM, Gold JM. General and specific cognitive deficits in schizophrenia. Biol Psychiatry 2004; 55:826.

24. Kraus MS, Keefe RS. Cognition as an outcome measure in schizophrenia. Br J Psychiatry Suppl 2007; 50:s46.

25. Wilk CM, Gold JM, McMahon RP, et al. No, it is not possible to be schizophrenic yet neuropsychologically normal. Neuropsychology 2005; 19:778.

26. Palmer BW, Heaton RK, Paulsen JS, et al. Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 1997; 11:437.

27. Bora E, Murray RM. Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: do the cognitive deficits progress over, or after, the onset of psychosis? Schizophr Bull 2014; 40:744.

28. Bilder RM, Goldman RS, Robinson D, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000; 157:549.

29. Snitz BE, Macdonald AW 3rd, Carter CS. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull 2006; 32:179.

30. Goldberg TE, Ragland JD, Torrey EF, et al. Neuropsychological assessment of monozygotic twins discordant for

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 12 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

schizophrenia. Arch Gen Psychiatry 1990; 47:1066.

31. Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, on cognition and mood. Schizophr Res 2006; 85:222.

32. Moore AR, O'Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging 1999; 15:15.

33. Kraepelin E. Dementia Praecox and Paraphrenia, Krieger, New York 1971.

34. Torrey EF. Studies of individuals with schizophrenia never treated with antipsychotic medications: a review. Schizophr Res 2002; 58:101.

35. Dickerson FB, Sommerville J, Origoni AE, et al. Experiences of stigma among outpatients with schizophrenia. Schizophr Bull 2002; 28:143.

36. Drapalski AL, Lucksted A, Perrin PB, et al. A model of internalized stigma and its effects on people with mental illness. Psychiatr Serv 2013; 64:264.

37. Yanos PT, Lysaker PH, Roe D. Internalized stigma as a barrier to improvement in vocational functioning among people with schizophrenia-spectrum disorders. Psychiatry Res 2010; 178:211.

38. Tsang HW, Fung KM, Chung RC. Self-stigma and stages of change as predictors of treatment adherence of individuals with schizophrenia. Psychiatry Res 2010; 180:10.

39. Yanos PT, Lucksted A, Drapalski AL, et al. Interventions targeting mental health self-stigma: A review and comparison. Psychiatr Rehabil J 2015; 38:171.

40. Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry 1988; 145:11.

41. Bombin I, Arango C, Buchanan RW. Significance and meaning of neurological signs in schizophrenia: two decades later. Schizophr Bull 2005; 31:962.

42. Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and the heterogeneity of schizophrenia. Am J Psychiatry 2000; 157:560.

43. Arango C, Bartko JJ, Gold JM, Buchanan RW. Prediction of neuropsychological performance by neurological signs in schizophrenia. Am J Psychiatry 1999; 156:1349.

44. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J 2005; 150:1115.

45. Pillinger T, Beck K, Gobjila C, et al. Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry 2017; 74:261.

46. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry Suppl 2004; 47:S64.

47. Blueler M. The Schizophrenic Disorders: Long-Term Patient and Family Studies, Yale University Press, London 1978.

48. Modestin J, Huber A, Satirli E, et al. Long-term course of schizophrenic illness: Bleuler's study reconsidered. Am J Psychiatry 2003; 160:2202.

49. Harding CM, Brooks GW, Ashikaga T, et al. The Vermont longitudinal study of persons with severe mental illness, I: Methodology, study sample, and overall status 32 years later. Am J Psychiatry 1987; 144:718.

50. Harding CM, Brooks GW, Ashikaga T, et al. The Vermont longitudinal study of persons with severe mental illness, II: Long- term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia. Am J Psychiatry 1987; 144:727.

51. Recovery from Schizophrenia: An International Perspective; A Report from the WHO Collaborative Project, The International Study of Schizophrenia, Hopper K, Harrison G, Janca A, Sartorius N (Eds), Oxford University Press, New York 2007.

52. Harrison G, Hopper K, Craig T, et al. Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 2001; 178:506.

53. Robinson DG, Woerner MG, McMeniman M, et al. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 2004; 161:473.

54. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 13 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Year Outcomes From the NIMH RAISE Early Treatment Program. Am J Psychiatry 2016; 173:362.

55. Fischer BA, Carpenter WT. Remission. In: Clinical Handbook of Schizophrenia, Mueser KT, Jeste DV (Eds), Guilford Publica tions, New York 2008. p.559.

56. Andreasen NC, Carpenter WT Jr, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162:441.

57. Bellack AS. Scientific and consumer models of recovery in schizophrenia: concordance, contrasts, and implications. Schizophr Bull 2006; 32:432.

58. Schneider K. Clinical Psychopathology, Grune & Stratton, New York 1959.

59. Rosen C, Grossman LS, Harrow M, et al. Diagnostic and prognostic significance of Schneiderian first-rank symptoms: a 20- year longitudinal study of schizophrenia and bipolar disorder. Compr Psychiatry 2011; 52:126.

60. Thorup A, Petersen L, Jeppesen P, Nordentoft M. Frequency and predictive values of first rank symptoms at baseline among 362 young adult patients with first-episode schizophrenia Results from the Danish OPUS study. Schizophr Res 2007; 97:60.

61. Kendler KS, Gruenberg AM, Tsuang MT. Subtype stability in schizophrenia. Am J Psychiatry 1985; 142:827.

62. Kendler KS, Gruenberg AM, Tsuang MT. A family study of the subtypes of schizophrenia. Am J Psychiatry 1988; 145:57.

63. Malaspina D, Owen MJ, Heckers S, et al. Schizoaffective Disorder in the DSM-5. Schizophr Res 2013; 150:21.

64. Debbané M, Eliez S, Badoud D, et al. Developing psychosis and its risk states through the lens of schizotypy. Schizophr Bull 2015; 41 Suppl 2:S396.

65. World Health Organization. Schizophrenia, schizotypal and delusional disorders. International Statistical Classification of Dis ease and Related Health Problems. Tenth Revision. Version:2015. http://apps.who.int/classifications/icd10/browse/2015/en#/ F20-F29.

Topic 6962 Version 25.0

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 14 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

GRAPHICS

Negative symptoms in schizophrenia

Negative symptom cluster

Negative symptom As manifested by:

Diminished expression Affective flattening Unchanging facial expression

Little spontaneous movement

Little use of expressive gestures

Poor eye contact

Affective non-responsivity

Lack of vocal inflections

Alogia Poverty of speech

Thought blocking

Increased latency of response

Avolition-apathy Apathy Poor grooming and hygiene

Failure of appropriate role responsibilities

Anergy

Asociality/anhedonia Failure to engage with peers socially

No interest in stimulating activities

Little interest in sex

Little to no intimacy with others

Modified with permission from: Andreasen NC. Negative symptoms in schizophrenia: Definition and reliability. Arch Gen Psychiatry 1982; 39:784. Copyright © 1982 American Medical Association. All rights reserved.

Graphic 81542 Version 13.0

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 15 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

First-rank symptoms in schizophrenia

1. Audible thoughts - hearing one's thoughts spoken aloud

2. Somatic passivity - the feeling of being touched or strange unexplained sexual sensations

3. Thought insertion - the feeling an external force is putting thoughts into one's mind

4. Thought withdrawal - thoughts are withdrawn

5. Thought broadcasting - the feeling people can read one's mind

6. Made feelings - the feeling an external force is making you experience something

7. Made impulses - the feeling an external force is making you want something

8. Made volition - the feeling an external force is making you act a certain way

9. Voices arguing/discussing (often referring to the patient as "he" or "she")

10. Voices commenting - voices narrate one's actions as if giving a running commentary

11. Delusional percepts - a physical sensation (such as seeing or feeling something) that is interpreted as a very special event has happened and something important is realized

Graphic 76914 Version 1.0

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 16 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Differential diagnosis of delusions

Adapted from: American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th Ed: DSM-5. Washington, D.C.:

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 17 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

American Psychiatric Association, 2013.

Graphic 100456 Version 2.0

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 18 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

DSM-5 diagnostic criteria for schizophrenia

A. Two (or more) of the following, each present for a significant portion of time during a one-month period (or less if successfully treated). At least one of these must be (1), (2), or (3):

1) Delusions.

2) Hallucinations.

3) Disorganized speech (eg, frequent derailment or incoherence).

4) Grossly disorganized or catatonic behavior.

5) Negative symptoms (ie, diminished emotional expression or avolition).

B. For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational functioning).

C. Continuous signs of the disturbance persist for at least 6 months. This six-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (ie, active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or by two or more symptoms listed in Criterion A present in an attenuated form (eg, odd beliefs, unusual perceptual experiences).

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

E. The disturbance is not attributable to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or another medical condition.

F. 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 of schizophrenia, are also present for at least one month (or less if successfully treated).

Specify if:

The following course specifiers are only to be used after a 1-year duration of the disorder and if they are not in contradiction to the diagnostic course criteria.

First episode, currently in acute episode: First manifestation of the disorder meeting the defining diagnostic symptom and time criteria. An acute episode is a time period in which the symptom criteria are fulfilled.

First episode, currently in partial remission: Partial remission is a period of time during which an improvement after a previous episode is maintained and in which the defining criteria of the disorder are only partially fulfilled.

First episode, currently in full remission: Full remission is a period of time after a previous episode during which no disorder-specific symptoms are present.

Multiple episodes, currently in acute episode: Multiple episodes may be determined after a minimum of two episodes (ie, after a first episode, a remission and a minimum of one relapse).

Multiple episodes, currently in partial remission.

Multiple episodes, currently in full remission.

Continuous: Symptoms fulfilling the diagnostic symptom criteria of the disorder are remaining for the majority of the illness course, with subthreshold symptom periods being very brief relative to the overall course.

Unspecified.

Specify if:

With catatonia

Specify current severity:

Severity is rated by a quantitative assessment of the primary symptoms of psychosis, including delusions, hallucinations, disorganized speech, abnormal psychomotor behavior, and negative symptoms. Each of these symptoms may be rated for its current severity (most severe in the last seven days) on a 5-point scale ranging from 0 (not present) to 4 (present and severe).

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 19 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

NOTE: Diagnosis of schizophrenia can be made without using this severity specifier.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright © 2013). American Psychiatric Association. All Rights Reserved.

Graphic 54426 Version 12.0

3/24/18, 10*43 AMSchizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis - UpToDate

Page 20 of 20https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-…search_result&selectedTitle=1~150&usage_type=default&display_rank=1

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 1 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Official reprint from UpToDate www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment

Authors: T. Scott Stroup, MD, MPH, Stephen Marder, MD Section Editor: Murray B Stein, MD, MPH Deputy Editor: Richard Hermann, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2018. | This topic last updated: May 23, 2017.

INTRODUCTION — Schizophrenia is a psychiatric disorder involving chronic or recurrent psychosis. It is commonly associated with impairments in social and occupational functioning [1]. It is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [2].

Antipsychotic medications are first-line medication treatment for schizophrenia. They have been shown in clinical trials to be effective in treating symptoms and behaviors associated with the disorder. Antipsychotic medications have significant side effects; assessment and management of these adverse effects are an important part of treatment. Evidence-based psychosocial interventions in conjunction with pharmacotherapy can help patients achieve recovery.

This topic addresses the pharmacotherapy of schizophrenia in acute and maintenance phase treatment. Discussed separately are the use of long-acting antipsychotics and management of side effects during pharmacotherapy for schizophrenia; the epidemiology, pathogenesis, clinical manifestations, and diagnosis of schizophrenia; psychosocial interventions for schizophrenia; and common comorbid presentations of schizophrenia. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Pharmacotherapy for schizophrenia: Side effect management" and "Schizophrenia in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Psychosocial interventions for schizophrenia" and "Anxiety in schizophrenia" and "Depression in schizophrenia" and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis" and "Guidelines for prescribing clozapine in schizophrenia".)

ACUTE PHASE SYMPTOMS — The focus of treatment in schizophrenia changes as individuals enter different phases of the illness. An acute phase occurs when patients with a prior history of schizophrenia have a psychotic relapse, or during the first episode of psychosis. At this time, the focus is on reducing the severity of psychotic thoughts and behaviors. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Clinical manifestations'.)

Pre-treatment assessment — When feasible, patients who are started on an antipsychotic medication should receive a baseline physical examination with a neurological exam. Particular attention should be focused on factors that may be affected adversely by antipsychotic medication: (See "Pharmacotherapy for schizophrenia: Side effect management".)

When feasible, laboratory evaluations should be initiated before starting an antipsychotic. With the exception of patients treated with clozapine, the antipsychotic can usually be started before the results of laboratory tests are available.

Drug efficacy — Antipsychotic drugs are first-line treatment for schizophrenia.

Positive symptoms — Randomized trials have shown that antipsychotics reduce positive symptoms of schizophrenia, such as hallucinations, delusions, and suspiciousness, compared to placebo [3]. Antipsychotics eliminate or reduce these symptoms to a tolerable level in about 70 percent of patients with schizophrenia [4]. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Positive symptoms'.)

With the exception of clozapine, careful systematic reviews and meta-analyses have not found convincing evidence that any of the antipsychotics are more effective than others for positive symptoms in acute schizophrenia [5]. Clozapine is more effective for patients who do not respond fully to other antipsychotics, but due to increased risk of agranulocytosis is reserved for those who do not respond well to or cannot tolerate other antipsychotics. (See 'Treatment-resistant schizophrenia' below and "Evaluation and management of treatment-resistant schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)

Negative symptoms — Negative symptoms of schizophrenia, such as diminished emotional expression and lack of motivation, have proven particularly difficult to treat.

®

Body mass index (BMI)●

Waist circumference●

Heart rate●

Blood pressure●

Signs of a movement disorder:●

Extrapyramidal symptoms (EPS): akathisia, parkinsonism, dystonias•

Tardive dyskinesia: abnormal movements of the face, peri-oral areas, tongue, extremities•

CBC, electrolytes, fasting glucose, lipid profile, liver, renal and thyroid function tests●

White blood cell (WBC) count with differential for patients treated with clozapine●

ECG for patients with a cardiac history or those being treated with antipsychotics that may prolong the QT interval such as clozapine, thioridazine, iloperidone, ziprasidone.

●

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 2 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Most classes of medications tested have not shown clinically meaningful effects on negative symptoms [6], but cariprazine has shown positive effects in a randomized clinical trial [7]. (see "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Negative symptoms'):

Antipsychotic selection — There are important differences among the antipsychotics in areas other than efficacy, including side effects and available formulations (table 1 and table 2). As a result, the selection of an antipsychotic is often based on these considerations. The selection may vary for select populations including individuals in a first psychotic episode, individuals who are only partial responders to antipsychotics, patients who are agitated, and individuals who are sensitive to particular side effects such as weight gain, EPS, or sedation. (See 'Poor response to initial treatment' below and 'First-episode psychosis' below and 'Acutely agitated' below and "Pharmacotherapy for schizophrenia: Side effect management".)

Antipsychotic medications are commonly grouped into two categories, with “second-generation” (or “atypical”) applied to clozapine and all antipsychotics first marketed after clozapine was approved in 1989, and “first-generation” applied to antipsychotics marketed previously. Recent clinical research, however, has strongly suggested that the distinction between first- and second-generation antipsychotics has questionable validity and is confusing [5]. The pharmacologic properties, therapeutic effects, and adverse effects are not distinct between and are heterogeneous within the groups. Nevertheless, the terms first- and second-generation antipsychotic are still in widespread use. A valid distinction is that the newer (second-generation) antipsychotics tend to cause fewer extrapyramidal side effects than the older ones, particularly at the high end of approved dosage ranges.

Administration — The dose of most antipsychotic drugs should be titrated from an initial dose to the therapeutic range as quickly as tolerated. Quetiapine, clozapine, and iloperidone need to be increased gradually before reaching a therapeutic dose. The timeframe for titration differs for each drug and also depends on the individual patient’s tolerance of the drug’s tendency to cause sedation and hypotension. In most cases, patients can reach a therapeutic level in five or six days with quetiapine and iloperidone, and two to three weeks with clozapine. Suggested dosing and side effect profiles for each antipsychotic drug are shown in tables (table 1 and table 2).

Because identifying the appropriate dose range can be difficult in the pre-marketing phases of drug development, the antipsychotic doses listed (table 2) deviate somewhat from those approved by the US Food and Drug Administration, reflecting more recent research findings or clinical experience. Examples include:

Resolution of psychotic symptoms generally occurs over several days and may take as much as four to six weeks. Clinicians should avoid the impulse to change the medication or dose prematurely. Once the dose reaches the therapeutic range, the decision to increase the dose should follow at least several days of treatment during which the individual shows little or no improvement. Higher dosing should be accompanied by careful observation of the patient for side effects. If patients fail to show improvement on doses above the usual therapeutic range, the dose should be reduced.

As an example, a patient treated with risperidone can be started on 2 mg administered as a single daily dose or 1 mg twice a day. If this dose is well tolerated (ie, minimal sedation, hypotension, or akathisia) the dose can be increased to 3 mg on the second day and 4 mg on the third day. Since 4 mg is in the therapeutic range for most patients, the clinician may then choose to continue this dose for an additional two weeks before considering an increase. If the patient shows only minimal or no improvement, the dose can be increased up to 8 mg daily with careful monitoring for clinical response and side effects. Doses of risperidone above 8 mg daily are associated with substantial risk of EPS.

Because of dose-related toxicities, antipsychotics should be used at the lowest dose that is effective for an individual. The toxicities of antipsychotic drugs typically increase with higher doses while therapeutic effects can reach a maximum. At high doses, the adverse effects of an antipsychotic may surpass the marginal benefit of dosage increases. As a result, increasing the dose of antipsychotic for a patient who is already experiencing significant EPS is unlikely to result in additional symptom reduction [8-10].

Course of response — When a patient with schizophrenia is administered an antipsychotic medication, the initial response is often a side effect such as sedation, restlessness, or postural hypotension. It is important to explain this to patients, or they may conclude that the medication is ineffective or worsening their condition. Most patients who will improve on an antipsychotic show the most rapid improvement in the first two weeks [11]. Although the rate of improvement may slow after two weeks, patients will often continue to improve during subsequent weeks and months.

During the first weeks of treatment, patients may first experience a decrease in the severity of symptoms. As a result, the impact of symptoms on patient behavior may be reduced [12]. Hallucinations or delusions may be less frightening or the patient may find that they can distract themselves by focusing their attention elsewhere [13]. Delusions that are based on misinterpretations from an earlier time may linger, whereas the tendency to misinterpret new information may be reduced.

POOR RESPONSE TO INITIAL TREATMENT — Patients should be observed on a stable dose of an antipsychotic for two to six weeks before concluding the drug is ineffective. The duration of the trial will vary depending on a number of factors:

A 2017 clinical trial found cariprazine, a newer antipsychotic, to be efficacious in reducing negative symptoms compared with risperidone [7]. The trial randomly assigned 461 patients with stable schizophrenia and predominant negative symptoms to receive cariprazine or risperidone. After 26 weeks, patients assigned to cariprazine showed a greater mean reduction in negative symptoms on the Positive and Negative Syndrome Scale compared with risperidone-treated patients, with a small to medium effect size. Cariprazine did not have a differential effect on positive symptoms, depression, or EPS, but improved social functioning compared with risperidone.

●

A 2015 meta-analysis studied the efficacy of many classes of medications for negative symptoms in 12,318 patients with schizophrenia in 168 randomized trials [6]. Small statistically significant reductions in negative symptoms were found for second-generation antipsychotics, antidepressants, glutamatergic agents, and combinations of these medications, but not for first-generation antipsychotics and brain stimulation. None of the beneficial effects for any of the medication strategies were considered to be of a clinically significant magnitude. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Negative symptoms'.)

●

Haloperidol is effective and most useful at doses drastically below the FDA-specified maximum of 100 mg/day. Optimal haloperidol dosages are usually below 10 mg/day and almost always below 20 mg/day.

●

Optimal dosages of risperidone are lower than the approved 16 mg/day; typically, a maximum dose for risperidone is 6 to 8 mg/day.●

Although patients improve most rapidly during the first two weeks, they may continue to improve for several weeks or even months on a stable dose [11].●

However, recent evidence suggests that if patients show only a minimal response to an antipsychotic drug during the first two weeks, it is unlikely that the individual will have a robust response [14]. The 2009 Schizophrenia PORT recommends that trials last for two to six weeks. This timeframe will be slightly longer for antipsychotics such as iloperidone and quetiapine, which require slow titration.

●

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 3 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Dose adjustments — In cases of nonresponse or partial response, the antipsychotic dose can be gradually increased toward the high end of the recommended range (table 2).

Most careful studies of doses above the recommended range have not found higher doses to be more effective than the maximal recommended dose [15,16]. If used, trials of higher doses should be time limited, with reassessment planned within three months. Unless clear evidence of improvement is seen, high doses should not be continued [17].

A dose reduction can be helpful in cases where side effects, such as akathisia, parkinsonism, sedation, or insomnia have obscured the benefit of a higher antipsychotic dose, or have been mistaken for signs of ineffective treatment, such as agitation or negative symptoms.

Changing to another antipsychotic — Switching antipsychotics can be helpful when a poor response is related to side effects. As an example, in the large US effectiveness study of antipsychotic treatment for schizophrenia, the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE), patients who gained weight during the first phase of antipsychotic treatment frequently lost weight when they were changed to ziprasidone, an antipsychotic that is not associated with weight gain [18].

Switching antipsychotics is less clearly beneficial when the initial medication lacked effectiveness. Most studies have shown that poor responders to one antipsychotic are likely to be poor responders to another antipsychotic except when the second agent is clozapine. (See 'Treatment-resistant schizophrenia' below.)

As an example, an analysis of patients who were on olanzapine, quetiapine, or risperidone prior to the CATIE trial showed that the patients on olanzapine or risperidone who were randomly assigned to continue the same antipsychotic had better outcomes than patients who were randomly assigned to change antipsychotics [19].

Two basic strategies for changing antipsychotics are [20,21]:

Discontinuation of antipsychotic medications is generally well tolerated, except for clozapine, for which both cholinergic rebound and withdrawal-emergent movement disorders have been reported [22-24]. A slow taper of clozapine over one to two weeks is recommended. Chlorpromazine and thioridazine can also cause cholinergic rebound and should be reduced over a week or more.

Adding a second antipsychotic — Clinicians often add a second antipsychotic when patients have a suboptimal response to a single drug. Little empirical evidence supports this practice [25]. Although some randomized trials indicated that augmentation of clozapine with another antipsychotic may have some benefit, a meta-analysis of this practice found the supporting evidence to be weak [26].

TREATMENT-RESISTANT SCHIZOPHRENIA — Patients with schizophrenia who respond inadequately to an initial antipsychotic, dose adjustments, or a change in antipsychotics are classified as having treatment-resistant schizophrenia. The efficacy of interventions for treatment-resistant schizophrenia, including clozapine, is discussed separately. Guidelines for clozapine prescribing, dosing, monitoring, and side-effect management are described separately. (See "Evaluation and management of treatment- resistant schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)

SPECIFIC SUBGROUPS

Persistent suicidality — Clozapine has been shown in randomized trials to reduce suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide [27]. A patient with schizophrenia who has persistent suicidal ideation warranting clinician concern may benefit from a trial of clozapine. Guidelines for clozapine prescribing, dosing, monitoring, and side-effect management are described separately. Management of suicidal patients is described separately. (See "Guidelines for prescribing clozapine in schizophrenia" and "Suicidal ideation and behavior in adults".)

Acutely agitated — Clinical management of the acutely agitated patient with schizophrenia is a common objective on inpatient units and other settings. Agitation can be defined as a state characterized by motor restlessness, excitement, and mental tension.

Treatment of agitation in patients with schizophrenia should be guided by the cause, which can include extrapyramidal symptoms (EPS), substance use, or psychosis:

Although antipsychotic medications can take days to weeks before having a robust antipsychotic effect, they generally have a calming effect within minutes for agitated patients. The route of administration influences time to onset, as described below (table 3). (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

A standard cross-titration for a stable patient: Simultaneous taper of the current medication with titration of the replacement drug in three to four steps over several days to several weeks.

●

For patients at higher risk of relapse, the current medication is maintained at its full dose as the new medication is increased. Once the second drug has reached its target dose, the first medication may be gradually decreased and discontinued. In most cases this change can be managed in one to two weeks.

●

Extrapyramidal symptoms — Akathisia can be difficult to distinguish from psychotic agitation when patients are unable to describe the experience of restlessness [28]. Akathisia can be treated with a benzodiazepine; eg, lorazepam can be started at 0.5 mg orally twice daily and incrementally increased to a maximum of 6 to 10 mg/day.

●

Substance use — Up to half of individuals with schizophrenia have a comorbid substance use disorder [29]. Use of stimulants such as phencyclidine (PCP), methamphetamine, and cocaine can cause agitation, as can withdrawal from alcohol or benzodiazepines. Agitation from substance use or withdrawal can be diagnosed by a history, physical exam, and toxicology. (See 'Comorbid disorders' below and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)

●

Psychosis — Psychotic symptoms of schizophrenia, such as frightening delusions, suspiciousness, and command hallucinations can cause patients to become agitated. The agitation associated with psychosis can be treated with an antipsychotic or an antipsychotic combined with a benzodiazepine. The selection of a drug and the route of administration depend on a number of considerations including the urgency of calming the patient and the cooperativeness of the patient [30]. As noted below, the choice of an antipsychotic depends on the formulation selected. It is important to note that the treatment goal is to induce a calmer state, which can often be accomplished without inducing sedation.

●

Standard oral formulations: Although many clinicians tend to favor sedating antipsychotics for agitated patients, non-sedating agents can also be effective for reducing agitation. Risperidone 1 to 2 mg or olanzapine 5 to 10 mg will usually be effective in these circumstances.

●

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 4 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Although repeat administration of an oral or intramuscular antipsychotic is common when the prior dose does not sufficiently reduce agitation, the overall antipsychotic dose should be limited, because these medications can cause significant side effects such as hypotension, EPS, and sedation, particularly at high doses over a brief period of time [11]. Maximum antipsychotic doses are shown in a table (table 3).

To limit the amount of antipsychotic used, most physicians either start with a combination of an antipsychotic and benzodiazepine or use a benzodiazepine when patients fail to respond to one or two doses of an antipsychotic for agitation. Lorazepam can be administered as 1 to 2 mg orally or 0.5 to 1 mg intramuscularly for calming.

First-episode psychosis — Patients in a first psychotic episode tend to have higher response rates than patients who have experienced multiple psychotic episodes. These individuals also respond to lower antipsychotic doses [3]. At the same time, younger patients and first episode patients have a greater vulnerability to side effects such as weight gain and extrapyramidal side effects (EPS) [31]. Since many first episode patients are also reluctant to take an antipsychotic, it is important to minimize adverse effects.

The Schizophrenia Patient Outcomes Research Team (PORT) recommended treating first episodes with antipsychotics other than clozapine or olanzapine. Both of these medications are associated with more weight gain, insulin resistance and dyslipidemia than other antipsychotics [3]. In addition, clozapine can cause agranulocytosis.

The Schizophrenia PORT recommended that first-episode patients receive antipsychotic doses in the lower half of the recommended dose range [3]. As examples, a first- episode patient would be treated with 1 to 3 mg of risperidone or 10 mg of aripiprazole daily. An exception to this recommendation should be made for quetiapine, which may require titration to 500 to 600 mg daily.

MAINTENANCE PHASE — Patients with schizophrenia who have recovered from an acute psychotic episode will usually reach a stable or maintenance phase in which psychotic symptoms are reasonably well controlled. The goal of maintenance antipsychotic treatment of schizophrenia is to minimize symptoms and functional impairments, avoid relapses, and promote recovery that allows self-determination, full integration into society, and pursuit of personal goals.

Efficacy of antipsychotic medication — For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely, even for patients who have achieved remission from a first psychotic episode. This suggestion is in accordance with the recommendation of the Schizophrenia PORT [3]. The lowest effective dose that achieves therapeutic goals should be used. Patients should participate in the clinical decision-making regarding the duration of antipsychotic drug treatment.

Multiple randomized trials have found that maintenance antipsychotic medication reduces the risk of relapse over a period of up to two years. A meta-analysis of 6493 patients with schizophrenia in 65 randomized trials of 7 to 12 months duration found that patients who continued on an antipsychotic experienced a lower relapse rate compared to patients withdrawn from an antipsychotic and receiving placebo (27 versus 64 percent; number needed to treat to benefit = 3, 95% CI 2–3) [32]. Other studies of up to two years have found similar results [33].

A seven-year follow-up assessment of patients randomly assigned to either a dose reduction strategy or to maintenance antipsychotic treatment found results that conflict with the studies of up to two years. Two reports that follow describe an intervention and follow-up assessment of patients who experienced a first episode of psychosis and subsequently met criteria for remission prior to enrollment in the trial [34,35].

More studies of longer term outcomes of maintenance treatment versus dose reduction are needed before we would suggest an approach other than indefinite continuation of maintenance treatment for patients with schizophrenia following an acute episode of psychosis.

As these trials demonstrate, some people with schizophrenia do well without continuous antipsychotic treatment; however, they are not identifiable prospectively [36].

Other considerations regarding selection of antipsychotic medication for maintenance treatment mirror those for pharmacotherapy during the acute phase. (See 'Drug efficacy' above.)

Medication adherence — Long-acting injectable antipsychotics may be useful for patients with schizophrenia who experience frequent relapses due to non-adherence to antipsychotic medications. They also may be helpful for patients who will not take oral antipsychotics regularly. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)

Oral rapidly dissolving formulations: Oral rapidly dissolving formulations are available for risperidone, olanzapine, asenapine, and aripiprazole. These formulations are helpful when a patient is willing to take a pill by mouth, but either cannot or does not swallow it. Dosing for these formulations is the same as for standard oral formulations, eg, risperidone 1 to 2 mg or olanzapine 5 to 10 mg.

●

Short-acting intramuscular (IM) injectable formulations (eg, haloperidol, olanzapine, aripiprazole, and ziprasidone): Olanzapine 5 or 10 mg administered intramuscularly is a good choice under most circumstances. IM haloperidol is effective but should be given with benztropine or diphenhydramine to reduce the risk of severe EPS including dystonias.

●

A combination of haloperidol 5 mg, lorazepam 2 mg, and benztropine 1 mg given intramuscularly can be effective to treat severe agitation in schizophrenia.•

We advise against the use of IM chlorpromazine, which can induce severe postural hypotension.•

Akathisia from any IM antipsychotic can contribute to agitation.•

Injectable IM antipsychotics have two potential advantages over oral antipsychotics. First, they can be administered safely to uncooperative individuals. Second, patients reach an effective plasma concentration sooner than with oral formulations. For example, patients may experience a calming effect within 10 to 30 minutes following IM administration. Calming effects may take 30 to 60 minutes following oral administration.

•

The initial trial randomly assigned 128 patients to continue maintenance treatment or to a dose reduction strategy [34]. After two years, patients assigned to the dose reduction strategy had a higher rate of relapse, without offsetting advantages, compared to patients continuing on maintenance treatment.

●

A subsequent assessment at seven years follow-up included 103 of the 128 patients (81 percent) who participated in the trial [35]. Patients who had originally been assigned to the dose reduction strategy experienced a higher rate of recovery (ie, symptomatic and functional remission) compared to patients originally assigned to maintenance treatment.

●

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 5 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Other strategies to promote better adherence to antipsychotics include simplifying medication regimens (eg, fewer medications, fewer pills, fewer daily doses) and active engagement of patients in treatment planning (ie, shared decision making).

Cognitive impairment — Improving cognitive impairment has increasingly become an objective of treatment for schizophrenia. Preliminary studies suggest that antipsychotic medication may improve cognition when received early in the course of schizophrenia [37,38]. Studies of patients with chronic schizophrenia have generally found less improvement in cognition during antipsychotic treatment [38-41]. Trials of other medications (including n-methyl-d-aspartate (NMDA) glutamatergic receptor agonists, glycine, D-serine, ampakine CX516, D-cycloserine, donepezil, rivastigmine, and galantamine) have failed to show significant benefit [42-50].

Comorbid disorders — Depressive disorders and anxiety disorders can be challenging to diagnose in patients with schizophrenia. A primary comorbid disorder needs to be distinguished from symptoms of schizophrenia, antipsychotic drug side effects, and other clinical presentations. Properly diagnosed, however, these syndromes can respond to antidepressant and anxiolytic medications [51]. (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)

Substance abuse and dependence occur at a high prevalence in schizophrenia [52]. The combination of a severe mental illness and a substance use disorder (SUD), commonly described as “dual diagnosis”, is associated with increased morbidity, poorer functioning, decreased adherence to medication, and higher rates of relapse compared to either disorder individually [53]. Integrated treatment strategies for dual diagnosis that include pharmacotherapy have been developed for individuals with schizophrenia and SUDs. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topics (see "Patient education: Schizophrenia (The Basics)")●

Patients treated with an antipsychotic for schizophrenia should be assessed prior to treatment if possible and at regular intervals for: (See 'Pre-treatment assessment' above.)

●

Signs of a movement disorder including extrapyramidal symptoms and tardive dyskinesia•

Symptoms of metabolic syndrome including measurements of body mass index, waist circumference, hemoglobin A1c, serum lipids, and blood pressure•

ECG for patients with a history of cardiac disease or when starting an antipsychotic that prolongs the QT interval•

We recommend antipsychotic medication as first-line medication treatment for acute and maintenance phase treatment for schizophrenia (Grade 1A). (See 'Drug efficacy' above.)

●

For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely at the lowest effective dose that achieves therapeutic goals (Grade 2C). This approach is suggested even for patients who have achieved remission from a first psychotic episode. (See 'Maintenance phase' above.)

●

The selection of which antipsychotic medication to use for an individual patient with schizophrenia should be made based on patient clinical factors and the side effect profiles of antipsychotic drugs. With the exception of clozapine for patients with refractory symptoms, there is not convincing evidence to favor one antipsychotic over the others based on efficacy. (See 'Drug efficacy' above.)

●

Because olanzapine is associated with significant weight gain and metabolic adverse effects, leading guidelines state that it should not be used as a first-line agent for first-episode patients, but should be considered for patients who fail treatment with a first-line agent.

•

Other strategies for the patient with schizophrenia who has not adequately responded to an antipsychotic drug include:●

Changing to another antipsychotic has been shown to be an effective strategy for addressing side effect problems but is not clearly associated with improved efficacy, with the exception of clozapine. (See 'Changing to another antipsychotic' above.)

•

Clozapine. (See "Evaluation and management of treatment-resistant schizophrenia", section on 'Clozapine trial' and "Guidelines for prescribing clozapine in schizophrenia".)

•

Adding a second antipsychotic medication has not been proven efficacious in randomized trials. For patients with psychotic symptoms that do not respond to two trials of antipsychotic monotherapy, a trial of clozapine is strongly recommended before combining two antipsychotics. (See 'Adding a second antipsychotic' above.)

•

Hospitalized patients with schizophrenia may require treatment for agitation. If agitation is associated with psychotic symptoms of schizophrenia, it can be treated with a standard oral formulation, rapid dissolving, or intramuscularly injected antipsychotic, depending on the level of patient participation. Other causes of agitation should be ruled out, including akathisia and substance abuse or withdrawal. (See 'Acutely agitated' above.)

●

Long-acting injectable (LAI) antipsychotic medication may be useful for patients with schizophrenia when non-adherence to oral antipsychotics leads to frequent relapse. LAI antipsychotics are administered at two to four week intervals. As an example, fluphenazine decanoate can be administered at a dose between 6.25 to 50 mg intramuscularly every two weeks. Extrapyramidal symptoms can be prominent at higher doses. (See 'Medication adherence' above and "Pharmacotherapy for

●

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 6 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington 2013.

2. Murray CJL, Lopez AD. The Global Burden of Disease, Harvard University Press, Cambridge, MA 1996. p.21.

3. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71.

4. Dixon LB, Lehman AF, Levine J. Conventional antipsychotic medications for schizophrenia. Schizophr Bull 1995; 21:567.

5. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31.

6. Fusar-Poli P, Papanastasiou E, Stahl D, et al. Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr Bull 2015; 41:892.

7. Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 2017; 389:1103.

8. McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991; 48:739.

9. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157:514.

10. Stone JM, Davis JM, Leucht S, Pilowsky LS. Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta- analysis of the SPECT and PET in vivo receptor imaging literature. Schizophr Bull 2009; 35:789.

11. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60:1228.

12. Mizrahi R, Kiang M, Mamo DC, et al. The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders. Schizophr Res 2006; 88:111.

13. Mizrahi R, Bagby RM, Zipursky RB, Kapur S. How antipsychotics work: the patients' perspective. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:859.

14. Kinon BJ, Chen L, Ascher-Svanum H, et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology 2010; 35:581.

15. Kinon BJ, Volavka J, Stauffer V, et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. J Clin Psychopharmacol 2008; 28:392.

16. Royal College of Psychiatrists. Consensus statement on high dose antipsychotic medication. CR138, Royal College of Psychiatrists, London 2006.

17. UK National Institute for Health and Clinical Excellence Guidelines http://guidance.nice.org.uk/CG/WaveR/26.

18. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611.

19. Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry 2006; 163:2090.

20. Jibson MD, Tandon R. Treatment of acute psychotic episodes. In: Schizophrenia: a new guide for clinicians, Csernansky, JG (Eds), Marcel Dekker, New York 2001. p.107 .

21. Kinon BJ, Basson BR, Gilmore JA, et al. Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry 2000; 61:833.

22. Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997; 58:252.

23. Ahmed S, Chengappa KN, Naidu VR, et al. Clozapine withdrawal-emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998; 59:472.

24. Shiovitz TM, Welke TL, Tigel PD, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull 1996; 22:591.

25. Gören JL, Parks JJ, Ghinassi FA, et al. When is antipsychotic polypharmacy supported by research evidence? Implications for QI. Jt Comm J Qual Patient Saf 2008; 34:571.

26. Barbui C, Signoretti A, Mulè S, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35:458.

27. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60:82.

28. Buckley PF. Treating movement disorders and akathisia as side effects of antipsychotic pharmacotherapy. J Clin Psychiatry 2008; 69:e14.

29. Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes. Schizophr Res 1999; 35 Suppl:S93.

30. Marder SR. Treatment of agitation in patients with schizophrenia. J Clin Psychiatry 2008; 69:e17.

31. Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420.

32. Leucht S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2012; :CD008016.

33. Davis JM. Maintenance therapy and the natural course of schizophrenia. J Clin Psychiatry 1985; 46:18.

34. Wunderink L, Nienhuis FJ, Sytema S, et al. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68:654.

35. Wunderink L, Nieboer RM, Wiersma D, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913.

schizophrenia: Long-acting injectable antipsychotic drugs".)

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 7 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

36. Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med 2012; 42:2145.

37. Davidson M, Galderisi S, Weiser M, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am J Psychiatry 2009; 166:675.

38. Keefe RS, Sweeney JA, Gu H, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52- week comparison. Am J Psychiatry 2007; 164:1061.

39. Harvey PD, Patterson TL, Potter LS, et al. Improvement in social competence with short-term atypical antipsychotic treatment: a randomized, double-blind comparison of quetiapine versus risperidone for social competence, social cognition, and neuropsychological functioning. Am J Psychiatry 2006; 163:1918.

40. Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64:633.

41. Sergi MJ, Green MF, Widmark C, et al. Social cognition [corrected] and neurocognition: effects of risperidone, olanzapine, and haloperidol. Am J Psychiatry 2007; 164:1585.

42. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007; 164:1593.

43. Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev 2006; :CD003730.

44. Goff DC, Herz L, Posever T, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 2005; 179:144.

45. Kohler CG, Martin EA, Kujawski E, et al. No effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. Cogn Neuropsychiatry 2007; 12:412.

46. Mazeh D, Zemishlani H, Barak Y, et al. Donepezil for negative signs in elderly patients with schizophrenia: an add-on, double-blind, crossover, placebo-controlled study. Int Psychogeriatr 2006; 18:429.

47. Freudenreich O, Herz L, Deckersbach T, et al. Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) 2005; 181:358.

48. Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo- controlled, double-blind investigation. Schizophr Res 2006; 85:73.

49. Kumari V, Aasen I, ffytche D, et al. Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double- blind fMRI study. Neuroimage 2006; 29:545.

50. Buchanan RW, Conley RR, Dickinson D, et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry 2008; 165:82.

51. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull 2009; 35:383.

52. Kessler RC, Nelson CB, McGonagle KA, et al. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry 1996; 66:17.

53. Institute of Medicine. Improving the Quality of Health Care for Mental and Substance-Use Conditions: Quality Chasm Series, National Academy Press, 2006. p.210.

Topic 14805 Version 20.0

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 8 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

GRAPHICS

Selected adverse effects of antipsychotic medications for schizophrenia

Weight

gain/diabetes mellitus

Hyper- cholesterolemia

EPS/TD Prolactin elevation

Sedation Anticholinergic

side effects Orthostatic hypotension

QTc prolongation

First generation agents

Chlorpromazine +++ +++ + ++ +++ +++ +++ +

Fluphenazine + + +++ +++ + –/+ – ND

Haloperidol + + +++ +++ ++ –/+ – +

Loxapine ++ ND ++ ++ ++ + + +

Perphenazine ++ ND ++ ++ ++ + – ND

Pimozide + ND +++ ++ + + + ++

Thioridazine* ++ ND + +++ +++ ++++ ++++ +++

Thiothixene ++ ND +++ ++ + + + +

Trifluoperazine ++ ND +++ ++ + + + ND

Second generation agents

Aripiprazole + – + – + – – –/+

Asenapine ++ – ++ ++ ++ – + +

Brexpiprazole + + + –/+ + –/+ –/+ –/+

Cariprazine + –/+ ++ –/+ + –/+ –/+ –/+

Clozapine ++++ ++++ –/+ –/+ +++ +++ +++ +

Iloperidone ++ ++ –/+ –/+ + + +++ ++

Lurasidone –/+ –/+ ++ –/+ ++ – + –/+

Olanzapine ++++ ++++ + + ++ ++ + +

Paliperidone +++ + +++ +++ + – ++ +

Pimavanserin + - -/+ - + + ++ +

Quetiapine +++ +++ –/+ –/+ ++ ++ ++ +

Risperidone +++ + +++ +++ + + + +

Ziprasidone –/+ –/+ + + + – + ++

Adverse effects may be dose dependent.

EPS: extrapyramidal symptoms; TD: tardive dyskinesia; ND: no data. * Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to text. ¶ Based upon limited experience. Δ Clozapine also causes granulocytopenia or agranulocytosis in approximately 1 percent of patients requiring regular blood cell count monitoring. Clozapine has been associated with excess risk of myocarditis and venous thromboembolic events including fatal pulmonary embolism. These issues are addressed in the UpToDate topic review of guidelines for prescribing clozapine section on adverse effects.

References: ​ 1. Lexicomp Online. Copyright © 1978-2017 Lexicomp, Inc. All Rights Reserved. 2. The Medical Letter on Drugs and Therapeutics (April 2016); Some Relative Adverse Effects of Second-Generation Antipsychotics (table 3); Vol. 58 (1493):52. www.medicalletter.org. 3. Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-

analysis. Schizophr Res 2010; 123:225. 4. Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 2013; 69:1485.

Graphic 82533 Version 27.0

¶

¶

Δ

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 9 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Pharmacology of antipsychotics: Dosing (adult), formulations, kinetics and potential for drug interactions

Agent

Usual oral dose

range (mg/day)

Initial oral dose (mg/day)

Adjustment of oral dose in older* or medically

compromised patients

Usual maximum oral dose

(mg/day)

Formulations

Half-life after oral

administration (hours)

Primary metabolism

Enzyme(s) inhibited

(see note) Notes

First-generation antipsychotics (FGAs)

Chlorpromazine 400 to 600 25 to 200 Use low initial dose and increase more gradually

800 Tab, IM 30 CYP2D6, other CYPs and UGT- glucuronidation to active and inactive metabolites

CYP2D6 Oral absorption is variable and may require dose adjustment based on patient response.

Older adults and medically ill patients are unlikely to tolerate cardiovascular, sedating, and anticholinergic side effects.

Fluphenazine 2 to 15 2 to 10 1 to 2.5 mg daily initially, adjust dose gradually based on response

12 Tab, IM, LAI, oral solution

33 CYP2D6 CYP2D6 Oral absorption is highly variable and dose must be individualized based on patient response.

Haloperidol 2 to 20 2 to 10 1 to 5 mg daily; adjust dose gradually based on response

30 Tab, IM, LAI, oral solution

20 CYPs 2D6, 3A4 and UGT- glucuronidation; some metabolites potentially active or toxic

CYPs 2D6, 3A4 (moderate)

The US labeled maximum recommended dose of 100 mg/day (oral) is considerably higher than more recent practice supports.

Bioavailability with oral dosing is about 60%; dose adjustments between oral and parenteral administration should be made accordingly.

Intravenous use has not been approved by the US Food and Drug Administration and is associated with increased risk of QT prolongation; refer to accompanying text.

Loxapine 20 to 80 20 Generally follows standard adult dosing, although a dose reduction may be indicated in some cases

100 Capsule; oral inhalation for use in healthcare settings as alternative to IM injection.

Oral solution and

6 to 8 (parent drug)

12 (active metabolites)

CYPs 1A2, 2D6, 3A4 and UGT- glucuronidation to active and inactive metabolites

None Onset of oral (swallowed capsule) and IM within 30 minutes.

¶ Δ

◊ §

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 10 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…arch_result&selectedTitle=2~150&usage_type=default&display_rank=2

IM injection available in countries other than United States.

Perphenazine 12 to 24 8 to 16 Initiate dose at 8 mg/day and titrate more gradually to the usual adult range

24 (a higher daily dose may be acceptable, refer to notes)

Tab 9 to 12 (parent drug)

10 to 19 (active metabolite)

CYPs 2D6, 3A4 and other CYPs to active and inactive metabolites

CYP2D6 Bioavailability is variable (60 to 80%).

Higher daily doses, eg, up to 32 mg per day were shown to be similar in tolerability and efficacy to some SGAs and in practice up to 64 mg per day total may be acceptable in some circumstances.

Pimozide 8 to 10 1 to 2 1 mg/day initially and titrate more gradually to the usual adult range

10

4 (CYP2D6 poor metabolizer)

Tab 55

150 (CYP2D6 poor metabolizers)

CYPs 1A2, 2D6, 3A4 and others

CYP2D6 Bioavailability is variable due to extensive hepatic first- pass metabolism.

Thiothixene (tiotixene)

10 to 20 5 to 10 Use low initial dose and titrate more gradually to the usual adult dose range

30 Capsule 34 CYP1A2 and other CYPs

None Oral absorption is variable and dose must be individualized based on patient response.

Thioridazine 200 to 600 150 Use low initial dose and titrate more gradually to the usual adult dose range

600 Tab 4 to 10 (parent drug)

21 to 25 (active metabolites)

CYP2D6 and other CYPs to active (mesoridazine) and inactive metabolites

CYP2D6

Trifluoperazine 15 to 20 4 to 10 Initiate dose at 4 mg/day and titrate more gradually to the usual adult range

40 Tab 3 to 12 (parent drug)

22 (active metabolites)

CYP1A2 and other CYPs to active and inactive metabolites

None Bioavailability is variable.

Second-generation antipsychotics (SGAs)

Aripiprazole 10 to 15 10 to 15 None 30 Tab, ODT, LAI, oral solution

Aripiprazole lauroxil LAI

75 to 94 CYPs 2D6 and 3A4 to active and inactive metabolites

None For augmentation of antidepressant, a lower daily dose of 2 to 5 mg is useful.

Asenapine 10 to 20 10 None.

Exception: Use contraindicated in severe hepatic impairment.

20 Sublingual tab 24 CYP1A2 and UGT- glucuronidation

None Patient should not eat or drink within 10 minutes of sublingual (SL) administration.

SL preparation should not be swallowed due to poor gastrointestinal absorption.

Brexpiprazole 2 to 4 0.5 to 1 Dose adjustments are needed in renal or hepatic impairment

4 Tab 91 CYP2D6 and 3A4 None

Cariprazine 1.5 to 6 1.5 Not recommended in severe renal or hepatic impairment

6 Capsule 48 to 96 (parent drug)

7 to 21 days (active

CYP3A4 to active and inactive metabolites

None

[1]

¥

¥

¥

¥

‡

†

†

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 11 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…earch_result&selectedTitle=2~150&usage_type=default&display_rank=2

metabolites)

Clozapine 150 to 600 25 to 50 Titrate gradually to reduced maintenance range of 100 to 150 mg/day; maximum 300 mg/day.

Lower doses advised in renal or hepatic impairment; specific dose adjustment recommendations are not available.

900 Tab, ODT, oral suspension

12 CYP1A2, other CYPs, and UGT- glucuronidation

CYP2D6 (moderate)

Hypotension is the most frequent dose limiting factor during titration.

Other side effects requiring monitoring include agranulocytosis, sedation, and sialorrhea.

Once titrated to 300 to 450 mg daily, rate of titration may be increased to 100 mg once or twice weekly.

Iloperidone 12 to 24 2 Not recommended in severe hepatic impairment

24

12 (CYP2D6 poor metabolizer or receiving 2D6 inhibitor cotreatment)

Tab 18 to 26 CYP2D6 and other CYPs to active and inactive metabolites

CYP3A4 (moderate)

Orthostatic hypotension is usually the dose limiting factor in titration.

Lurasidone 40 to 80 40

20 (renal or hepatic insufficiency)

Dose adjustments are needed in renal and hepatic impairment

160

80 (moderate or severe renal impairment, moderate hepatic impairment)

40 (severe hepatic insufficiency)

Tab 29 to 37 (at steady state)

CYP3A4 to active and inactive metabolites

None Needs to be taken with a meal to be adequately absorbed.

Olanzapine 10 to 20 5 to 10 Initially 1.25 to 2.5 mg/day; typical maintenance 5 mg/day; maximum 10 mg/day

30 Tab, ODT, IM, LAI 30 to 38 CYP1A2 and UGT- glucuronidation

None

Paliperidone 6 to 12 6 Older adults or renal impairment: 3 mg/day

12 ER tab, LAI 23 Paliperidone is excreted mainly unchanged in urine necessitating dose reduction in renal insufficiency

None Tablets need to be swallowed whole.

Pimavanserin 34 34 Not recommended in hepatic impairment or severe renal impairment (not studied)

34 Tab 57 parent drug (200 for active metabolite)

CYP3A4 and 3A5 to active metabolite

None Approved for reducing Parkinson disease related psychosis.

Dose adjustment needed if used with strong inhibitors of CYP3A. Efficacy may be reduced if used with strong inducers of CYP3A. Refer to separate table of CYP3A inhibitors and inducers available in UpToDate.

Quetiapine 150 to 750 (immediate

50 Initially 25 to 50 mg/day; use

750 (immediate

Tab, ER tab 6 to 12 CYP3A4 None Titration most often limited by

†

¥

‡

¥

‡

‡

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 12 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…arch_result&selectedTitle=2~150&usage_type=default&display_rank=2

release)

400 to 800 (extended release)

substantially lower maintenance dose.

Dose adjustment needed in hepatic impairment .

release)

800 (extended release)

excessive sedation or orthostatic hypotension which should be monitored.

Risperidone 2 to 6 1 to 2 Initially 0.25 to 0.5 mg/day; typical maintenance 1 mg/day; maximum 2 mg/day.

Dose adjustments are needed in renal and hepatic impairment .

8 Tab, ODT, LAI, oral solution

20 CYP2D6 to active (paliperidone) and inactive metabolites; P-gp substrate

CYP2D6 (moderate)

Ziprasidone 40 to 160 40 to 80 Lower doses advised in hepatic impairment; specific adjustment recommendations are not available

200 Capsule, IM 7 oral

2 to 5 IM

CYP3A4 None Oral preparation is not dependent on renal function for clearance but a component of the IM injection is cleared by the kidney.

Important note: Doses shown are total daily dose, oral administration, for maintenance treatment of schizophrenia in otherwise healthy adults. The dosing and other information provided in this table differs from dosing used in management of behavioral symptoms of dementia in older adults; in general these medications are not recommended for that use. For additional information, refer to the relevant UpToDate clinical topics and the Lexicomp drug monographs included within UpToDate.

ODT: orally dissolving tablet; Tab: tablet; ER tab: extended-release tablet; IM: short-acting intramuscular injection; LAI: long-acting injectable (eg, depot); CYP: cytochrome P-450; P-gp: membrane P-glycoprotein transporters; UGT-glucuronidation: uridine 5'diphosphate-glucuronyltransferases. * First- and second-generation antipsychotics are included on the Beers list of medications to be used with caution in older adults and should in general be avoided except for schizophrenia and bipolar disorder. ¶ First-generation antipsychotics (FGAs) undergo extensive hepatic metabolism; levels may be elevated in hepatic impairment necessitating dose reduction and more gradual dose titration to avoid toxicity. FGAs should be used with caution at significantly reduced doses or avoided in severe hepatic impairment. Δ Usual maximum total oral daily dose for maintenance treatment of schizophrenia in adult patients without significant comorbidity. Doses shown may not be the maximum dose used in some clinical trials or in exceptional patients. ◊ Dose adjustments of several antipsychotic medications listed in this table are recommended in presence of strong or moderate inhibitors or inducers of CYP drug metabolism; for specific recommendations refer to the individual Lexicomp drug monographs. § Only potent to moderate inhibitor effects are listed in this table. For additional information including moderate to weak inhibitor or inducer effects, and to determine specific drug interactions, refer to individual drug monographs section on drug interactions and the Lexi-Interact program included with UpToDate. ¥ Smoking may decrease blood concentrations of antipsychotics primarily metabolized by CYP1A2. ‡ For specific dose adjustments in setting of renal or hepatic impairment, refer to Lexicomp drug monograph. † Active metabolites of cariprazine are equipotent to cariprazine. Due to the long half-life of cariprazine and active metabolites, changes in dose will not reach plasma steady-state for several weeks or months.

References: 1. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209. 2. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older

Adults. J Am Geriatr Soc 2015; 63:2227. Prepared with data from: ​

1. US product information (available online at http://dailymed.nlm.nih.gov/dailymed/about.cfm) and Health Canada product monograph. 2. Lexicomp Online. Copyright © 1978-2018 Lexicomp, Inc. All Rights Reserved. 3. Wynn GH, et al (eds) Clinical Manual of Drug Interaction Principles for Medical Practice APA publishing, Washington DC. Copyright © 2009.

Graphic 60624 Version 31.0

‡

‡

[2]

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 13 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…arch_result&selectedTitle=2~150&usage_type=default&display_rank=2

Antipsychotics for initial management of the acutely agitated adult patient with psychosis

Formulation Route Initial dose

(mg) Frequency

(hours)

Maximum initial dose

per 24 hours (mg)

Time to peak plasma

concentration (hours)

Notes

First-generation agents

Haloperidol Short-acting lactate injection

IM, IV 2 to 5 0.5 to 2* 20 0.5 to 1 Sedation, hypotension and prolongation of QTc interval more pronounced with injection. ↑ EPS risk.

Oral solution PO 0.5 to 5 6 30 2

Droperidol Injection (short- acting)

IM, IV 2.5 to 5 2 to 4* 40 0.5 Rapid onset of 3 to 10 minutes advantageous in severely agitated violent patients. Dose related QTc prolongation and risk of cardiac arrhythmias. ↑ EPS risk.

Fluphenazine Short-acting hydrochloride injection

IM 1.25 6 10 ND 1 mg short-acting IM injection is equivalent to approximately 2.5 mg oral. ↑ EPS risk.

Oral solution PO 1 to 2.5 6 10 3

Chlorpromazine Injection (short- acting)

IM, IV 25 1 to 4 200 0.5 Hypotension, sedation and injection site pain are limiting side effects. Not a first- line agent.

Second-generation agents

Aripiprazole Disintegrating tablet, oral solution

PO 10 to 15 2 30 3 to 5 Less sedating. Minimal prolongation of QTc interval or orthostatic hypotension.

Olanzapine Injection (short- acting)

IM 5 to 10 2 to 4 30 0.25 to 0.75 Decreased clearance in female and/or non-smoking patients.

Disintegrating tablet

PO 5 to 10 0.5 to 2 20 5

Risperidone Disintegrating tablet, oral solution

PO 1 to 2 0.5 to 2 4 1.5 Decreased clearance in renal and/or hepatic impairment.

Ziprasidone Short-acting mesylate injection

IM 10 to 20 2 to 4 40 0.5 to 1 Dose related QTc prolongation and risk of cardiac arrhythmias.

The approach to pharmacologic treatment of the acutely agitated patient, including specific medication choices and combinations depending upon presentation (eg, toxic ingestion, withdrawal syndrome, or known psychiatric history) is provided in the accompanying topic reviews and in an algorithm. Dose reduction by one-half is needed for older adults, debilitated patients, and if used in combination with other sedation. Refer to accompanying text for discussion of electrocardiograph and other monitoring for agents known to cause prolongation of the QTc interval.

IM: intramuscular; IV: intravenous; EPS: extrapyramidal symptoms; PO: per os (by mouth); ND: no data. * It may be necessary to repeat initial dose or fraction thereof after 15 to 20 minutes in patients with severe agitation until desired level of sedation attained. ¶ Selected patients without schizophrenia may need a higher cumulative haloperidol dose (eg, up to 30 mg) during the first 24 hours of treatment to achieve and maintain adequate sedation.

Graphic 60846 Version 12.0

¶

3/24/18, 10*44 AMPharmacotherapy for schizophrenia: Acute and maintenance phase treatment - UpToDate

Page 14 of 14https://www.uptodate.com/contents/pharmacotherapy-for-schizophreni…arch_result&selectedTitle=2~150&usage_type=default&display_rank=2