4/14/23, 11:57 PM Schizophrenia - StatPearls - NCBI Bookshelf

Schizophrenia
Hany M, Rehman B, Azhar Y, et al.

Continuing Education Activity

Schizophrenia is a psychotic disorder characterized by hallucinations, delusions, and disturbances in thought, perception, and behavior. Traditionally,
schizophrenia may involve positive symptoms, such as hallucinations, delusions, formal thought disorders, and negative symptoms, such as paucity of
speech, anhedonia, and lack of motivation. This activity outlines the evaluation of schizophrenia and explains the role of the interprofessional team in
improving care for patients with this condition.

Objectives:

Review the epidemiology of schizophrenia.

Explain the characteristic features of schizophrenia.
Review the management of schizophrenia.
Summarize the importance of improving care coordination among the interprofessional team members to detect the positive and negative
symptoms of the condition, which will enhance the delivery of care for those with schizophrenia.

Access free multiple choice questions on this topic.

Introduction
Derived from the Greek 'schizo' (splitting) and 'phren' (mind) with the term first coined by Eugen Bleuler in 1908, schizophrenia is a functional
psychotic disorder characterized by the presence of delusional beliefs, hallucinations, and disturbances in thought, perception, and behavior.
Traditionally, symptoms have been divided into two main categories: positive symptoms, which include hallucinations, delusions, and formal thought
disorders, and negative symptoms such as anhedonia, poverty of speech, and lack of motivation. The diagnosis of schizophrenia is clinical, made
exclusively after obtaining a full psychiatric history and excluding other causes of psychosis. Risk factors include birthing complications, the season
of birth, severe maternal malnutrition, maternal influenza in pregnancy, family history, childhood trauma, social isolation, cannabis use, minority
ethnicity, and urbanization.[1][2] Due to its relative complexity and heterogeneity, the etiology and pathophysiological mechanisms are not fully
understood. Despite a low prevalence, schizophrenia's global burden of disease is immense. Over half of the patients have significant co-morbidities,
both psychiatric and medical, making it one of the leading causes of disability worldwide.[3] The diagnosis correlates with a 20% reduction in life
expectancy, with up to 40% of deaths attributed to suicide.[4]

Etiology
Several studies postulate that the development of schizophrenia results from abnormalities in multiple neurotransmitters, such as dopaminergic,
serotonergic, and alpha-adrenergic hyperactivity or glutaminergic and GABA hypoactivity. Genetics also plays a fundamental role - there is a 46%
concordance rate in monozygotic twins and a 40% risk of developing schizophrenia if both parents are affected. The gene neuregulin (NGR1), which
is involved in glutamate signaling and brain development, has been implicated, alongside dysbindin (DTNBP1), which helps glutamate release, and
catecholamine O-methyl transferase (COMT) polymorphism, which regulates dopamine function.

As aforementioned, there are also several environmental factors associated with an enhanced risk of developing the disease:

Abnormal fetal development and low birth weight

Gestational diabetes
Preeclampsia
Emergency cesarean section and other birthing complications
Maternal malnutrition and vitamin D deficiency
Winter births - associated with a 10% higher relative risk
Urban residence - increases the risk of developing schizophrenia by 2 to 4%

The incidence is also up to ten times greater in children of African and Caribbean migrants compared to whites, according to a study conducted in
Britain.[1] The association between cannabis use and psychosis has been widely studied, with recent longitudinal studies suggesting a 40% increased
risk, while also suggesting a dose-effect relationship between the use of the drug and the risk of developing schizophrenia.[2]

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Epidemiology
Though the prevalence of the disease varies globally, estimates are that schizophrenia affects approximately 1% of adults, whereas prevalence in the
United States is 0.6 to 1.9% [5]. Men are slightly more likely to be diagnosed and have an earlier onset than women, while African-Caribbean
migrants and their descendants also have a higher incidence.[6]

Pathophysiology
There are three main hypotheses regarding the development of schizophrenia. The neurochemical abnormality hypothesis argues that an imbalance of
dopamine, serotonin, glutamate, and GABA results in the psychiatric manifestations of the disease. It postulates that four main dopaminergic pathways
are involved in the development of schizophrenia. This dopamine hypothesis attributes the positive symptoms of the illness to excessive activation of
D2 receptors via the mesolimbic pathway, while low levels of dopamine in the nigrostriatal pathway are theorized to cause motor symptoms through
their effect on the extrapyramidal system. Low mesocortical dopamine levels resulting from the mesocortical pathway are thought to elicit the
negative symptoms of the disease. Other symptoms such as amenorrhea and decreased libido may be caused by elevated prolactin levels due
to decreased availability of tuberoinfundibular dopamine as a result of blockage of the tuberoinfundibular pathway. Evidence showing exacerbation of
positive and negative symptoms in schizophrenia by NMDA receptor antagonists insinuates the potential role of glutaminergic hypoactivity while
serotonergic hyperactivity has also been shown to play a role in schizophrenia development.[5] 

There are also arguments that schizophrenia is a neurodevelopmental disorder based on abnormalities present in the cerebral structure, an absence of
gliosis suggesting in utero changes, and the observation that motor and cognitive impairments in patients precede the illness onset.

Conversely, the disconnect hypothesis focuses on the neuroanatomical changes seen in PET and fMRI scans. There is a reduction in grey matter
volume in schizophrenia, present not only in the temporal lobe but in the parietal lobes as well. Differences in the frontal lobes and hippocampus are
also seen, potentially contributing to a range of cognitive and memory impairments associated with the disease. 

History and Physical

There are slight variations in the diagnostic criteria of schizophrenia depending on the classification system used.

Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) 

Two or more of the following symptoms must be present for a significant portion of time during a one-month period:

Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms. 

There must also be social/occupational dysfunction, while signs of disturbance must persist for at least six months, including at least one month of
symptoms.

International Classification of Diseases (ICD-10)

The patient must exhibit at least one of the following, for a period greater than or equal to a month:

Thought insertion, echo, broadcast, or withdrawal

Delusions of control, influence, or passivity
Hallucinatory voices providing a running commentary of the patient
Persistent delusions that are culturally inappropriate or implausible

Or, at least two of the following symptoms must be observed, for a period greater than or equal to a month[7]:

Persistent hallucinations in any modality when accompanied by fleeting delusions

Breaks of interpolations in thought resulting in incoherence or neologisms
Catatonic behavior
Negative symptoms
Significant and consistent transformation in the overall quality of behavior manifesting as anhedonia and social withdrawal

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Unlike DSM-5, ICD-10 further subcategories schizophrenia based on the key presenting symptoms as either paranoid schizophrenia, hebephrenic
schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, post-schizophrenic depression, residual schizophrenia, and simple
schizophrenia.  

 In addition to asking about these symptoms, it is also important to elicit:

1. Past medical history, drug history, and family history

2. Social history, including the use of recreational drugs and alcohol
3. Any recent neurological impairments such as altered consciousness or memory problems, head injury, stroke, seizures, faints, dizzy spells,
visual impairment, marked tremor, or muscle stiffness
4. Potential organic causes of psychosis such as Parkinson's disease, multiple sclerosis, syphilis, AIDS, brain lesions, heavy metal toxicity,
delirium, metabolic/endocrine disorders, and dementias including Alzheimer's disease, frontotemporal dementia, and Lewy body dementias

A thorough risk assessment must also be undertaken to determine the risk of harm to self and others. The first schizophrenic episode usually occurs
during early adulthood or late adolescence. Individuals often lack insight at this stage; therefore, few will present directly to seek help for their
psychotic symptoms. Common presentations include a relative noticing social withdrawal, personality changes, or uncharacteristic behavior;
deliberate self-harm or suicide attempts; calling the police to report their delusional symptoms, or referral via the criminal justice system. The use of
screening tools such as COPS (Criteria of Prodromal Syndromes), SIPS (Structured Interview for Prodromal Syndromes), and PACE (Personal
Assessment and Crisis Evaluation Clinic) has been shown to increase the detection rate of schizophrenia in premorbid states although there is
controversy surrounding indicating treatment at this stage.

Evaluation
After conducting a full psychiatric history, it is imperative to conduct a thorough systems review and a mental state examination where appearance,
behavior, mood, speech, cognition, and insight need to be assessed, alongside determining evidence of perceptual delusions or formal thought
disorders. Though schizophrenia is primarily a clinical diagnosis, specific laboratory and radiographic investigations are useful to exclude other
potential causes:

Urea and electrolytes - an electrolyte imbalance can cause delirium

Serum calcium - hypoparathyroidism or hyperparathyroidism can, on occasion, have psychiatric manifestations
Blood glucose - hypoglycemia can produce confusion which can be mistaken for psychosis
Thyroid function tests - depression is associated with hypothyroidism and may present with psychotic features - severe hyperthyroidism also
correlates with changes in mental state
24-hour cortisol collection - both hypercortisolism (Cushing syndrome) and adrenocortical insufficiency (Addison disease) can present with
psychiatric symptoms
24 hour catecholamine/5-HIAA collection - in cases of suspected phaeochromocytoma/carcinoid syndrome
Urinary toxicology screen - detection of recreational drugs such as cannabis
CT head/MRI - in cases of significant neurological impairment or suspected neurological abnormality
HIV/syphilis serology - both infections can cause psychiatric symptoms

Treatment / Management
For the initial treatment of acute psychosis, it is recommended to start an oral second-generation antipsychotic (SGA) such as aripiprazole, olanzapine,
risperidone, quetiapine, asenapine, lurasidone, sertindole, ziprasidone, brexpiprazole, molindone, iloperidone, etc. Sometimes, if clinically needed,
alongside a benzodiazepine such as diazepam, clonazepam, or lorazepam to control behavioral disturbances and non-acute anxiety. First-generation
antipsychotics (FGA) like trifluoperazine, fluphenazine, haloperidol, pimozide, sulpiride, flupentixol, chlorpromazine, etc., are not commonly used as
the first line but can be used.

Once the acute phase is controlled, switching to a depot preparation like aripiprazole, paliperidone, zuclopenthixol, fluphenazine, haloperidol,
pipotiazine, or risperidone is recommended as it increases medication adherence and compliance, improving outcomes and decreasing relapses.

Cognitive behavioral therapy (CBT) and the use of art and drama therapies help counteract the negative symptoms of the disease, improve insight, and
assist relapse prevention.

Clozapine is used in case of treatment resistance - if there has been a poor response to at least two different antipsychotics, and require initial weekly
blood tests for six months, biweekly for six months, and then every four weeks to monitor white blood cell count due to the risk of agranulocytosis.

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Other options in treatment resistance include combining antipsychotics, adding lamotrigine, mirtazapine, donepezil, D-alanine, D-serine, estradiol,
memantine, or allopurinol to an antipsychotic. The role of electroconvulsive therapy (ECT) is limited but has been used.

During the maintenance phase, prophylaxis and rehabilitation back into the community are vital priorities - and establishing the minimum necessary
effective dose of antipsychotics should also take place during this period. Post-schizophrenic depression occurs in up to 30% of patients: if a dysphoric
mood is evident, consider reducing the antipsychotic dose, treating with antidepressants or anxiolytics, or switching to a second-generation
antipsychotic. There is significant substance abuse amongst patients with schizophrenia which can exacerbate both positive and negative symptoms;
therefore, psychosocial and pharma therapeutic approaches should be used to treat the misuse. Clozapine may be given in patients with extensive,
persisting substance misuse. 

The treatment of those identified as at risk of developing a psychotic disorder is controversial. Treatment of co-existing disorders and with individual
CBT and family intervention is advocated, although no long-term evidence exists regarding its efficacy in preventing a psychotic episode or reducing
its severity.

Differential Diagnosis
As psychotic features can manifest in various other mental disorders, there are wide-ranging differentials for schizophrenia, including but not limited
to:

Substance-induced psychotic disorder

Mood disorders with psychotic features
Sleep-related disorders
Delusional disorder
Paranoid personality disorder
Schizotypal personality disorder
Pervasive developmental disorder
Psychosis secondary to organic causes

Toxicity and Adverse Effect Management

Antipsychotic side effects subdivide into five categories.

Extrapyramidal

Tardive dyskinesia: though symptoms are irreversible, vitamin E has been shown to prevent further deterioration
Parkinsonism: bradykinesia, tremors, and rigidity can occur a week after administration - can be managed via a reduction in dose or the use
of an antimuscarinic such as oral benztropine 
Akathisia: can occur after a month of antipsychotic use and treated using propranolol and benzodiazepines
Acute dystonia: managed via a parenteral muscarinic such as benztropine administered intravenously or intramuscularly 

Anticholinergic

Dry mouth; urinary retention; blurred vision; glaucoma; constipation

Anti-adrenergic

Sexual dysfunction; tachycardia; postural hypotension

Antihistaminic

Weight gain, sedation; All patients should be advised to increase their physical activity and monitor their dietary intake.

Idiosyncratic

Altered glucose tolerance, skin photosensitivity, cholestatic jaundice, hypersensitivity reactions, yellow pigmentation of the skin, neuroleptic
malignant syndrome; The neuroleptic malignant syndrome may be fatal and is characterized by increasing rigidity, pyrexia, and fluctuating
consciousness - the patient should receive immediate medical care.

Recent efficacy studies such as Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and European First-Episode Schizophrenia Trials
(EUFEST) found no significant difference between the first-generation antipsychotics such as haloperidol and newer second-generation antipsychotics

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such as olanzapine and risperidone.[8] However, SGAs have far fewer extrapyramidal side effects than their FGA counterparts; therefore, they may
be preferentially used.

Prognosis
In schizophrenia, the prognosis is dependent on several factors. Insidious onset, childhood or adolescent onset, poor premorbid adjustment, and
cognitive impairment are indicative of a poor prognostic outcome, whereas acute onset, female sex, and living in a developed country signal
comparatively better prognostic factors. However, suicide is the most common cause of premature death in schizophrenia, with two-thirds of patients
reporting at least one episode of suicidal ideation.[9]

Complications
Treatment-resistant schizophrenia is when the condition fails to respond to at least two antipsychotic medications for at least six weeks; up to 30% of
patients with schizophrenia respond poorly to antipsychotics, and around 7% show no response. Clozapine is the therapeutic option in such instances.

Deterrence and Patient Education

A significant percentage of patients with schizophrenia die from cardiovascular disease.[10] Educating patients on the importance of modifying risk
factors such as increasing exercise, healthier diets, and smoking cessation will decrease their risk of cardiovascular problems and reduce the mortality
rate. Moreover, cognitive behavioral therapy has been shown to improve patient compliance and decrease future hospital admissions.

Enhancing Healthcare Team Outcomes

Alongside educating patients about the importance of making healthy lifestyle choices, it is also imperative that the physicians, nurses, and other allied
health professionals work together as an interprofessional team in diligently monitoring patients while admitted. Patients on clozapine need to have
their WBC measured regularly as they are at risk of agranulocytosis, while a risk assessment should be carried out on all new patients to evaluate their
risk of harm to self or others. Outside of the hospital setting, community psychiatric nurses and family physicians can also educate the patient and
provide further information while also monitoring for early signs of relapse. 

Review Questions
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Comment on this article.

References
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review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehav Rev. 2016 Jun;65:185-94. [PMC free
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PMC4159061] [PubMed: 25210417]
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8. Gründer G, Heinze M, Cordes J, Mühlbauer B, Juckel G, Schulz C, Rüther E, Timm J., NeSSy Study Group. Effects of first-generation
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9. Ventriglio A, Gentile A, Bonfitto I, Stella E, Mari M, Steardo L, Bellomo A. Suicide in the Early Stage of Schizophrenia. Front Psychiatry.
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17944000]

Publication Details

Author Information and Affiliations

Authors

Manassa Hany1; Baryiah Rehman2; Yusra Azhar3; Jennifer Chapman4.

Affiliations
1
Icahn School of Medicine at Mount Sinai
2 Keele University School of Medicine
3
Dow University of Health Sciences
4
Lahey Health Systems

Publication History

Last Update: January 30, 2023.

Copyright
Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (
http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not
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Publisher

StatPearls Publishing, Treasure Island (FL)

NLM Citation

Hany M, Rehman B, Azhar Y, et al. Schizophrenia. [Updated 2023 Jan 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

https://www.ncbi.nlm.nih.gov/books/NBK539864/ 6/6