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  Disease summary:

  
  
  
  
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    Schizophrenia (SCZ) is a severe, chronic psychiatric syndrome that is a complex genetic disorder involving the interactions of multiple genetic and nongenetic factors.

    
    
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    Clinical diagnosis is based on abnormalities in multiple domains including positive symptom domain, negative symptoms, cognition, and mood symptoms. No blood or neuroimaging tests are pathognomic.

    
    
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    Presentation is generally in adolescence or early adulthood but a premorbid prodrome is often apparent earlier suggesting a neurodevelopmental trajectory.

    
    
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    The course is most often chronic with significant impairments in social and work functioning.

    
    
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    Neuroimaging finds decreased activation in task-induced magnetic resonance imaging (MRI) paradigms in several brain regions including the dorsolateral prefrontal cortex and anterior cingulate. Diffusion tensor imaging has also identified white matter tract abnormalities.

  
  
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  Differential diagnosis:

  
  
  
  
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    Major differential is with other psychotic disorders (bipolar disorder [BD], schizoaffective disorder, delusional disorder, and depression with psychotic features). Other significant differential includes (1) psychotic disorder due to medical conditions (eg, epilepsy, dementia, brain tumor, infections, and metabolic abnormalities), (2) substance use (eg, drugs of abuse, medications, toxins), and (3) brief or SCZ spectrum syndromes.

  
  
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  Monogenic forms:

  
  
  
  
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    There are no agreed upon monogenic forms, no single gene has been demonstrated to cause SCZ.

  
  
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  Family history:

  
  
  
  
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    Strongest risk for SCZ is a positive family history. Affected first-degree relatives confer a relative risk of 5% to 16%. A recent large-scale study shows that first-degree relatives are also at increased risk of BD (3.7%).

  
  
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  Twin studies:

  
  
  
  
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    Monozygotic twins have 0.9 concordance rate, dizygotic twins have 0.5, with an estimated heritability of approximately 0.8.

  
  
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  Nonfamilial genetics: Advanced paternal age is associated with elevated relative risk (two- to threefold). De novo single-nucleotide polymorphism (SNP) and copy-number variants (CNV) rates are increased in SCZ.

  
  
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  Environmental factors:

  
  
  
  
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    Multiple environmental factors have been associated with modest increased risk including obstetrical complications, prenatal infections, socioeconomic status, immigration status, urban living, maternal starvation, head injury, and cannabis use.

  
  
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  Genome-wide associations:

  
  
  
  
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    Significant genome-wide associations exist for both CNVs and SNPs. Large CNVs are associated with larger risk, but produce pleiotropic phenotypes (ie, not specific for SCZ). Testing for CNVs or SNPs is not yet clinically validated for diagnosis or treatment selection.

  
  
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  Pharmacogenomics:

  
  
  
  
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    Most antipsychotic medication is metabolized by the cytochrome P450 (CYP) system. Clinical efficacy of CYP testing has not been established.

Diagnostic Criteria for SCZ

The clinical diagnostic criteria for SCZ are described in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV TR) and the International Classification of Diseases, 10th edition (ICD-10). DSM-IV TR is primarily used in the United States and ICD-10 in Europe. There is good agreement between the two systems.

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  DSM1V criteria: (1) Two or more characteristic symptoms of delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms (only one if delusions are bizarre, or hallucinations with multiple voices or running commentary), (2) significant functional decline in work, self-care, or interpersonal relations, (3) duration of 6 months with 1 month of active symptoms, (4) exclusions include schizoaffective disorder, mood disorder with psychotic features, substance, general medical conditions, and autism spectrum disorders unless prominent active delusions and hallucinations. There are five subtypes: paranoid, disorganized, catatonic, undifferentiated, and residual.

  
  
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  ICD-10 criteria: (1) Active-phase symptoms include one of either thought abnormalities (echo, insertion, withdrawal, or broadcasting), delusions of control or passivity, hallucinations of running commentary or conversing voices, culturally inappropriate delusions or two of either other hallucinations with delusions, thought disorder, catatonia, or negative symptoms, (2) significant functional decline not required, (3) duration of 1 month of active symptoms, (4) exclusions include psychosis during mood symptoms, alcohol or substance use, or organic brain diseases. There are seven subtypes: paranoid, hebephrenic, catatonic, undifferentiated, residual, simple, postschizophrenic depression.

Diagnostic evaluation should include the following:

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  Clinical evaluation of patient that includes review of current and past symptoms, and duration and effect on the patient’s functioning. In addition, a standard general medical review and physical examination are indicated including weight, height, and body mass index (BMI).

  
  
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  Exclusion of medical conditions and substance intoxication that may cause psychotic symptoms via standard laboratory chemistries such as complete blood count (CBC), electrolytes, blood urea nitrogen (BUN)/creatinine, calcium and phosphorus, thyroid-stimulating hormone (TSH), liver function tests (LFTs), HIV screening, syphilis testing, vitamin B₁₂ and folate, and urine drug screen. Further testing should be based on level of clinical suspicion from history and physical particularly if presentation has atypical features.

  
  
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  Imaging studies such as MRI and computed tomography (CT) are not generally recommended as yield is expected to be low unless there is additional clinical suspicion or atypical features.

Clinical Characteristics

Initial Presentation

The initial presentation can take several forms. Often onset is acute with symptoms beginning over a short period of time that brings the patient to medical attention and hospitalization. Symptoms may evolve more slowly over a “prodromal” period of several years in which symptoms such as suspiciousness, depression, sleep problems, and decreased functioning may be noted, ultimately culminating in acute symptoms. Retrospective and premorbid studies show that cognitive deficits in intellectual, language, and behavioral measure may be present in childhood suggesting a neurodevelopmental etiology.

Acute (Positive) Symptoms

The characteristic acute symptoms are hallucinations and delusions. Hallucinations are false perceptions that can occur in any sensory modality, but most commonly are auditory. Typical examples include hearing a variety of sounds or hearing third person voices commenting negatively on the patient. Command hallucinations may direct a patient to perform specific potentially dangerous activities. Delusions are fixed, false beliefs that are not culturally appropriate. Typical examples include beliefs that the patient is being persecuted, or that random events have special meaning known only to the patient.

Negative Symptoms

These are those symptoms that most negatively affect societal functioning and quality including lack of motivation (avolition), flat or blunted affect, poverty of speech (alogia), inability to experience pleasure (anhedonia), and associality. Negative symptoms are less responsive to antipsychotic treatment.

Cognitive Symptoms

Deficits in a variety of areas that are independent of positive or negative symptoms have been characterized and include abnormalities in processing speed, attention or vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving, and verbal comprehension.

Comorbidity

A number of psychiatric syndromes are often comorbid, including depression and substance abuse. Life-time suicide risk is approximately 5%. An elevated mortality rate from all causes is observed. There is a markedly elevated risk of cardiovascular disease.

Screening

Genetic testing is not currently offered for SCZ. Genetic testing of DNA variants for diagnosis, reproductive choices, or treatment decisions is not yet validated and thus not recommended. Some clinicians advocate for pharmacogenetic testing of CYP2D6 as a guide to antipsychotic dosing, however, there is controversy regarding its clinical utility. Surveys of treating clinicians and family members have indicated strong interest in providing and receiving genetic information and these recommendations may change in the future.

Counseling

Traditional elements of genetic counseling apply. Familial clustering is observed, but the relatively low incidence, modest first-degree relative recurrence risk, late onset, and small modern family size can make familial cases difficult to discriminate from sporadic cases. There are no clear Mendelian forms of schizophrenia. General estimates of first-degree relative recurrence risks are 5% to 16%. Two recent large-scale population-based studies demonstrated recurrence risks for many family constellations for schizophrenia (first-degree, 8.2-10.7; second-degree, 2.5-3.8; third-degree, 2.3) as well as sibling recurrence risks of 3.7 for BD.

Management

The mainstay of treatment is antipsychotic medication. These have been shown to improve overall symptoms and decrease relapse risk. A variety of psychosocial interventions have been shown be effective including social skills training, psychoeducation, cognitive behavior therapy, and cognitive remediation.

Antipsychotics

Introduced in 1960s, first-generation antipsychotics (FGA), also referred to as typical antipsychotics, such as chlorpromazine and haloperidol, are potent dopamine receptor type 2 antagonists. The blockade is also thought to explain the observed nontherapeutic extrapyramidal side effects and prolactin elevation. In contrast, a second-generation antipsychotic (SGA) medications were developed that have been termed “atypical antipsychotics” and have reduced extrapyramidal side effects. In general, FGAs and SGAs do not differ in efficacy for positive symptoms, but have differing side effect profiles with FGAs having higher rates of extrapyramidal symptoms and tardive dyskinesia, and SGAs having increased weight gain and metabolic syndrome.

Management is divided into acute phase and maintenance phase. Acute phase, first-episode treatment may occur in the inpatient or outpatient setting, focuses on stabilization, diagnostic workup, and initiation of antipsychotic treatment. The majority of treatment guidelines suggest beginning treatment with an SGA (but not clozapine). Maintenance phase treatment focuses on preventing relapse with pharmacologic adherence and psychosocial therapy as well as monitoring and prevention of antipsychotic-related side effects including tardive dyskinesia and metabolic syndrome. Two antipsychotics, ziprasidone and aripiprazole have been shown to produce less weight gain in maintenance of schizophrenia and may be considered. Other medications are often used as adjuncts. These include antidepressants, anticonvulsants, and lithium to address affective symptoms and benzodiazepines for anxiety and agitation.

Treatment refractory schizophrenia is defined as significant psychosis despite having been treated with adequate dosing of two or more antipsychotics. Treatment with clozapine is recommended at that point which requires monitoring of white blood cell and absolute neutrophil counts because of the risk of agranulocytosis.

Medical Monitoring