Schizophrenia

Last updated: October 25, 2022

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Schizophrenia is a psychiatric disorder characterized by psychotic symptoms (e.g., hallucinations), negative symptoms (e.g., decreased expressiveness), and cognitive impairment (e.g., lack of executive function). The majority of individuals with schizophrenia experience symptoms early in adulthood. The exact etiology is unknown but thought to be related to increased dopaminergic activity in the mesolimbic neuronal pathway and decreased dopaminergic activity in the prefrontal cortical pathway. Management of schizophrenia includes ruling out underlying medical causes, initiating antipsychotic medication, and creating a comprehensive treatment plan that includes both pharmacological and psychosocial interventions. Lifelong therapy, including monitoring for the adverse effects of antipsychotic medication, is necessary.

  • Prevalence: < 1% [1]
  • Sex: > (∼1.4:1) [2]
  • Age of onset: late teens to mid-30s [3]
    • Men: typically early 20s
    • Women: typically late 20s

Epidemiological data refers to the US, unless otherwise specified.

Risk factors

  • Genetic factors: risk significantly increased if relatives are also affected [4]
  • Environmental factors
    • Stress and psychosocial factors
    • Frequent use of cannabis during early teens (associated with increased incidence and worse course of positive symptoms) [5][6]
    • Urban environment
    • Advanced paternal age at conception

Dysregulation of neurotransmitters [7]

Structural and functional changes to the brain [8][9]

Schizophrenia typically manifests with a prodrome of negative symptoms (e.g., social withdrawal) and psychosis that precedes the positive psychotic symptoms (e.g., hallucinations and bizarre delusions). [3]

Positive symptoms of schizophrenia

Psychosis

Abnormal motor behavior

  • Grossly disorganized behavior: an abnormal behavior characterized by inadequate goal-directed activity (e.g., purposeless movements) and bizarre emotional responses (e.g., smiling or laughing when inappropriate)
  • Catatonia (See “Subtypes and variants” below.)

Negative symptoms of schizophrenia

  • Flat affect: reduced or absent emotional expression
  • Avolition: reduced or absent ability to initiate purposeful activities
  • Alogia: impaired thinking that manifests with reduced speech output or poverty of speech (e.g., always replying to questions with one-word answers)
  • Anhedonia: inability to feel pleasure from activities that were formerly pleasurable or from any new positive stimuli
  • Apathy: lack of emotion or concern, especially with regard to matters that are normally considered important
  • Emotional and social withdrawal

Other features

Early-onset schizophrenia [3]

  • Definition: onset of schizophrenia < 18 years of age
  • Epidemiology: rare disorder [10]
  • Clinical features
  • Prognosis: typically more severe than adult-onset schizophrenia with worse outcomes the earlier the onset of symptoms

Hallucinations are more common than delusions at younger ages, but must be clearly differentiated from age-appropriate imaginative activity.

Catatonia

Approach [12]

Schizophrenia is a clinical diagnosis that should be made by a psychiatrist.

Brain imaging is not required for the diagnosis of schizophrenia but can show cortical atrophy, decreased hippocampal and temporal mass, and enlargement of the cerebral ventricles. [14]

DSM-5 diagnostic criteria [3]

Approach [12][15][16]

  • Ensure patient and provider safety in cases of acute psychoses.
  • Establish a therapeutic alliance when taking care of patients with delusions.
    • Acknowledge the patient's emotional state.
    • Avoid validation of delusions or confronting patients about the delusional nature of their symptoms.
  • Hospitalize patients who are:
    • At risk of harming themselves or others
    • Experiencing a first episode of psychosis
  • All patients should receive:
    • Specialized psychiatric care and a comprehensive treatment plan
    • Treatment with an antipsychotic medication
    • Adjunctive treatment with nonpharmacological interventions
    • Integrated care of psychiatric and medical comorbidities (e.g., depression, metabolic syndrome)
  • Prior to starting treatment patients should have:
    • Assessment of symptom severity using quantitative tools, e.g., the Brief Psychiatric Rating Scale [19]
    • Baseline diagnostic studies to screen for and facilitate treatment of complications
  • After starting treatment patients should be regularly reassessed to:

The diagnosis of schizophrenia and the initiation of long-term antipsychotic medication should be determined and managed by a psychiatrist.

Nonpharmacological interventions [12]

  • Provide adjunctive nonpharmacological interventions to all patients.
    • Cognitive-behavioral therapy: improves the quality of life and reduces positive symptoms
    • Psychoeducation : associated with improved social functioning and lower relapse rates
    • Supported employment services: improves employment outcomes
  • Family interventions : reduce core symptoms and relapse rates

Baseline studies prior to starting pharmacological treatment [12]

Selection of an initial antipsychotic medication [12]

Because of the risk of side effects, patients should not be started on long-acting injectable antipsychotics without a trial of the oral formulation of the same medication first. [12]

Clozapine and olanzapine are not recommended as first-line agents for patients experiencing their first episode of schizophrenia. Clozapine is associated with severe agranulocytosis, olanzapine with significant metabolic side effects. [17]

Reassessment

Symptom severity should be reassessed with a quantitative tool 2–4 weeks after initiating treatment.

Negative symptoms are more difficult to treat and may continue after positive symptoms have resolved. [21]

Partial or no response to initial antipsychotic medication [12]

  • Successful antipsychotic therapy should improve symptoms by > 20% after approximately 2 weeks.
  • If the patient has not had > 20% improvement by 2 weeks, or improvement subsequently plateaus at < 50% improvement:
    • Consider mitigating factors: cannabis use, medication interaction, poor absorption, effect of smoking on drug metabolism, concomitant disorder (e.g., depression) [12]
    • Consider increasing the dose of the initial medication one time.
    • If there is no response after this change, consider using a different antipsychotic. [12]
    • If there is no response after an adequate trial of 2 different antipsychotics, the patient is considered to have treatment-resistant schizophrenia.

Treatment-resistant schizophrenia [12]

All patients taking clozapine require regular monitoring of their absolute neutrophil count because of the risk of fatal agranulocytosis.

Continuation of medication [12]

Stopping antipsychotics during pregnancy risks relapse; it should only be done under guidance from experts in perinatal psychiatry.

Preventing relapse is one of the primary goals of schizophrenia treatment. [22][23]

Definition [24]

  • No established definition for relapse exists.
  • Commonly used criteria include:
    • Hospitalization for psychosis (most common)
    • Quantified decline on a clinical scale [23]
    • Exacerbation of symptoms or violent or self-injurious behavior

Epidemiology

  • Occurs in > 50% of patients who stop antipsychotics and 16% of those who continue treatment [25]
  • The risk is highest in patients who stop medications within 2 years of an acute episode of psychosis. [26]

Risk factors for relapse [24]

  • Nonadherence to medication (most common cause) [25]
  • Stress
  • Intercurrent mental illness, e.g., depression
  • Substance use [18][27]
  • History of hospitalizations or previous relapse
  • Treatment interruption (e.g., as a result of health insurance lapse)

Symptoms of relapse [28][29]

  • Symptoms generally occur in a predictable order and usually over a period of less than 4 weeks.
  • Onset may be abrupt, with as little as one day from the onset of symptoms to psychosis. [25]

Relatives can be a valuable source of collateral history as up to 75% will have noticed symptoms in the 4 weeks prior to relapse. [25]

Treatment [26]

  • Early intervention during prodromal symptoms may prevent relapse.
  • Reinstitute antipsychotics or increase the dose of currently used medication.
  • Consider adding a benzodiazepine (to reduce anxiety associated with relapse).

Prevention [24]

  • Encourage adherence to antipsychotic medications.
  • Provide concurrent nonpharmacological therapy. [30]
  • Educate patients and relatives on the signs of relapse in order to facilitate early intervention.

Complications of relapse [22][23][24]

  • Progressive functional impairment and cognitive decline [25]
  • Decreased responsiveness to long-term therapy
  • Worsened quality of life

Relapse in schizophrenia is best managed with aggressive prevention (i.e., continuous use of antipsychotic medications and adjunct nonpharmacological therapy).

General principles [31]

Systematic screening for multiple medical comorbidities and integrated team care is recommended for all patients with schizophrenia. [31]

Most common comorbidities [31][32]

Management of mental health comorbidities [12]

Patients recently discharged from hospital are at a significantly increased risk for suicide. Frequent outpatient visits are warranted. [20]

Management of medical comorbidities

Primary prevention

Patients taking antipsychotics are at increased risk of heatstroke secondary to poikilothermia; regular exercise is still encouraged but patients should be advised to take precautions on hot days and be alert to the symptoms of heatstroke. [16]

Recommended screening for patients taking antipsychotics [12]

Screening studies and recommended intervals for patients with schizophrenia taking antipsychotics [12][18]
Common complications Potential presentations Recommended studies Recommended intervals
Movement disorders
  • Symptom screening
  • Assessment with structured evaluation tool, e.g., abnormal involuntary movement scale
  • Symptom screening every visit
  • Structured assessment:
    • If new symptoms are detected on screening
    • Every 6 months for patients at high risk of movement disorders
    • Every 12 months for all other patients
Cardiovascular complications
  • As clinically indicated
  • ECG: after any changes to medication or dosage if the drug has a risk of prolonging QTc
Metabolic complications
  • 4 months after initiating a new regimen and then at least annually
Weight gain
Hyperprolactinemia [16]
  • Symptom screening: every visit until the patient is on a stable dose of antipsychotics, then annually if taking an antipsychotic with elevated risk [35]
  • Prolactin level if symptom screening is positive
Agranulocytosis (patients taking clozapine) [36]
  • For patients whose neutrophils remain within the normal range (ANC > 1500/mcL):
    • First 6 months: weekly
    • At 6–12 months: every 2 weeks
    • After 12 months: monthly
  • For patients with neutropenia:
    • Moderate (ANC 500–900/mcL): three times weekly until within the normal range
    • Severe (ANC < 500/mcL): daily until within the moderate range

Management of antipsychotic adverse effects and associated comorbidities [12][13]

Consult psychiatry if an adjustment of psychiatric medications is required.

Schizophrenia is a progressive disorder that causes significant impairment, with many patients presenting with psychosocial dysfunction.

Patients with schizophrenia are at an increased risk for alcohol use disorder, depression, violence, and suicide (∼ 5% complete suicide).

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