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.
- Genetic factors: risk significantly increased if relatives are also affected 
- Environmental factors
Dysregulation of neurotransmitters 
- ↓ Dopamine in prefrontal cortical pathway may cause .
- ↑ Dopamine in mesolimbic pathway may lead to .
- ↑ Serotonergic activity
- ↓ Dendritic branching
- ↓ Glutamatergic neurotransmission may lead to psychosis.
- ↓ GABA leads to ↑ dopamine activity.
Structural and functional changes to the brain 
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). 
Positive symptoms of schizophrenia
- and/or (auditory hallucinations are most common)
- , , e.g., , ,
- or : e.g., , ,
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
- Impaired memory
- Poor executive functioning
- Mood symptoms and anxiety
- Neurological abnormalities: sensory disturbances and impaired coordination
- Metabolic abnormalities: hypertension, diabetes, hyperlipidemia
Subtypes and variants
Early-onset schizophrenia 
- Definition: onset of schizophrenia < 18 years of age
- Epidemiology: rare disorder 
- Diagnostic criteria are identical to those used for adults (see “Diagnostics” below).
- History preceding the onset of psychosis
- Hallucinations (mainly auditory) occur more commonly than delusions.
- Catatonia is less common than in adult-onset schizophrenia.
- Prognosis: typically more severe than adult-onset schizophrenia with worse outcomes the earlier the onset of symptoms
- Definition: a behavioral syndrome characterized by abnormal movements and reactivity to the environment
- Retarded catatonia: immobility, posturing, negativism (resisting external commands), staring, mutism
- Excited catatonia: excessive, purposeless movement in both the upper and lower limbs, restlessness, and impulsivity
- Malignant catatonia: fever, autonomic instability (e.g., tachycardia, tachypnea, abnormal BP, and sweating), rigidity, and delirium (resembles )
- Benzodiazepines (Intravenous or sublingual lorazepam): first-line for all forms of catatonia
- Electroconvulsive therapy
- Discontinue dopamine blocking drugs (e.g., antipsychotics); only reinitiate after catatonia resolves
- Treat the underlying psychiatric condition with appropriate pharmacotherapy
- Supportive measures
- Schizophrenia is a clinical diagnosis based on the DSM-5 criteria.
- Consult psychiatry urgently. 
- Diagnostic studies may be indicated to:
- See “Diagnostics” in “Approach to psychosis” for details.
DSM-5 diagnostic criteria 
- At least two of the following symptoms must be present, with at least one of these from the first three symptoms listed:
- The above symptoms persist for ≥ 1 month.
- There are continuous cognitive or affective disturbances for ≥ 6 months.
- Symptoms must cause social, occupational, or personal functional impairment lasting ≥ 6 months.
- Schizoaffective disorder and mood disorder with psychotic features have been ruled out.
- Medical or substance use disorder has been ruled out.
- Ensure patient and provider safety in cases of acute psychoses.
- Establish a therapeutic alliance when taking care of patients with delusions.
Hospitalize patients who are:
- At risk of harming themselves or others
- Experiencing a first episode of psychosis
- All patients should receive:
- Prior to starting treatment patients should have:
- Assessment of symptom severity using quantitative tools, e.g., the Brief Psychiatric Rating Scale 
- Baseline diagnostic studies to screen for and facilitate treatment of complications
- After starting treatment patients should be regularly reassessed to:
Nonpharmacological and pharmacological treatment
Nonpharmacological interventions 
- 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
- Cognitive remediation therapy in patients with cognitive impairment
- Social skills training
- Supported employment services: improves employment outcomes
- Consider assertive community treatment in patients who are at ongoing risk of hospitalization, incarceration, and/or unstable housing
- Family interventions : reduce core symptoms and relapse rates
Baseline studies prior to starting pharmacological treatment 
- Pregnancy test: Pregnancy may alter the management of schizophrenia.
- Laboratory studies (to establish a pretreatment baseline) :
- ECG: Assess for potential QTc prolongation or evidence of cardiovascular disease.
Selection of an initial antipsychotic medication 
- Antipsychotics (e.g., risperidone, aripiprazole, quetiapine) are the first-line treatment for schizophrenia.
- Treatment can be initiated with either a first generation or a second generation antipsychotic. 
- Base the selection of antipsychotics on:
- In pregnant patients, older generations of antipsychotics with a greater evidence base may be preferable. 
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. 
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. 
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. 
Partial or no response to initial antipsychotic medication 
- 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) 
- Consider increasing the dose of the initial medication one time.
- If there is no response after this change, consider using a different antipsychotic. 
- 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 
- Definition: persistent positive symptoms (i.e., delusions, hallucinations, and/or disorganized speech) despite trials of ≥ 6 weeks of 2 different antipsychotics at therapeutic doses 
- An estimated 25–30% of patients will be resistant to 2 medications. 
Clozapine is the drug of choice for treatment-resistant schizophrenia. 
- No response to 2 other antipsychotics
- Persistent aggressive behavior or suicidal intentions
- Clozapine is not used as first-line therapy because of its adverse effects, which include:
- Enrollment in a national patient registry and frequent monitoring of clozapine levels and CBC are mandated for clozapine use. 
Continuation of medication 
- Antipsychotic medication should be continued indefinitely if it has effectively reduced initial symptoms.
- Pregnancy is not an indication to stop treatment. 
Long-acting (injectable) antipsychotics may be considered based on patient preference or poor adherence to the medication regimen. ; 
- Nonadherence is common for several reasons : 
- Medication side effects (e.g., galactorrhea)
- Lack of patient insight into the need for treatment
- Difficulties adhering to a daily medication regimen
- Patients may prefer injectable medications because they are convenient and produce a stable drug effect.
- Examples of long-acting injectable antipsychotics include:
- Nonadherence is common for several reasons : 
Preventing relapse is one of the primary goals of schizophrenia treatment. 
- No established definition for relapse exists.
- Commonly used criteria include:
- Hospitalization for psychosis (most common)
- Quantified decline on a clinical scale 
- Exacerbation of symptoms or violent or self-injurious behavior
- Occurs in > 50% of patients who stop antipsychotics and 16% of those who continue treatment 
- The risk is highest in patients who stop medications within 2 years of an acute episode of psychosis. 
Risk factors for relapse 
- Nonadherence to medication (most common cause) 
- Intercurrent mental illness, e.g., depression
- Substance use 
- History of hospitalizations or previous relapse
- Treatment interruption (e.g., as a result of health insurance lapse)
Symptoms of relapse 
- Symptoms generally occur in a predictable order and usually over a period of less than 4 weeks.
- Dysphoric symptoms (most common)
- Emotional disturbance
- Psychotic symptoms
- Onset may be abrupt, with as little as one day from the onset of symptoms to psychosis. 
Relatives can be a valuable source of collateral history as up to 75% will have noticed symptoms in the 4 weeks prior to relapse. 
- 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).
- See “Management of agitated or violent patients” for acute stabilization measures.
- Encourage adherence to antipsychotic medications.
- Provide concurrent nonpharmacological therapy. 
- Educate patients and relatives on the signs of relapse in order to facilitate early intervention.
Complications of relapse 
- Progressive functional impairment and cognitive decline 
- 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).
Management of complications and comorbiditities
General principles 
- Risk factors for secondary medical illness include: 
- Routine health care is commonly underaddressed in patients with schizophrenia, resulting in significant morbidity. 
Systematic screening for multiple medical comorbidities and integrated team care is recommended for all patients with schizophrenia. 
Most common comorbidities 
- Coronary artery disease
- Diabetes mellitus
- Metabolic syndrome
- Obstructive sleep apnea
- Hepatitis B and hepatitis C
- Tobacco use disorder 
- Substance use disorders 
Management of mental health comorbidities 
Major depressive disorder: Up to 75% of patients experience depressive symptoms. 
- Perform regular screenings for major depressive disorder.
- In patients with symptoms of depression, consider: 
- Suicide: 5–15% of patients with schizophrenia commit suicide. 
Patients recently discharged from hospital are at a significantly increased risk for suicide. Frequent outpatient visits are warranted. 
Management of medical comorbidities
- Dietary and exercise advice
- Education on:
- Expected side effects of antipsychotics, including serious complications such as
- Importance of attending regular screenings
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. 
Recommended screening for patients taking antipsychotics 
|Screening studies and recommended intervals for patients with schizophrenia taking antipsychotics |
|Common complications||Potential presentations||Recommended studies||Recommended intervals|
|Movement disorders|| || |
|Metabolic complications|| |
|Weight gain|| |
|Hyperprolactinemia || |
|Agranulocytosis (patients taking clozapine) || || |
Management of antipsychotic adverse effects and associated comorbidities 
- Strategies to reduce and manage adverse effects include:
- Using the lowest possible dose
- Switching to another agent
- Dividing doses if possible
- Regular monitoring of patients taking clozapine (see above)
- Initiate standard therapy for comorbidities if feasible (e.g., diabetes management, lipid-lowering agents for hyperlipidemia).
- See “Management of antipsychotic adverse effects” and “Extrapyramidal disorders” for details.
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.
- Predictive factors for a favorable course of illness 
- Predictive factors for an unfavorable course of illness