What is the recommended treatment for schizophrenia?

Treatment of Schizophrenia

Initiate antipsychotic monotherapy immediately after ≥1 week of psychotic symptoms causing distress or functional impairment, starting with risperidone 1-2 mg/day or olanzapine 7.5-10 mg/day as first-line options, combined with psychosocial interventions. 1, 2

When to Start Treatment

• Begin antipsychotic treatment after one week or more of psychotic symptoms with associated distress or functional impairment 1, 2
• Start earlier if symptoms cause severe distress or pose safety concerns to self or others 1, 2
• Delay treatment only when symptoms are clearly related to substance use or medical conditions without safety concerns 1

First-Line Antipsychotic Selection

The choice of antipsychotic must be made collaboratively with the patient through shared decision-making, prioritizing side-effect and efficacy profiles. 1, 2

• Do not use first-generation versus second-generation classification to guide drug choice—this distinction is not pharmacologically or clinically meaningful 1
• Risperidone is the recommended first-line agent for first-episode psychosis in adults, starting at 1 mg twice daily and gradually titrating to the target range of 1.25-3.5 mg/day 2, 3
• Alternative high-quality second-line options include olanzapine 7.5-15 mg/day, quetiapine 100-300 mg/day, and aripiprazole 15-30 mg/day 2, 4
• For established schizophrenia, risperidone, olanzapine, amisulpride, and paliperidone are recommended initial options 5

Critical Dosing Principles for First-Episode Patients

• First-episode patients are more sensitive to both therapeutic effects and side effects—maximum doses should be 4 mg/day risperidone or 20 mg/day olanzapine 2
• Initial target doses should be risperidone 2 mg/day or olanzapine 7.5-10 mg/day 2
• For ongoing schizophrenia, olanzapine should be administered once daily beginning with 5-10 mg initially, with a target dose of 10 mg/day within several days 4

Duration of Adequate Trial

• Administer at therapeutic dose for at least 4-6 weeks before assessing efficacy 1, 2, 5
• Assume good adherence during this initial trial period 1

Algorithm for Treatment Progression

If First Antipsychotic Fails (After 4-6 Weeks)

• Switch to a second antipsychotic with a different pharmacodynamic profile 1, 2
• If first-line was risperidone, switch to olanzapine, quetiapine, or aripiprazole 2
• If first-line was a D2 partial agonist, consider switching to paliperidone 1
• Use gradual cross-titration informed by half-life and receptor profile 1, 5
• Continue for another 4-6 weeks at therapeutic dose 1, 2

If Second Antipsychotic Fails (Treatment-Resistant Schizophrenia)

• After failure of two adequate antipsychotic trials (each at therapeutic dose for 4-6 weeks), initiate clozapine 2, 5
• Do not delay clozapine initiation in treatment-resistant cases—earlier use improves outcomes 5
• Clozapine should be titrated based on response and tolerability, with a target plasma level of at least 350 ng/mL 5
• Specific monitoring for clozapine includes weekly blood cell counts during the first 6 months 5

Critical Monitoring Requirements

Obtain comprehensive baseline measures before starting any antipsychotic: 6, 1, 2

• BMI and waist circumference
• Blood pressure
• HbA1c or fasting glucose
• Lipid panel
• Prolactin level
• Liver function tests
• Urea and electrolytes
• Full blood count
• Electrocardiogram

Follow-up monitoring schedule: 6, 1

• Fasting glucose at 4 weeks (if fasting sample cannot be obtained, use random sample as initial screening, then prioritize fasting measure if abnormal) 6
• BMI, waist circumference, and blood pressure weekly for 6 weeks 6, 1
• Repeat complete metabolic panel at 3 months, then annually 6, 1

Metabolic Risk Management

• Offer metformin prophylactically when starting olanzapine or clozapine 1, 2, 5
• Check renal function before starting metformin, and avoid in renal failure 1
• Start metformin at 500 mg once daily, and increase by 500 mg every 2 weeks, targeting 1 g twice daily based on tolerability 1
• Lifestyle advice (healthy diet, promotion of physical activity, and tobacco cessation) should be offered to all 6

Managing Adverse Effects

Hyperprolactinemia

• Patients should be counseled on risks of untreated asymptomatic hyperprolactinemia, including reduced bone mineral density and increased risk of breast cancer in women 6
• Where appropriate, consider switching to a D2 partial agonist or adding adjunctive low-dose aripiprazole 6

Akathisia

• Can potentially be managed with dose reduction 6
• A switch to quetiapine or olanzapine can be considered 6
• Alternatively, adjunctive propranolol (10 mg or up to 30 mg, two to three times daily) may be an option 6

Weight Gain

• Treatment strategies include switching to an antipsychotic with a more benign metabolic profile, adjunctive metformin treatment, or adjunctive treatment with a GLP-1 receptor agonist 6

Mandatory Psychosocial Interventions

Adequate treatment requires combination of pharmacological agents plus psychosocial interventions. 1, 2

• Provide psychoeducation to patient and family about illness, treatments, and expected outcomes 1
• Offer coordinated specialty care programs 2
• Include cognitive-behavioral therapy for psychosis, family interventions, social skills training, and supported employment services 2
• Offer structured group programs tailored to immediate patient needs 1
• Ensure continuity of care with same treating clinician for at least first 18 months 1

Duration of Maintenance Treatment

• First-episode patients should receive maintenance psychopharmacological treatment for 1-2 years after the initial episode 2, 5
• Continue treatment with the same medication if symptoms have improved 2
• Long-term maintenance dosing may be lower than acute treatment doses to minimize side effects while preventing relapse 5

Common Pitfalls to Avoid

• Do not use doses that are too high, especially in first-episode patients 2
• Do not switch medications too quickly—allow adequate trial duration of 4-6 weeks 2
• Do not pursue high-dose strategies instead of switching antipsychotics 2
• Do not delay clozapine in treatment-resistant cases 2, 5
• Do not neglect psychosocial interventions 2
• Do not provide inadequate metabolic monitoring 2
• Antipsychotic polypharmacy should generally be avoided except in specific augmentation strategies for clozapine 5

Long-Acting Injectable Formulations

• Long-acting injectable formulations should be considered for patients with adherence issues 5
• Risperidone ISM allows therapeutic levels to be achieved within 2 hours of intramuscular administration without loading doses or oral supplementation 7