Initial Antipsychotic Treatment for Schizophrenia
Start with antipsychotic monotherapy using a second-generation antipsychotic, with the initial choice based on side-effect profile rather than efficacy, as all agents except clozapine demonstrate similar effectiveness for positive symptoms. 1, 2
Recommended First-Line Agents
The choice between these agents should be made collaboratively with the patient based on their tolerance for specific side effects:
Risperidone (starting dose 2 mg/day, target 4-8 mg/day) offers robust efficacy (effect size 0.56 vs placebo) but carries higher risk of prolactin elevation and extrapyramidal symptoms 3, 4
Olanzapine (starting dose 5-10 mg/day, target 10 mg/day) demonstrates strong efficacy (effect size 0.59 vs placebo) but requires concurrent metformin (500 mg daily, titrated to 1 g twice daily) to mitigate significant weight gain and metabolic effects 1, 2, 5, 4
Amisulpride (effect size 0.6 vs placebo) shows superior efficacy for negative symptoms (effect size 0.47 vs placebo) but has higher QTc prolongation risk and prolactin elevation 1, 4
Critical Treatment Timeline
Administer the first antipsychotic at therapeutic dose for exactly 4 weeks before assessing response, assuming good adherence 1, 2
If inadequate response after 4 weeks, switch to a different antipsychotic with a distinct receptor profile (e.g., if started on a D2 partial agonist, switch to amisulpride, risperidone, paliperidone, or olanzapine with metformin) 1, 2
After failure of two adequate trials (4 weeks each at therapeutic dose), initiate clozapine, as it is the only antipsychotic with documented superiority for treatment-resistant cases 1, 2, 6
Mandatory Baseline Assessment
Before initiating any antipsychotic, document:
- Target psychotic symptoms, preexisting abnormal movements, BMI, waist circumference, blood pressure, fasting glucose, lipid panel, prolactin, liver function tests, complete blood count, and electrocardiogram 1, 2, 6
Monitoring Schedule
Weekly assessments for first 6 weeks: BMI, waist circumference, blood pressure 2, 6
At 4 weeks: Fasting glucose 6
At 3 months and annually thereafter: Repeat all baseline metabolic parameters 2, 6
Critical Pitfalls to Avoid
Do not use the distinction between first-generation and second-generation antipsychotics to guide medication selection, as this classification is pharmacologically meaningless 1, 2
Do not switch medications before completing a full 4-week trial at therapeutic dose 1, 2
Do not use clozapine as first-line treatment—it should only be initiated after two failed monotherapy trials 1, 2, 6
Do not prescribe antipsychotic polypharmacy except after failed clozapine trial, as monotherapy is the evidence-based standard 1, 6
Do not exceed recommended dose ranges (risperidone >16 mg/day, olanzapine >20 mg/day), as higher doses increase side effects without improving efficacy 3, 5
Essential Adjunctive Treatment
Combine pharmacotherapy with psychosocial interventions including psychoeducation for patient and family, structured group programs, and continuity of care, as medication alone is insufficient 2, 6
Consider long-acting injectable formulations if adherence is uncertain, as they reduce hospitalization rates and improve long-term outcomes 6, 7