In a patient with psychotic depression who is stable on olanzapine 12.5 mg daily and sertraline 200 mg daily, why should the olanzapine dose be increased?

Why Increase Olanzapine in Stable Psychotic Depression?

You should NOT increase olanzapine from 12.5 mg if the patient is stable and in remission—continuing the current dose that achieved remission is the evidence-based approach to prevent relapse. 1

The Evidence for Continuation at Remission Dose

The landmark STOP-PD II trial definitively demonstrated that continuing the olanzapine dose that achieved remission (median 15 mg/day) significantly reduced relapse risk compared to discontinuing it (20.3% vs 54.8% relapse rate over 36 weeks; HR 0.25, p<0.001). 1 This study specifically enrolled patients who were stable on their remission doses and randomized them to continue or stop—there was no dose escalation arm because the remission dose was already effective. 1

Why Stability Means Maintaining Current Dose

• Within the therapeutic range, olanzapine's effect on relapse prevention does not depend on higher dosages—meaning 12.5 mg is as protective as higher doses if it achieved remission. 2

• The 2025 INTEGRATE guidelines recommend maintaining a therapeutic dose for at least 4 weeks before considering medication changes, and only switching if positive symptoms persist despite good adherence. 3 Your patient has neither persistent symptoms nor poor adherence—they are stable. 4, 3

• Dose escalation is indicated only when symptoms remain significant after adequate trial duration, not when remission has been achieved. 4, 3

The Cost-Benefit Analysis of Increasing Dose

Increasing olanzapine in a stable patient exposes them to greater metabolic harm without additional therapeutic benefit:

• Approximately 40% of patients on olanzapine experience significant weight gain, with dose-related increases in weight (0.13 lb/day), waist circumference, and total cholesterol. 1, 3

• Higher olanzapine exposure correlates with greater cortical thickness reduction, though this effect plateaus within therapeutic range. 2

• The STOP-PD II trial showed that even at remission doses, patients experienced measurable metabolic deterioration—unnecessarily increasing dose amplifies this risk without improving relapse prevention. 1

When Dose Adjustment IS Appropriate

You should consider changing the regimen only if:

• Breakthrough psychotic or depressive symptoms emerge (indicating inadequate coverage). 4, 3

• The patient develops intolerable side effects requiring dose reduction or switch. 3

• After 9 months of stability, you might consider gradual dose reduction (not increase) to find the minimum effective maintenance dose, though this must be balanced against relapse risk. 5

Practical Management Algorithm

1. Continue sertraline 200 mg + olanzapine 12.5 mg as the maintenance regimen. 1

2. Implement metabolic protection: Offer concurrent metformin to attenuate weight gain, as recommended by 2025 INTEGRATE guidelines. 4, 3

3. Monitor systematically: Weight, glucose, lipids at baseline and regularly; assess for breakthrough symptoms at each visit. 3

4. Plan long-term: After sustained remission (≥9 months), consider whether gradual olanzapine taper is appropriate, recognizing the high relapse risk demonstrated in STOP-PD II. 1, 5

Common Pitfall to Avoid

Do not conflate "therapeutic dose range" (5-20 mg for schizophrenia) with "optimal maintenance dose for psychotic depression remission." The dose that achieved remission IS the therapeutic dose for that individual patient—escalating beyond this point provides no additional protection and increases harm. 1, 2