What is the recommended dose of quetiapine (Seroquel) for augmentation in treatment-resistant depression?

Quetiapine Augmentation Dosing for Treatment-Resistant Depression

For treatment-resistant depression, quetiapine augmentation should be initiated at 50 mg once daily at bedtime and titrated to a target dose of 150-300 mg/day, though the FDA-approved maximum for bipolar depression is 300 mg/day. 1

FDA-Approved Dosing for Depression

The FDA label for quetiapine specifies dosing only for bipolar depression, not unipolar treatment-resistant depression 1:

• Day 1: 50 mg once daily at bedtime
• Day 2: 100 mg once daily at bedtime
• Day 3: 200 mg once daily at bedtime
• Day 4 and beyond: 300 mg once daily at bedtime (maximum approved dose) 1

Evidence-Based Dosing in Treatment-Resistant Depression

While quetiapine is commonly used off-label for treatment-resistant unipolar depression, the evidence base shows variable dosing strategies 2:

• Open-label studies used mean doses of 245 mg at 8 weeks and 346 mg at 26 weeks, with flexible dosing ranging from 50-300 mg/day 3
• Randomized controlled trials employed flexible dosing of 50-300 mg/day extended-release formulation 4
• The largest head-to-head trial (LQD trial) comparing quetiapine to lithium augmentation used flexible dosing, though specific dose ranges were not detailed in the provided evidence 5

Start with 50 mg at bedtime and increase by 50-100 mg every 2-3 days based on tolerability, targeting 150-300 mg/day. 1, 3

Critical Dosing Considerations

Elderly and Debilitated Patients

• Start at 25 mg/day (half the standard starting dose)
• Increase in 50 mg/day increments with slower titration
• Use caution due to increased risk of hypotensive reactions 1

Hepatic Impairment

• Start at 25 mg/day
• Increase daily in 25-50 mg/day increments to effective dose 1

Drug Interactions Requiring Dose Adjustment

• With potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): Reduce quetiapine dose to one-sixth of original dose 1
• With potent CYP3A4 inducers (phenytoin, carbamazepine, rifampin): Increase quetiapine dose up to 5-fold of original dose after 7-14 days of chronic inducer use 1

Clinical Efficacy Context

Quetiapine augmentation demonstrates modest efficacy in treatment-resistant depression but with important caveats:

• In the LQD trial, quetiapine showed superior reduction in depressive symptom burden compared to lithium over 12 months, though time to discontinuation did not differ 5
• Response rates in open-label studies were 29% on MADRS and 54% on CGI-I at 8 weeks 3
• A randomized placebo-controlled trial in depression with comorbid anxiety showed quetiapine superior to placebo on HAM-D (mean difference -3.64) and HAM-A (mean difference -4.02) 4

However, quetiapine performed poorly in OCD augmentation trials, being significantly inferior to fluoxetine plus clomipramine or fluoxetine plus placebo 6, suggesting its efficacy may be diagnosis-specific.

Safety Monitoring Requirements

Common Adverse Effects

• Sedation (54%), dry mouth (38%), and dizziness (29%) are most frequent 3
• Weight gain occurred in 40% of patients treated for 26 weeks 3
• Metabolic dysregulation requires ongoing monitoring 6

Serious Adverse Events

• Overdose occurred in 3% of patients in the LQD trial 5
• Monitor for akathisia and tardive dyskinesia risk with long-term use 2

Patient Perspectives

• Greater apprehension about side effects was reported for lithium pre-treatment, but greater experience of negative side effects was reported for quetiapine during treatment 7
• Sedation and weight gain are the most concerning tolerability issues affecting adherence 7, 3

Practical Algorithm

1. Confirm treatment resistance: At least 2 adequate antidepressant trials (minimum licensed dose for ≥4 weeks each) with <25% improvement 6

2. Initiate quetiapine:

   • Standard patients: 50 mg at bedtime
   • Elderly/debilitated: 25 mg at bedtime 1

3. Titrate over 4-7 days:

   • Increase by 50-100 mg every 2-3 days
   • Target 150-300 mg/day based on response and tolerability 1, 3

4. Assess response at 8-12 weeks before determining treatment failure 6

5. Monitor metabolic parameters (weight, glucose, lipids) at baseline, 3 months, and annually 6

The benefits of quetiapine augmentation must be weighed against metabolic and sedation risks, with only modest effect sizes compared to placebo and approximately one-third of patients achieving clinically meaningful response. 6, 4, 3