In treatment-resistant depression, augmentation with aripiprazole is preferred over olanzapine. The pharmacological rationale relates to aripiprazole's unique receptor profile, which includes:

• A Full antagonism at D2, D3, and D4 receptors with no serotonergic activity
• B Inverse agonism at D2 receptors and agonism at D1 receptors
• C Partial agonism at D2 and 5-HT1A receptors with antagonism at 5-HT2A receptors ✓
• D Selective blockade of D3 receptors without D2 activity

Explanation

Aripiprazole is a 'third-generation' atypical antipsychotic functioning as a partial agonist at D2 and D3 receptors and at 5-HT1A receptors, plus an antagonist at 5-HT2A receptors. In hypodopaminergic prefrontal regions (relevant to depression), partial D2 agonism functions as net agonism boosting mood; in hyperdopaminergic mesolimbic areas, it functions as net antagonism. 5-HT1A partial agonism augments antidepressant effect. Unlike olanzapine, aripiprazole carries minimal metabolic adverse effects (weight gain, dyslipidemia), making it a safer augmenter.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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