Chapter 7: Treatments for Mood Disorders: So-Called "Antidepressants" and "Mood Stabilizers"

A fundamental shift in treatment philosophy emphasizes achieving complete remission rather than partial symptom reduction, recognizing that initial monotherapies frequently fall short of this goal. For unipolar depression, the chapter systematically reviews selective serotonin reuptake inhibitors and their varied receptor binding profiles beyond serotonin transporter blockade, serotonin-partial agonist reuptake inhibitors that combine transporter inhibition with 5HT1A partial agonism for enhanced efficacy, and serotonin-norepinephrine reuptake inhibitors whose dual mechanism functionally operates through a "two-and-a-half" action whereby norepinephrine transporter blockade selectively increases dopamine availability in prefrontal cortical regions, benefiting both mood and cognitive function. The discussion extends to norepinephrine-dopamine reuptake inhibitors particularly suited for anhedonia, noradrenergic and specific serotonergic agents leveraging alpha-2 antagonism for robust monoamine elevation, and multimodal agents with superior cognitive enhancement properties. For treatment-resistant presentations, augmentation strategies employ dopamine-serotonin antagonists or rapid-onset NMDA receptor antagonists whose mechanisms include promotion of synaptogenesis and neuroplasticity through AMPA receptor activation and downstream signaling cascades. Second-line monotherapies including tricyclic antidepressants and monoamine oxidase inhibitors are evaluated against their safety profiles and dietary constraints. The bipolar spectrum receives differentiated analysis, distinguishing between serotonin-dopamine antagonists and classic mood stabilizers based on their directional efficacy—whether agents address symptoms from the manic pole or the depressed pole. Throughout, the chapter emphasizes mechanism-based classification that clarifies pharmacological action and informs rational polypharmacy decisions.