Depression

Depression, formally major depressive disorder, is characterized by persistent low mood or anhedonia (reduced pleasure) accompanied by cognitive, somatic, and functional symptoms for at least two weeks. It affects approximately 5-8% of adults annually and is a leading cause of disability worldwide. First-line evidence-based treatments include psychotherapy (cognitive behavioral therapy, interpersonal therapy, behavioral activation) for mild-to-moderate presentations, with SSRI or SNRI pharmacotherapy added for moderate-to-severe symptoms or insufficient psychotherapy response.

Nutraceutical interventions have evidence as adjuncts for specific indications. EPA-dominant omega-3 (1-2g EPA daily, EPA at least 60% of total) produces effect sizes SMD approximately −0.5 for major depression, with stronger effect in inflammatory subtypes (elevated hs-CRP above 3 mg/L). Saffron (30mg/day standardized extract) shows non-inferiority to fluoxetine and imipramine in multiple RCTs for mild-to-moderate depression. SAM-e (400-1600mg daily) has evidence as SSRI augmentation for partial responders. L-methylfolate (15mg daily) benefits depression with folate deficiency or MTHFR polymorphisms, often as SSRI adjunct.

Safety screening is essential. SAM-e and L-methylfolate can precipitate mania in bipolar-spectrum individuals; use validated screening tools (Mood Disorder Questionnaire, family history) before initiation. St. John’s Wort is effective for mild depression but interacts with numerous medications via CYP3A4 induction and is not included in our protocols for this reason. Exercise, sleep regulation, and cognitive behavioral therapy produce effect sizes that match or exceed most supplement interventions and should not be displaced by pharmacotherapy or supplements alone.