Why Antidepressants Don’t Always Make You Feel Better

Depression is more than sadness—it's a systemic condition affecting mind and body. While the serotonin deficiency theory led to the widespread use of SSRIs like Prozac, research now suggests depression is far more complex. Only about 10% of SSRI efficacy is biological, with a significant placebo effect. Worse, long-term SSRI use may increase depression risk and double suicide rates.

Genetic studies have identified over 700 variants linked to depression, yet serotonin-related genes account for just a fraction. Key genes like BDNF (affecting brain plasticity) and COMT (impacting dopamine metabolism) play a greater role. Additionally, depression isn't solely a brain disorder—chronic stress, inflammation, and metabolic dysfunction all contribute.

Polyvagal Theory and heart rate variability research suggest depression may be a biological energy crisis, where prolonged stress leads to mitochondrial dysfunction. When the body remains in fight-or-flight mode too long, the inflammatory reflex disrupts cellular function, leading to depressive symptoms.

This shift in understanding calls for new treatment approaches. Rather than focusing only on serotonin, addressing inflammation, nervous system regulation, and mitochondrial health may provide more effective long-term solutions.