Many antidepressants work by entering cells and binding to targets inside the cytoplasm or organelles, contrary to the traditional view that they act only at extracellular sites on cell surface proteins. The ability of a drug to cross membranes depends on its charge and lipid solubility, described by parameters LogP, pKa, and LogD at pH 7.4. Some antidepressants have an unusually large volume of distribution, reflecting both binding to membranes and trapping inside acidic organelles. For SSRIs and SNRIs, the exact cellular compartment where they engage their target transporters remains unknown. Rapidly acting antidepressants like ketamine and psychedelics also rely on these intracellular mechanisms, an area termed location-biased or inside-out pharmacology.
Ketamine, an anesthetic that produces dissociative anesthesia—characterized by perceptual detachment, analgesia, and altered consciousness—also acts as a rapid antidepressant at low doses and serves as a tool to study consciousness and neuropsychiatric disorders. Its effects stem from actions on cortical circuits: blocking NMDA receptors and HCN1 channels, disinhibiting pyramidal neurons, and altering thalamocortical connectivity. The review synthesizes findings from pharmacology, cell-specific imaging, and systems neuroscience to explain how ketamine alters cortical dynamics to drive dissociation. It also explores the possibility that ketamine enters intracellular compartments, modulating neuronal excitability, signaling, and epigenetic state after a single dose. Understanding these processes may inform new treatments for treatment-resistant depression and the study of consciousness.