Antidepressants enter cells, organelles, and membranes.

We begin by summarizing several examples of antidepressants whose therapeutic actions begin when they encounter their targets in the cytoplasm or in the lumen of an organelle. These actions contrast with the prevailing view that most neuropharmacological actions begin when drugs engage their therapeutic targets at extracellular binding sites of plasma membrane targets-ion channels, receptors, and transporters. We review the chemical, pharmacokinetic, and pharmacodynamic principles underlying the movements of drugs into subcellular compartments. We note the relationship between protonation-deprotonation events and membrane permeation of antidepressant drugs. The key properties relate to charge and hydrophobicity/lipid solubility, summarized by the parameters LogP, pKa, and LogDpH7.4. The classical metric, volume of distribution (Vd), is unusually large for some antidepressants and has both supracellular and subcellular components. A table gathers structures, LogP, PKa, LogDpH7.4, and Vd data and/or calculations for most antidepressants and antidepressant candidates. The subcellular components, which can now be measured in some cases, are dominated by membrane binding and by trapping in the lumen of acidic organelles. For common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), the target is assumed to be the eponymous reuptake transporter(s), although in fact the compartment of target engagement is unknown. We review special aspects of the pharmacokinetics of ketamine, ketamine metabolites, and other rapidly acting antidepressants (RAADs) including methoxetamine and scopolamine, psychedelics, and neurosteroids. Therefore, the reader can assess properties that markedly affect a drug's ability to enter or cross membranes-and therefore, to interact with target sites that face the cytoplasm, the lumen of organelles, or a membrane. In the current literature, mechanisms involving intracellular targets are termed "location-biased actions" or "inside-out pharmacology". Hopefully, these general terms will eventually acquire additional mechanistic details.