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Antidepressants enter cells, organelles, and membranes

Neuropsychopharmacology volume 49, pages 246–261 (2024)Cite this article

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Abstract

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.

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Fig. 1: A cellular-level “inside-out” view of antidepressant actions.
Fig. 2: The concept of LogP and LogDpH.
Fig. 3: Weak bases accumulate in acidic vesicles.

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Funding

The group of HAL has been funded by the National Institute of Mental Health (MH1230823), the National Institute of General Medical Science (GM123582), National Institute on Drug Abuse (DA043829, DA049140), and the California Tobacco-Related Disease Research Program (27IP-0057). KB was supported by the Della Martin Foundation and the Howard Hughes Medical Institute. The group of EC was supported by the Academy of Finland (294710, 303124, 307416 and 327192), Sigrid Jusélius Foundation, and Jane and Aatos Erkko Foundation.

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Authors and Affiliations

  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Zack Blumenfeld & Henry A. Lester

  2. Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Zack Blumenfeld

  3. Department of Neurosciences and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, USA

    Kallol Bera

  4. Neuroscience Center, University of Helsinki, Helsinki, Finland

    Eero Castrén

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  1. Zack Blumenfeld
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  2. Kallol Bera
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  4. Henry A. Lester
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All authors wrote and edited all portions of the manuscript. KB provided final formatting of Table 1 and the Supplementary Files and also conceived the Figures.

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Correspondence to Henry A. Lester.

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Blumenfeld, Z., Bera, K., Castrén, E. et al. Antidepressants enter cells, organelles, and membranes. Neuropsychopharmacol. 49, 246–261 (2024). https://doi.org/10.1038/s41386-023-01725-x

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