[Mechanisms of Action of Antidepressive Pharmacotherapy: Brain and Mind-body and Environment]

Overview

Journal Nervenarzt

Date 2025 Jan 17

PMID 39821675

Authors

Moritz Spangemacher

Jonathan Reinwald

Hana Adolphi

Laura Kartner

Lea J Mertens

Christian N Schmitz

Gerhard Grunder

Affiliations

Soon will be listed here.

Abstract

Background: Novel antidepressive substances are challenging the explanations for the mechanisms of action of traditional psychopharmacology.

Objective: What could be the shared effects of various antidepressants and in this context what role do extrapharmacological factors, such as the body and environment, play?

Material And Method: The available literature on clinical and preclinical data for assumed combined active factors of serotonergic psychedelic drugs, (es)ketamine, monoaminergic antidepressants and zuranolone are presented and the influence of context factors on the individual mechanisms of action is discussed.

Results: There are many indications that classical and novel pharmacological approaches could share similar mechanisms of action in the treatment of depression. These mechanisms favor long-term neuroplasticity, which can trigger subsequent molecular cascades and vice versa. Furthermore, an improvement in the negative bias in emotional processing could be detected for most antidepressive substances. The influence of extrapharmacological factors appears to be necessary so that the biopsychological alterations can have an antidepressive effect.

Conclusion: Instead of attributing factors such as environment, body and social interaction to placebo effects, they should be tested as essential components of the antidepressive effect and considered in the clinical practice.

References

Georgiou P, Zanos P, Mou T, An X, Gerhard D, Dryanovski D . Experimenters' sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nat Neurosci. 2022; 25(9):1191-1200. PMC: 10186684. DOI: 10.1038/s41593-022-01146-x. View

Beurel E, Toups M, Nemeroff C . The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron. 2020; 107(2):234-256. PMC: 7381373. DOI: 10.1016/j.neuron.2020.06.002. View

Krishnan V, Nestler E . The molecular neurobiology of depression. Nature. 2008; 455(7215):894-902. PMC: 2721780. DOI: 10.1038/nature07455. View

Jauhar S, Arnone D, Baldwin D, Bloomfield M, Browning M, Cleare A . A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression. Mol Psychiatry. 2023; 28(8):3149-3152. PMC: 10618084. DOI: 10.1038/s41380-023-02095-y. View

Enkavi G, Girych M, Moliner R, Vattulainen I, Castren E . TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends Biochem Sci. 2024; 49(5):445-456. DOI: 10.1016/j.tibs.2024.02.001. View

Page C, Epperson C, Novick A, Duffy K, Thompson S . Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Mol Psychiatry. 2024; 29(12):3802-3813. PMC: 11692567. DOI: 10.1038/s41380-024-02625-2. View

Sayali C, Barrett F . The costs and benefits of psychedelics on cognition and mood. Neuron. 2023; 111(5):614-630. DOI: 10.1016/j.neuron.2022.12.031. View

Bottemanne H, Morlaas O, Claret A, Sharot T, Fossati P, Schmidt L . Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression. JAMA Psychiatry. 2022; 79(11):1124-1132. PMC: 9520441. DOI: 10.1001/jamapsychiatry.2022.2996. View

Nardou R, Sawyer E, Song Y, Wilkinson M, Padovan-Hernandez Y, de Deus J . Psychedelics reopen the social reward learning critical period. Nature. 2023; 618(7966):790-798. PMC: 10284704. DOI: 10.1038/s41586-023-06204-3. View

10.

Zilcha-Mano S, Roose S, Barber J, Rutherford B . Therapeutic alliance in antidepressant treatment: cause or effect of symptomatic levels?. Psychother Psychosom. 2015; 84(3):177-82. PMC: 4417334. DOI: 10.1159/000379756. View

11.

Fuchs T, Schlimme J . Embodiment and psychopathology: a phenomenological perspective. Curr Opin Psychiatry. 2009; 22(6):570-5. DOI: 10.1097/YCO.0b013e3283318e5c. View

12.

Yildirim E, Erol K, Ulupinar E . Effects of sertraline on behavioral alterations caused by environmental enrichment and social isolation. Pharmacol Biochem Behav. 2012; 101(2):278-87. DOI: 10.1016/j.pbb.2011.12.017. View

13.

Cooper A, Strunk D, Ryan E, DeRubeis R, Hollon S, Gallop R . The therapeutic alliance and therapist adherence as predictors of dropout from cognitive therapy for depression when combined with antidepressant medication. J Behav Ther Exp Psychiatry. 2015; 50:113-9. PMC: 4679463. DOI: 10.1016/j.jbtep.2015.06.005. View

14.

Madsen M, Fisher P, Burmester D, Dyssegaard A, Stenbaek D, Kristiansen S . Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019; 44(7):1328-1334. PMC: 6785028. DOI: 10.1038/s41386-019-0324-9. View

15.

Harmer C, Duman R, Cowen P . How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017; 4(5):409-418. PMC: 5410405. DOI: 10.1016/S2215-0366(17)30015-9. View

16.

Cussotto S, Clarke G, Dinan T, Cryan J . Psychotropic Drugs and the Microbiome. Mod Trends Psychiatry. 2021; 32:113-133. DOI: 10.1159/000510423. View

17.

Reed M, Vanicek T, Seiger R, Klobl M, Spurny B, Handschuh P . Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval. Neuroimage. 2021; 236:118039. PMC: 7610799. DOI: 10.1016/j.neuroimage.2021.118039. View

18.

Moncrieff J, Cooper R, Stockmann T, Amendola S, Hengartner M, Horowitz M . The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022; 28(8):3243-3256. PMC: 10618090. DOI: 10.1038/s41380-022-01661-0. View

19.

Cutler A, Mattingly G, Maletic V . Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder. Transl Psychiatry. 2023; 13(1):228. PMC: 10293235. DOI: 10.1038/s41398-023-02514-2. View

20.

Grunder G, Brand M, Mertens L, Jungaberle H, Kartner L, Scharf D . Treatment with psychedelics is psychotherapy: beyond reductionism. Lancet Psychiatry. 2023; 11(3):231-236. DOI: 10.1016/S2215-0366(23)00363-2. View