Modern concept of depression pathogenesis: the contribution of I.P. Lapin’s research team

Abstract

BACKGROUND: The advent of neuroleptics and antidepressant therapy marked a significant step forward in clinical psychiatry. Numerous experiments worldwide had been dedicated to a search for the potential neurobiological mechanisms underlying the potency of new psychopharmacological drugs. The first laboratory of psychopharmacology in the USSR was established in 1960 at the Leningrad Psychoneurological Institute. It was headed by Professor Izyaslav Petrovich Lapin. The foundational article by Lapin I.P. and Oksenkrug G.F. (The Lancet, 1969) continues to be cited 55 years after its publication, which determines the interest in the role of this research team in shaping temporal concepts of the pathogenesis of depression and the development of psychopharmacology.

AIM: To analyze the contribution of Lapin I.P. and his research team to the development of experimental approaches for studying the mechanisms of depression.

METHODS: We analyzed the articles and monographs authored by Professor Lapin I.P., both individually and in co-authorship, available in PubMed, Google Scholar, eLIBRARY.RU, and in the bibliographic collection of the V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology.

RESULTS: This analysis highlights the significance of Lapin I.P. and his scientific team’s work in advancing our understanding of serotonin role in the mechanisms of depression and in the development of animal depression models. The scientific contribution of this team is an important milestone towards future research into the neurobiological mechanisms underlying depression, as well as the development of therapeutic approaches.

CONCLUSION: Lapin’s scientific publications and the work of his team in the field of psychopharmacology have had a significant impact on the development of neuroscience and continue to be of unquestionable importance in advancing scientific practice more than 50 years later.

Keywords

psychopharmacology / affective disorder / neuroscience / history of medicine / history of psychiatry

References

[1] Haddad PM, Nutt DJ, Green AR. A Brief History of Psychopharmacology. In: Haddad PM, Nutt DJ, editors. Seminars in Clinical Psychopharmacology. College Seminars Series. 3rd ed. Cambridge: Cambridge University Press; 2020. p. 1–34.

[2] Lehmann HE. Before they called it psychopharmacology. Neuropsychopharmacology. 1993;8(4):291–303. doi: 10.1038/npp.1993.69

[3] Danilov DS. [The history of irreversible non-selective maoi antidepressants in russia (for their 70th anniversary)]. Obozrenie psihiatrii i medicinskoj psihologii im. V.M. Behtereva. 2023;57(2):75–92. Russian. doi: 10.31363/2313-7053-2023-670

[4] Braslow JT, Marder SR. History of Psychopharmacology. Annu Rev Clin Psychol. 2019;15:25–50. doi: 10.1146/annurev-clinpsy-050718-095514

[5] Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122(5):509–522. doi: 10.1176/ajp.122.5.509

[6] Robinson E. Psychopharmacology: From serendipitous discoveries to rationale design, but what next? Brain Neurosci Adv. 2018;2:23982128188126629. doi: 10.1177/2398212818812629

[7] Silvestrini B. Trazodone: from the mental pain to the “dys-stress” hypothesis of depression. Clin Neuropharmacol. 1989;12(Suppl 1):S4–S10. doi: 10.1097/00002826-198901001-00002

[8] Fuller RW, Wong DT, Molloy BB. Three pharmaceutical researchers working at Eli Lilly in the 1980s changed the treatment of depression with their invention of Prozac [Internet]. Philadelphia: Science History Institute; c2025 [cited 2025 April 2]. Available from: https://www.sciencehistory.org/education/scientific-biographies/ray-w-fuller-david-t-wong-and-bryan-b-molloy

[9] [Lapin Izyaslav Petrovich. On the 75th anniversary of his birth]. Social’naja i klinicheskaja psihiatrija. 2005;15(4):107. Russian.

[10] Lapin IP, Oxenkrug GF. Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet. 1969;1(7586):132–136. doi: 10.1016/s0140-6736(69)91140-4

[11] Kovalzon VM. [A modern view of the serotonin theory of depression. On the 90th anniversary of the outstanding Soviet and Russian psychopharmacologist Izyaslav Petrovich Lapin (1930–2012)]. Rossijskij nevrologicheskij zhurnal. 2020;25(3):40–44. Russian. doi: 10.30629/2658-7947-2020-25-3-40-44

[12] Oxenkrug GF. This week’s citation classic. Current contents [Internet]. 1987[cited 2025 April 2];(2):16. Available from: https://garfield.library.upenn.edu/classics1987/A1987F401700001.pdf

[13] Allikmets LH, Lapin IP. Influence of lesions of the amygdaloid complex on behaviour and on effects of antidepressants in rats. Int J Neuropharmacol. 1967;6(2):99–108. doi: 10.1016/0028-3908(67)90058-5

[14] Vakhing VA, Allikmets LK, Lapin IP. Onset of vomiting after microinjections of serotonin into the hypothalamus, septum, and amygdala of cats receiving imipramine. Bul Exp Biol Med. 1968;66(3):983–985. doi: 10.1007/BF00833732

[15] Allikmets LH, Vakhing VA, Lapin IP. [Effects of direct injection of mediators and chemicals influencing their metabolism into the amygdala, septum and hypothalamus in cats]. Zhurnal vysshej nervnoj dejatel’nosti im. I.P. Pavlova. 1968;18(6):1044–1049. Russian.

[16] Allikmets LH, Vahing VA, Lapin IP. Dissimilar influences of imipramine, benactyzine and promazine on effects of micro-injections of noradrenaline, acetylcholine and serotonin into the amygdala in the cat. Psychopharmacologia. 1969;15(5):392–403. doi: 10.1007/BF00403714

[17] Allikmets L, Lapin I. [Behavioral effects of the destruction of individual limbic structures in rats]. Zhurnal vysshej nervnoj dejatel’nosti im. I.P. Pavlova. 1966;8(2):129–139. Russian.

[18] Lapin IP, Shlik J. Tryptophan depletion and its implications for psychiatry. In: Nemeroff CB, Schatzberg AJ, editors. Essentials of Clinical Psychopharmacology. 2nd ed. Washington: American Psychiatric Publishing; 2007. p. 145–159.

[19] Franklin M, Bermudez I, Murck H, et al. Sub-chronic dietary tryptophan depletion — an animal model of depression with improved face and good construct validity. J Psychiatr Res. 2012;46(2):239–247. doi: 10.1016/j.jpsychires.2011.10.003

[20] Franklin M, Hlavacova N, Li Y, et al. Contrasting effects of vortioxetine and paroxetine on pineal gland biochemistry in a tryptophan-depletion model of depression in female rats. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):499–502. doi: 10.1016/j.pnpbp.2017.08.008

[21] Hlavacova N, Li Y, Pehrson A, et al. Effects of vortioxetine on biomarkers associated with glutamatergic activity in an SSRI insensitive model of depression in female rats. Prog Neuropsychopharmacol Biol Psychiatry. 20182;82:332–338. doi: 10.1016/j.pnpbp.2017.07.008

[22] Picard K, Bisht K, Poggini S, et al. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain Behav Immun. 2021;97:423–439. doi: 10.1016/j.bbi.2021.07.022

[23] Kashapov FF. [The biology of the amygdala complex in the anxiety and aggressiveness]. Jepoha nauki. 2017;(10):8–14. Russian. doi: 10.1555/2409-3203-2017-0-10-8-14

[24] Schmaal L, Pozzi E, Ho TC, et al. ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing. Transl Psychiatry. 2020;10(1):172. doi: 10.1038/s41398-020-0842-6

[25] Qiao H, An SC, Ren W, et al. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res. 2014;275:191–200. doi: 10.1016/j.bbr.2014.08.040

[26] Lapin IP, Oxenkrug GF, Osipova SV, et al. The frog as a subject for screening thymoleptic drugs. J Pharm Pharmacol. 1970;22(10):781–782. doi: 10.1111/j.2042-7158.1970.tb08429.x

[27] Lapin IP, Mirzaev S. Potentiation of the inhibitory effect of 5-hydroxytryptophan on the righting reflex in the frog as a sensitive test for antidepressants. J Pharmacol Methods. 1979;2(1):81–85. doi: 10.1016/0160-5402(79)90019-6

[28] Kotelnikova SO, Sadovsky MS, Kraineva VA, et al. [Modeling the depressive-like state of learned helplessness in rats of different stocks]. Laboratornye zhivotnye dlja nauchnyh issledovanij. 2022;5(2):26–31. Russian. doi: 10.29296/2618723X-2022-02-03

[29] Wang Q, Timberlake MA 2nd, Prall K, et al. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2017;77:99–109. doi: 10.1016/j.pnpbp.2017.04.008

[30] Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–147. doi: 10.1007/7854_2010_108

[31] Czéh B, Simon M. Benefits of animal models to understand the pathophysiology of depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2021;106:110049. doi: 10.1016/j.pnpbp.2020.110049

[32] Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902. doi: 10.1038/nature07455

[33] Tanti A, Belzung C. Open questions in current models of antidepressant action. Br J Pharmacol. 2010;159(6):1187–11200. doi: 10.1111/j.1476-5381.2009.00585.x

[34] Willner P, Scheel-Krüger J, Belzung C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev. 2013;37(10 Pt 1):2331–2371. doi: 10.1016/j.neubiorev.2012.12.007

[35] Boldrini M, Santiago AN, Hen R, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38(6):1068–1077. doi: 10.1038/npp.2013.5

[36] Sial OK, Parise EM, Parise LF, et al. Ketamine: The final frontier or another depressing end? Behav Brain Res. 2020;383:112508. doi: 10.1016/j.bbr.2020.112508

[37] Lapin IP. [Stress. Anxiety. Depression. Alcoholism. Epilepsy. Neurokinurenine mechanisms and new treatment approaches]. St. Petersburg: Dean; 2004. Russian.

[38] Chu A, Wadhwa R. Selective Serotonin Reuptake Inhibitors. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2023 [cited 2025 April 2]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554406

Funding

Federation of European Neuroscience SocietiesФедерация европейских нейробиологических обществ

RIGHTS & PERMISSIONS

Neznanov N.G., Tumova M.A., Freize V.V., Gerasimchuk E.S., Radionov D.S., Khobeysh M.A., Malyshko L.V., Anokhina M.V., Palchikova E.I., Sorokin M.Y.