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. 2024;22(5):904-915.
doi: 10.2174/1570159X21666230811141557.

The HPA Axis as Target for Depression

Affiliations

The HPA Axis as Target for Depression

Andreas Menke. Curr Neuropharmacol. 2024.

Abstract

Major depressive disorder (MDD) is a stress-related mental disorder with a lifetime prevalence of 20% and, thus, is one of the most prevalent mental health disorders worldwide. Many studies with a large number of patients support the notion that abnormalities of the hypothalamus-pituitaryadrenal (HPA) axis are crucial for the development of MDD. Therefore, a number of strategies and drugs have been investigated to target different components of the HPA axis: 1) corticotrophinreleasing hormone (CRH) 1 receptor antagonists; 2) vasopressin V1B receptor antagonists, 3) glucocorticoid receptor antagonists, and 4) FKBP5 antagonists. Until now, V1B receptor antagonists and GR antagonists have provided the most promising results. Preclinical data also support antagonists of FKBP5, which seem to be partly responsible for the effects exerted by ketamine. However, as HPA axis alterations occur only in a subset of patients, specific treatment approaches that target only single components of the HPA axis will be effective only in this subset of patients. Companion tests that measure the function of the HPA axis and identify patients with an impaired HPA axis, such as the dexamethasone-corticotrophin-releasing hormone (dex-CRH) test or the molecular dexamethasonesuppression (mDST) test, may match the patient with an effective treatment to enable patient-tailored treatments in terms of a precision medicine approach.

Keywords: CRH1; FKBP5; HPA axis; SSR149415; V1B receptor antagonist; antidepressants; biomarkers; depression; glucocorticoid receptor.; precision medicine; stress; vasopressin.

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Conflict of interest statement

The author acknowledges the health insurance company, AOK, the Bavarian General Practitioner’s Association, Medice and Neuraxpharm.

Figures

Fig. (1)
Fig. (1)
The hypothalamus-pituitary-adrenal (HPA) axis: The corticotrophin-releasing hormone (CRH) is released by the paraventricular nucleus (PVN) of the hypothalamus and then binds to the corticotrophin-releasing hormone 1 CRH1 receptors in the anterior pituitary (target 1). The secretion of adrenocorticotropic hormone (ACTH) into the peripheral circulation is activated. In addition, arginine-vasopressin (AVP) is also produced in the PVN and released into the pituitary circulation, where it potentiates the effects of CRH on ACTH release via activation of V1B receptors (target 2). ACTH induces the release of cortisol in the adrenal cortex, which exerts its effects on peripheral cells. Cortisol also activates the negative feedback loops by stimulating the glucocorticoid receptors (GR) in the pituitary and the hypothalamus to reinstate homeostasis (target 3). The GR complex consists of the co-chaperones FKBP51 and FKBP52 of the heat-shock protein hsp90 dimer and the co-chaperone molecule p23. When FKBP51 is bound to the receptor complex, cortisol binds with lower affinity (target 4). After cortisol binding, FKBP51 is exchanged against FKBP52, and nuclear translocation and transcriptional activity are enabled. In terms of an ultrashort negative feedback loop, GR activation leads to transcription and translation of FKBP51, which reduces GR sensitivity. Reprinted from Psychoneuroendocrinology, Volume 91, Carolin Leistner, Andreas Menke, How to measure glucocorticoid receptor’s sensitivity in patients with stress-related psychiatric disorders, 235-260, Copyright (2018), with permission from Elsevier.

References

    1. Ebmeier K.P., Donaghey C., Steele J.D. Recent developments and current controversies in depression. Lancet. 2006;367(9505):153–167. doi: 10.1016/S0140-6736(06)67964-6. - DOI - PubMed
    1. Vos T., Barber R.M., Bell B., Bertozzi-Villa A., Biryukov S., Bolliger I., Charlson F., Davis A., Degenhardt L., Dicker D., Duan L., Erskine H., Feigin V.L., Ferrari A.J., Fitzmaurice C., Fleming T., Graetz N., Guinovart C., Haagsma J., Hansen G.M., Hanson S.W., Heuton K.R., Higashi H., Kassebaum N., Kyu H., Laurie E., Liang X., Lofgren K., Lozano R., MacIntyre M.F., Moradi-Lakeh M., Naghavi M., Nguyen G., Odell S., Ortblad K., Roberts D.A., Roth G.A., Sandar L., Serina P.T., Stanaway J.D., Steiner C., Thomas B., Vollset S.E., Whiteford H., Wolock T.M., Ye P., Zhou M., Ãvila M.A., Aasvang G.M., Abbafati C., Ozgoren A.A., Abd-Allah F., Aziz M.I.A., Abera S.F., Aboyans V., Abraham J.P., Abraham B., Abubakar I., Abu-Raddad L.J., Abu-Rmeileh N.M.E., Aburto T.C., Achoki T., Ackerman I.N., Adelekan A., Ademi Z., Adou A.K., Adsuar J.C., Arnlov J., Agardh E.E., Al Khabouri M.J., Alam S.S., Alasfoor D., Albittar M.I., Alegretti M.A., Aleman A.V., Alemu Z.A., Alfonso-Cristancho R., Alhabib S., Ali R., Alla F., Allebeck P., Allen P.J., AlMazroa M.A.A., Alsharif U., Alvarez E., Alvis-Guzman N., Ameli O., Amini H., Ammar W., Anderson B.O., Anderson H.R., Antonio C.A.T., Anwari P., Apfel H., Arsenijevic V.S.A., Artaman A., Asghar R.J., Assadi R., Atkins L.S., Atkinson C., Badawi A., Bahit M.C., Bakfalouni T., Balakrishnan K., Balalla S., Banerjee A., Barker-Collo S.L., Barquera S., Barregard L., Barrero L.H., Basu S., Basu A., Baxter A., Beardsley J., Bedi N., Beghi E., Bekele T., Bell M.L., Benjet C., Bennett D.A., Bensenor I.M., Benzian H., Bernabe E., Beyene T.J., Bhala N., Bhalla A., Bhutta Z., Bienhoff K., Bikbov B., Abdulhak A.B., Blore J.D., Blyth F.M., Bohensky M.A., Basara B.B., Borges G., Bornstein N.M., Bose D., Boufous S., Bourne R.R., Boyers L.N., Brainin M., Brauer M., Brayne C.E.G., Brazinova A., Breitborde N.J.K., Brenner H., Briggs A.D.M., Brooks P.M., Brown J., Brugha T.S., Buchbinder R., Buckle G.C., Bukhman G., Bulloch A.G., Burch M., Burnett R., Cardenas R., Cabral N.L., Nonato I.R.C., Campuzano J.C., Carapetis J.R., Carpenter D.O., Caso V., Castaneda-Orjuela C.A., Catala-Lopez F., Chadha V.K., Chang J-C., Chen H., Chen W., Chiang P.P., Chimed-Ochir O., Chowdhury R., Christensen H., Christophi C.A., Chugh S.S., Cirillo M., Coggeshall M., Cohen A., Colistro V., Colquhoun S.M., Contreras A.G., Cooper L.T., Cooper C., Cooperrider K., Coresh J., Cortinovis M., Criqui M.H., Crump J.A., Cuevas-Nasu L., Dandona R., Dandona L., Dansereau E., Dantes H.G., Dargan P.I., Davey G., Davitoiu D.V., Dayama A., De la Cruz-Gongora V., de la Vega S.F., De Leo D., del Pozo-Cruz B., Dellavalle R.P., Deribe K., Derrett S., Des Jarlais D.C., Dessalegn M., deVeber G.A., Dharmaratne S.D., Diaz-Torne C., Ding E.L., Dokova K., Dorsey E.R., Driscoll T.R., Duber H., Durrani A.M., Edmond K.M., Ellenbogen R.G., Endres M., Ermakov S.P., Eshrati B., Esteghamati A., Estep K., Fahimi S., Farzadfar F., Fay D.F.J., Felson D.T., Fereshtehnejad S-M., Fernandes J.G., Ferri C.P., Flaxman A., Foigt N., Foreman K.J., Fowkes F.G.R., Franklin R.C., Furst T., Futran N.D., Gabbe B.J., Gankpe F.G., Garcia-Guerra F.A., Geleijnse J.M., Gessner B.D., Gibney K.B., Gillum R.F., Ginawi I.A., Giroud M., Giussani G., Goenka S., Goginashvili K., Gona P., de Cosio T.G., Gosselin R.A., Gotay C.C., Goto A., Gouda H.N., Guerrant R., Gugnani H.C., Gunnell D., Gupta R., Gupta R., Gutierrez R.A., Hafezi-Nejad N., Hagan H., Halasa Y., Hamadeh R.R., Hamavid H., Hammami M., Hankey G.J., Hao Y., Harb H.L., Haro J.M., Havmoeller R., Hay R.J., Hay S., Hedayati M.T., Pi I.B.H., Heydarpour P., Hijar M., Hoek H.W., Hoffman H.J., Hornberger J.C., Hosgood H.D., Hossain M., Hotez P.J., Hoy D.G., Hsairi M., Hu H., Hu G., Huang J.J., Huang C., Huiart L., Husseini A., Iannarone M., Iburg K.M., Innos K., Inoue M., Jacobsen K.H., Jassal S.K., Jeemon P., Jensen P.N., Jha V., Jiang G., Jiang Y., Jonas J.B., Joseph J., Juel K., Kan H., Karch A., Karimkhani C., Karthikeyan G., Katz R., Kaul A., Kawakami N., Kazi D.S., Kemp A.H., Kengne A.P., Khader Y.S., Khalifa S.E.A.H., Khan E.A., Khan G., Khang Y-H., Khonelidze I., Kieling C., Kim D., Kim S., Kimokoti R.W., Kinfu Y., Kinge J.M., Kissela B.M., Kivipelto M., Knibbs L., Knudsen A.K., Kokubo Y., Kosen S., Kramer A., Kravchenko M., Krishnamurthi R.V., Krishnaswami S., Defo B.K., Bicer B.K., Kuipers E.J., Kulkarni V.S., Kumar K., Kumar G.A., Kwan G.F., Lai T., Lalloo R., Lam H., Lan Q., Lansingh V.C., Larson H., Larsson A., Lawrynowicz A.E.B., Leasher J.L., Lee J-T., Leigh J., Leung R., Levi M., Li B., Li Y., Li Y. liang, J.; Lim, S.; Lin, H-H.; Lind, M.; Lindsay, M.P.; Lipshultz, S.E.; Liu, S.; Lloyd, B.K.; Ohno, S.L.; Logroscino, G.; Looker, K.J.; Lopez, A.D.; Lopez-Olmedo, N.; Lortet-Tieulent, J.; Lotufo, P.A.; Low, N.; Lucas, R.M.; Lunevicius, R.; Lyons, R.A.; Ma, J.; Ma, S.; Mackay, M.T.; Majdan, M.; Malekzadeh, R.; Mapoma, C.C.; Marcenes, W.; March, L.M.; Margono, C.; Marks, G.B.; Marzan, M.B.; Masci, J.R.; Mason-Jones, A.J.; Matzopoulos, R.G.; Mayosi, B.M.; Mazorodze, T.T.; McGill, N.W.; McGrath, J.J.; McKee, M.; McLain, A.; McMahon, B.J.; Meaney, P.A.; Mehndiratta, M.M.; Mejia-Rodriguez, F.; Mekonnen, W.; Melaku, Y.A.; Meltzer, M.; Memish, Z.A.; Mensah, G.; Meretoja, A.; Mhimbira, F.A.; Micha, R.; Miller, T.R.; Mills, E.J.; Mitchell, P.B.; Mock, C.N.; Moffitt, T.E.; Ibrahim, N.M.; Mohammad, K.A.; Mokdad, A.H.; Mola, G.L.; Monasta, L.; Montico, M.; Montine, T.J.; Moore, A.R.; Moran, A.E.; Morawska, L.; Mori, R.; Moschandreas, J.; Moturi, W.N.; Moyer, M.; Mozaffarian, D.; Mueller, U.O.; Mukaigawara, M.; Murdoch, M.E.; Murray, J.; Murthy, K.S.; Naghavi, P.; Nahas, Z.; Naheed, A.; Naidoo, K.S.; Naldi, L.; Nand, D.; Nangia, V.; Narayan, K.M.V.; Nash, D.; Nejjari, C.; Neupane, S.P.; Newman, L.M.; Newton, C.R.; Ng, M.; Ngalesoni, F.N.; Nhung, N.T.; Nisar, M.I.; Nolte, S.; Norheim, O.F.; Norman, R.E.; Norrving, B.; Nyakarahuka, L.; Oh, I.H.; Ohkubo, T.; Omer, S.B.; Opio, J.N.; Ortiz, A.; Pandian, J.D.; Panelo, C.I.A.; Papachristou, C.; Park, E-K.; Parry, C.D.; Caicedo, A.J.P.; Patten, S.B.; Paul, V.K.; Pavlin, B.I.; Pearce, N.; Pedraza, L.S.; Pellegrini, C.A.; Pereira, D.M.; Perez-Ruiz, F.P.; Perico, N.; Pervaiz, A.; Pesudovs, K.; Peterson, C.B.; Petzold, M.; Phillips, M.R.; Phillips, D.; Phillips, B.; Piel, F.B.; Plass, D.; Poenaru, D.; Polanczyk, G.V.; Polinder, S.; Pope, C.A.; Popova, S.; Poulton, R.G.; Pourmalek, F.; Prabhakaran, D.; Prasad, N.M.; Qato, D.; Quistberg, D.A.; Rafay, A.; Rahimi, K.; Rahimi-Movaghar, V.; Rahman, S.; Raju, M.; Rakovac, I.; Rana, S.M.; Razavi, H.; Refaat, A.; Rehm, J.; Remuzzi, G.; Resnikoff, S.; Ribeiro, A.L.; Riccio, P.M.; Richardson, L.; Richardus, J.H.; Riederer, A.M.; Robinson, M.; Roca, A.; Rodriguez, A.; Rojas-Rueda, D.; Ronfani, L.; Rothenbacher, D.; Roy, N.; Ruhago, G.M.; Sabin, N.; Sacco, R.L.; Ksoreide, K.; Saha, S.; Sahathevan, R.; Sahraian, M.A.; Sampson, U.; Sanabria, J.R.; Sanchez-Riera, L.; Santos, I.S.; Satpathy, M.; Saunders, J.E.; Sawhney, M.; Saylan, M.I.; Scarborough, P.; Schoettker, B.; Schneider, I.J.C.; Schwebel, D.C.; Scott, J.G.; Seedat, S.; Sepanlou, S.G.; Serdar, B.; Servan-Mori, E.E.; Shackelford, K.; Shaheen, A.; Shahraz, S.; Levy, T.S.; Shangguan, S.; She, J.; Sheikhbahaei, S.; Shepard, D.S.; Shi, P.; Shibuya, K.; Shinohara, Y.; Shiri, R.; Shishani, K.; Shiue, I.; Shrime, M.G.; Sigfusdottir, I.D.; Silberberg, D.H.; Simard, E.P.; Sindi, S.; Singh, J.A.; Singh, L.; Skirbekk, V.; Sliwa, K.; Soljak, M.; Soneji, S.; Soshnikov, S.S.; Speyer, P.; Sposato, L.A.; Sreeramareddy, C.T.; Stoeckl, H.; Stathopoulou, V.K.; Steckling, N.; Stein, M.B.; Stein, D.J.; Steiner, T.J.; Stewart, A.; Stork, E.; Stovner, L.J.; Stroumpoulis, K.; Sturua, L.; Sunguya, B.F.; Swaroop, M.; Sykes, B.L.; Tabb, K.M.; Takahashi, K.; Tan, F.; Tandon, N.; Tanne, D.; Tanner, M.; Tavakkoli, M.; Taylor, H.R.; Te Ao, B.J.; Temesgen, A.M.; Have, M.T.; Tenkorang, E.Y.; Terkawi, A.S.; Theadom, A.M.; Thomas, E.; Thorne-Lyman, A.L.; Thrift, A.G.; Tleyjeh, I.M.; Tonelli, M.; Topouzis, F.; Towbin, J.A.; Toyoshima, H.; Traebert, J.; Tran, B.X.; Trasande, L.; Trillini, M.; Truelsen, T.; Trujillo, U.; Tsilimbaris, M.; Tuzcu, E.M.; Ukwaja, K.N.; Undurraga, E.A.; Uzun, S.B.; van Brakel, W.H.; van de Vijver, S.; Dingenen, R.V.; van Gool, C.H.; Varakin, Y.Y.; Vasankari, T.J.; Vavilala, M.S.; Veerman, L.J.; Velasquez-Melendez, G.; Venketasubramanian, N.; Vijayakumar, L.; Villalpando, S.; Violante, F.S.; Vlassov, V.V.; Waller, S.; Wallin, M.T.; Wan, X.; Wang, L.; Wang, J.L.; Wang, Y.; Warouw, T.S.; Weichenthal, S.; Weiderpass, E.; Weintraub, R.G.; Werdecker, A.; Wessells, K.R.R.; Westerman, R.; Wilkinson, J.D.; Williams, H.C.; Williams, T.N.; Woldeyohannes, S.M.; Wolfe, C.D.A.; Wong, J.Q.; Wong, H.; Woolf, A.D.; Wright, J.L.; Wurtz, B.; Xu, G.; Yang, G.; Yano, Y.; Yenesew, M.A.; Yentur, G.K.; Yip, P.; Yonemoto, N.; Yoon, S-J.; Younis, M.; Yu, C.; Kim, K.Y.; Zaki, M.E.S.; Zhang, Y.; Zhao, Z.; Zhao, Y.; Zhu, J.; Zonies, D.; Zunt, J.R.; Salomon, J.A.; Murray, C.J.L. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. doi: 10.1016/S0140-6736(15)60692-4. - DOI - PMC - PubMed
    1. Monroe S.M., Harkness K.L. Major depression and its recurrences: Life course matters. Annu. Rev. Clin. Psychol. 2022;18(1):329–357. doi: 10.1146/annurev-clinpsy-072220-021440. - DOI - PubMed
    1. Lépine J.P., Briley M. The increasing burden of depression. Neuropsychiatr. Dis. Treat. 2011;7(Suppl. 1):3–7. - PMC - PubMed
    1. Laursen T.M., Musliner K.L., Benros M.E., Vestergaard M., Munk-Olsen T. Mortality and life expectancy in persons with severe unipolar depression. J. Affect. Disord. 2016;193:203–207. doi: 10.1016/j.jad.2015.12.067. - DOI - PubMed

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