Research Progress on Animal Models of Depression in Non-Human Primates

Yuhui CHEN; Xiaoli FENG

Article Contents

Article Navigation > Journal of Kunming Medical University > 2026 > Accepted Manuscript

Yuhui CHEN, Xiaoli FENG. Research Progress on Animal Models of Depression in Non-Human Primates[J]. Journal of Kunming Medical University.

Citation:

Yuhui CHEN, Xiaoli FENG. Research Progress on Animal Models of Depression in Non-Human Primates[J]. Journal of Kunming Medical University.

Yuhui CHEN, Xiaoli FENG. Research Progress on Animal Models of Depression in Non-Human Primates[J]. Journal of Kunming Medical University.

Citation:

Yuhui CHEN, Xiaoli FENG. Research Progress on Animal Models of Depression in Non-Human Primates[J]. Journal of Kunming Medical University.

PDF( 1156 KB)

Research Progress on Animal Models of Depression in Non-Human Primates

Yuhui CHEN,
Xiaoli FENG^,

College of Basic Medicine，Kunming Medical University，Kunming Yunnan 650500，China

Received Date: 2026-05-12
Accepted Date: 2026-07-02

Abstract

Abstract

Major Depressive Disorder （MDD） is a highly prevalent psychiatric disorder worldwide. Its pathogenesis is complex and not yet fully understood, and current clinical management is limited by delayed therapeutic onset of and treatment resistance in a subset of patients. Non-human primates share a high degree of similarity with humans in neural development, emotional regulation, stress response and other aspects, making them more translationally valuable animal models for the research on MDD mechanisms and drug development. This paper systematically consolidates classical NHP models of MDD established both domestically and internationally, elaborating in detail on the modeling principles, construction methodologies, as well as behavioral and physiological phenotypes of each model. This synthesis aims to provide novel insights for deepening our understanding of MDD pathophysiology and for developing innovative therapeutic strategies and drug screening paradigms.
- Major depressive disorder,
- Non-human primates,
- Animal models,
- Modeling methodologies

FullText(HTML)

References(54)

References

[1]	Liu L, Wang H, Chen X, et al. Gut microbiota and its metabolites in depression: From pathogenesis to treatment[J]. EBioMedicine, 2023, 90: 104527. doi: 10.1016/j.ebiom.2023.104527
[2]	Wang Y, Zhu J, Zhou J. Disease burden and attributable risk factors of major depressive disorder in China, Japan, and South Korea from 1990 to 2021 and its prediction to 2035[J]. Front Public Health, 2025, 13: 1510091. doi: 10.3389/fpubh.2025.1510091
[3]	Cui L, Li S, Wang S, et al. Major depressive disorder: Hypothesis, mechanism, prevention and treatment[J]. Signal Transduct Target Ther, 2024, 9: 30. doi: 10.1038/s41392-024-01738-y
[4]	Yamamoto M, Hirakata H, Toda K. Neural signaling mechanisms in depression: Bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies[J]. Front Cell Dev Biol, 2026, 14: 1777975. doi: 10.3389/fcell.2026.1777975
[5]	Eugene A R. Country-specific psychopharmacological risk of reporting suicidality comparing 38 antidepressants and lithium from the FDA Adverse Event Reporting System, 2017–2023[J]. Front Psychiatry, 2024, 15: 1442490. doi: 10.3389/fpsyt.2024.1442490
[6]	王宏, 季维智, 司维. 非人灵长类生物医学与人类健康[J]. 昆明理工大学学报(自然科学版), 2024, 49(4): 211-220. doi: 10.16112/j.cnki.53-1223/n.2024.04.661
[7]	Murphy J M. Depression and anxiety in relation to social status: A prospective epidemiologic study[J]. Arch Gen Psychiatry, 1991, 48(3): 223. doi: 10.1001/archpsyc.1991.01810270035004
[8]	Shively C A. Social subordination stress, behavior, and central monoaminergic function in female Cynomolgus monkeys[J]. Biol Psychiatry, 1998, 44(9): 882-891. doi: 10.1016/S0006-3223(97)00437-X
[9]	Wu J, Li Y, Huang Y, et al. Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female Cynomolgus macaques with depressive-like behaviors[J]. Nat Neurosci, 2023, 26(8): 1352-1364. doi: 10.1038/s41593-023-01379-4
[10]	Sun L J, Zhang L M, Liu D, et al. The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919)[J]. Metab Brain Dis, 2019, 34(5): 1375-1384. doi: 10.1007/s11011-019-00439-8
[11]	Qin D, Rizak J, Chu X, et al. A spontaneous depressive pattern in adult female Rhesus macaques[J]. Sci Rep, 2015, 5: 11267. doi: 10.1038/srep11267
[12]	Chu X. Preliminary validation of natural depression in macaques with acute treatments of the fast-acting antidepressant ketamine[J]. Behav Brain Res, 2019, 360: 60-68. doi: 10.1016/j.bbr.2018.11.044
[13]	Merz E C, Myers B, Hansen M, et al. Socioeconomic disparities in hypothalamic-pituitary-adrenal axis regulation and prefrontal cortical structure[J]. Biol Psychiatry Glob Open Sci, 2024, 4(1): 83-96. doi: 10.1016/j.bpsgos.2023.10.004
[14]	Correia A S, Cardoso A, Vale N. BDNF unveiled: Exploring its role in major depression disorder serotonergic imbalance and associated stress conditions[J]. Pharmaceutics, 2023, 15(8): 2081. doi: 10.3390/pharmaceutics15082081
[15]	Deng F L, Pan J X, Zheng P, et al. Metabonomics reveals peripheral and central short-chain fatty acid and amino acid dysfunction in a naturally occurring depressive model of macaques[J]. Neuropsychiatr Dis Treat, 2019, 15: 1077-1088. doi: 10.2147/NDT.S186071
[16]	Li W, Luo L Y, Yang X, et al. Depressed female Cynomolgus monkeys (Macaca fascicularis) display a higher second-to-fourth (2D: 4D) digit ratio[J]. Zool Res, 2019, 40(3): 219-225.
[17]	He Y, Li W, Wang Y, et al. Major depression accompanied with inflammation and multiple cytokines alterations: Evidences from clinical patients to Macaca fascicularis and LPS-induced depressive mice model[J]. J Affect Disord, 2020, 271: 262-271. doi: 10.1016/j.jad.2020.03.131
[18]	Bowlby J. Separation anxiety[J]. Int J Psychoanal, 1960, 41: 89-113.
[19]	Worlein J M. Nonhuman primate models of depression: Effects of early experience and stress[J]. Ilar j, 2014, 55(2): 259-273. doi: 10.1093/ilar/ilu030
[20]	Harlow H F, Suomi S J. Induced depression in monkeys[J]. Behav Biol, 1974, 12(3): 273-296. doi: 10.1016/S0091-6773(74)91475-8
[21]	Seay B, Hansen E, Harlow H F. Mother-infant separation in monkeys[J]. J Child Psychol Psychiatry, 1962, 3(3-4): 123-132. doi: 10.1111/j.1469-7610.1962.tb02047.x
[22]	Feng X, Wang L, Yang S, et al. Maternal separation produces lasting changes in Cortisol and behavior in Rhesus monkeys[J]. Proc Natl Acad Sci U S A, 2011, 108(34): 14312-14317. doi: 10.1073/pnas.1010943108
[23]	Boccia M L, Scanlan J M, Laudenslager M L, et al. Juvenile friends, behavior, and immune responses to separation in bonnet macaque infants[J]. Physiol Behav, 1997, 61(2): 191-198. doi: 10.1016/S0031-9384(96)00370-8
[24]	Pryce C R, Dettling A C, Spengler M, et al. Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring[J]. Biol Psychiatry, 2004, 56(2): 72-79. doi: 10.1016/j.biopsych.2004.05.002
[25]	Strekalova T, Liu Y, Kiselev D, et al. Chronic mild stress paradigm as a rat model of depression: Facts, artifacts, and future perspectives[J]. Psychopharmacology, 2022, 239(3): 663-693. doi: 10.1007/s00213-021-05982-w
[26]	Teng T, Shively C A, Li X, et al. Chronic unpredictable mild stress produces depressive-like behavior, hypercortisolemia, and metabolic dysfunction in adolescent Cynomolgus monkeys[J]. Transl Psychiatry, 2021, 11: 9. doi: 10.1038/s41398-020-01132-6
[27]	Markov D D. Sucrose preference test as a measure of anhedonic behavior in a chronic unpredictable mild stress model of depression: Outstanding issues[J]. Brain Sci, 2022, 12(10): 1287. doi: 10.3390/brainsci12101287
[28]	Zhang Z Y, Mao Y, Feng X L, et al. Early adversity contributes to chronic stress induced depression-like behavior in adolescent male Rhesus monkeys[J]. Behav Brain Res, 2016, 306: 154-159. doi: 10.1016/j.bbr.2016.03.040
[29]	Yin Y Y, Tian C Y, Fang X X, et al. The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919) in monkeys subjected to chronic unpredictable stress[J]. Front Pharmacol, 2020, 11: 586879. doi: 10.3389/fphar.2020.586879
[30]	Hassamal S. Chronic stress, neuroinflammation, and depression: An overview of pathophysiological mechanisms and emerging anti-inflammatories[J]. Front Psychiatry, 2023, 14: 1130989. doi: 10.3389/fpsyt.2023.1130989
[31]	Johnson S A, Fournier N M, Kalynchuk L E. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor[J]. Behav Brain Res, 2006, 168(2): 280-288. doi: 10.1016/j.bbr.2005.11.019
[32]	Lei A A, Phang V W X, Lee Y Z, et al. Chronic stress-associated depressive disorders: The impact of hpa axis dysregulation and neuroinflammation on the hippocampus-a mini review[J]. Int J Mol Sci, 2025, 26(7): 29-40.
[33]	Gulbaz Z U A, Mirza S, Naveed S, et al. Towards objective major depressive disorder detection: A systematic review and meta-analysis of diagnostic biomarkers[J]. Psychiatr Q, 2025: ■-■.
[34]	Sahu M K, Dubey R K, Chandrakar A, et al. A systematic review and meta-analysis of serum and plasma Cortisol levels in depressed patients versus control[J]. Indian J Psychiatry, 2022, 64(5): 440-448. doi: 10.4103/indianjpsychiatry.indianjpsychiatry_561_21
[35]	Aukema R J, Petrie G N, Baglot S L, et al. Acute stress activates basolateral amygdala neurons expressing corticotropin-releasing hormone receptor type 1 (CRHR1): Topographical distribution and projection-specific activation in male and female rats[J]. Neurobiol Stress, 2024, 33: 100694. doi: 10.1016/j.ynstr.2024.100694
[36]	Georgiou P, Farmer C A, Medeiros G C, et al. Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine[J]. J Affect Disord, 2025, 373: 126-132. doi: 10.1016/j.jad.2024.12.036
[37]	Yue Y, Zhang J, Li Y, et al. Disruptions of p11 (S100A10) and HPA axis homeostasis participate in the major depressive disorder (MDD) especially in female patients[J]. Neuropsychiatr Dis Treat, 2025, 21: 2237-2249. doi: 10.2147/NDT.S549538
[38]	Menke A. The HPA axis as target for depression[J]. Curr Neuropharmacol, 2024, 22(5): 904-915. doi: 10.2174/1570159X21666230811141557
[39]	Qin D, Li Z, Li Z, et al. Chronic glucocorticoid exposure induces depression-like phenotype in Rhesus macaque (Macaca mulatta)[J]. Front Neurosci, 2019, 13: 188. doi: 10.3389/fnins.2019.00188
[40]	Vorona K, Ryapolova A, Sokolova O, et al. Interferon-based therapeutics in cancer therapy: Past, present, and future[J]. Int J Mol Sci, 2025, 26(23): 11679. doi: 10.3390/ijms262311679
[41]	Miller A H. Advancing an inflammatory subtype of major depression[J]. Am J Psychiatry, 2025, 182(6): 516-524. doi: 10.1176/appi.ajp.20250289
[42]	Felger J C, Alagbe O, Hu F, et al. Effects of interferon-alpha on Rhesus monkeys: A nonhuman primate model of cytokine-induced depression[J]. Biol Psychiatry, 2007, 62(11): 1324-1333. doi: 10.1016/j.biopsych.2007.05.026
[43]	Escalona R, Fawcett J. Pramipexole in treatment resistant-depression, possible role of inflammatory cytokines[J]. Neuropsychopharmacology, 2017, 42(1): 363. doi: 10.1038/npp.2016.217
[44]	Li Z, Li Z, Lv X, et al. Intracerebroventricular administration of interferon-alpha induced depressive-like behaviors and neurotransmitter changes in Rhesus monkeys[J]. Front Neurosci, 2020, 14: 585604. doi: 10.3389/fnins.2020.585604
[45]	Bekhbat M, Block A M, Dickinson S Y, et al. Neurotransmitter and metabolic effects of interferon-alpha in association with decreased striatal dopamine in a non-human primate model of cytokine-Induced depression[J]. Brain Behav Immun, 2025, 125: 308-318. doi: 10.1016/j.bbi.2025.01.010
[46]	Lai J Y, Ho J X, Kow A S F, et al. Interferon therapy and its association with depressive disorders–A review[J]. Front Immunol, 2023, 14: 1048592. doi: 10.3389/fimmu.2023.1048592
[47]	Suomi S J, Harlow H F. Depressive behavior in young monkeys subjected to vertical chamber confinement[J]. J Comp Physiol Psychol, 1972, 80(1): 11-18. doi: 10.1037/h0032843
[48]	McKinney W T. Vertical-chamber confinement of juvenile-age Rhesus monkeys: A study in experimental psychopathology[J]. Arch Gen Psychiatry, 1972, 26(3): 223.
[49]	Moran E C. Effects of chlorpromazine on the vertical chamber syndrome in Rhesus monkeys[J]. Arch Gen Psychiatry, 1975, 32(11): 1409. doi: 10.1001/archpsyc.1975.01760290077009
[50]	Kim K, Kim J, Jung S, et al. Global prevalence of seasonal affective disorder by latitude: A systematic review and meta-analysis[J]. J Affect Disord, 2025, 390: 119807. doi: 10.1016/j.jad.2025.119807
[51]	Qin D, Chu X, Feng X, et al. The first observation of seasonal affective disorder symptoms in Rhesus macaque[J]. Behav Brain Res, 2015, 292: 463-469. doi: 10.1016/j.bbr.2015.07.005
[52]	Richardson E, Patterson R, Meltzer-Brody S, et al. Transformative therapies for depression: Postpartum depression, major depressive disorder, and treatment-resistant depression[J]. Annu Rev Med, 2025, 76: 81-93. doi: 10.1146/annurev-med-050423-095712
[53]	Pettman D, O’Mahen H, Blomberg O, et al. Effectiveness of cognitive behavioural therapy-based interventions for maternal perinatal depression: A systematic review and meta-analysis[J]. BMC Psychiatry, 2023, 23(1): 208. doi: 10.1186/s12888-023-04547-9
[54]	Chu X X, Dominic Rizak J, Yang S C, et al. A natural model of behavioral depression in postpartum adult female cynomolgus monkeys (macaca fascicularis)[J]. Dongwuxue Yanjiu, 2014, 35(3): 174-181.

Relative Articles(20)

Relative Articles

[1]	Shu’e ZENG, Zhixing LU, Yanjun WANG, Tian MENG, Ruina LIU. ALOX15B-GPX4 Axis in Alleviates Depression by Regulating Neuroinflammation and Ferroptosis. Journal of Kunming Medical University,
[2]	Haoran XING, Xi ZHANG, Yingying ZHANG, Tianhao BAO. Advancements in the Clinical Use of Antidepressants for Adolescent Depression. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20240725
[3]	Linjuan YANG, Wenjiao JIN, Jinzhi LU, Zhenghua XIONG, Bin YAN, Xuesong HAN. A Comparative Study of Rat Models of Intrauterine Adhesions Constructed in Different Ways. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20230322
[4]	Deng'ai DUAN, Yonghui ZHANG, Wei WANG, Xinju LIAO, Zhixiong ZHANG. Effect of Childhood Abuse on Non-suicidal Self-injury in Adolescents with First-episode Depression. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20230304
[5]	Zhaosong CHU, Xin WANG, Mengxin HE, Xiufeng XU, Na WANG, Zonglin SHEN. Research Progress on Gene Related to Suicide in Major Depressive Disorder：A Review. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20230301
[6]	Lei YU, Wenzhi WU, Yunqiao ZHANG, Xu YOU, Yong ZENG. Research Overview of HPA Axis in Depression. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20230222
[7]	Rongyu YANG, Fei SONG, Hao HUANG, Kaiwen DUAN, Shibing QIAN, Yingying XIANG. Research Progress on Animal Model of Chronic Periapical Periodontitis in SD Rats. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20221005
[8]	Xiao-yun WANG, Qiao-yun WANG, Ming-hua GU, Yu DING, Yu-wen GUANG, Ji-lan ZHANG. Mechanism of miR-373 on Behaviors of Depression-mice via P2X7R. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20211030
[9]	Cao Qing , Li Lan , Zou Ying , Li Yun Chuan , Li Yong , Long Jun Jun , Liu Hao Wen , He Liu Yu , Tian Er Miao . . Journal of Kunming Medical University,
[10]	Xian LI, Chang-liang JI, Shu-e ZENG, Shu-yun YANG, Hao-qi YANG, Ya-ting HOU. A Comparative Study of the Cognitive Function in Patients with Different Degrees of Depression. Journal of Kunming Medical University, doi: 10.12259/j.issn.2095-610X.S20201226
[11]	Zhang Nan , Hu Xin Yu , Dong Xian Xiang , Duan Wei Gang , Yun Yu . . Journal of Kunming Medical University,
[12]	Ren Xu , Wang Yi Feng , Dai Li Bing . The Establishment of SCID Mice Model on Endometriosis. Journal of Kunming Medical University,
[13]	Wu Jing Man . . Journal of Kunming Medical University,
[14]	Guang Xue Feng . . Journal of Kunming Medical University,
[15]	Zhang Hu . . Journal of Kunming Medical University,
[16]	Bao Wen Li . . Journal of Kunming Medical University,
[17]	Kui Ze Hong . . Journal of Kunming Medical University,
[18]	Du Ying Rong . . Journal of Kunming Medical University,
[19]	Chen Jin Run . . Journal of Kunming Medical University,
[20]	Na Zhao . . Journal of Kunming Medical University,