Does the antidepressant-like effect of mirtazapine and venlafaxine differ between male and female rats?

Adriana Álvarez Silva, Alonso Fernández-Guasti



Introduction. Depression is a global health problem with nearly 350 million people affected, mainly women. However, nowadays a rising amount of men are being diagnosed. This makes necessary the screening of new treatment options that are effective in women as well as in men.

Objective. To analyze if the administration of mirtazapine and venlafaxine to male and female rats shows a sex-related antidepressant-like effect, and the possible associated neurochemical mechanisms.

Method. Mirtazapine (40 mg/kg) or venlafaxine (60 mg/kg) were administered subchronically to young adult male and female (ovariectomized and steroid-primed) rats, and their antidepressant-like effects were evaluated using the forced swim test (FST). The active behaviors, swimming and climbing, were also analyzed.

Results. a) mirtazapine and venlafaxine reduced immobility in the FST in males and females; b) both antidepressants increased climbing and swimming in male rats; c) in female rats, mirtazapine and venlafaxine only increased swimming.

Discussion and conclusion. In males, the effects of mirtazapine and venlafaxine seem to be produced by the activation of the serotonergic and noradrenergic systems. Conversely, estradiol might be modulating the mechanisms of action of both antidepressants in females producing only an increased swimming and suggesting the participation of the serotonergic system.


Mirtazapine; venlafaxine; antidepressants; sex differences; forced swim test

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Addis, M. E. (2008). Gender and depression in men. Clinical Psychology: Science and Practice, 15(3), 153-168. doi: 10.1111/j.1468-2850.2008.00125.x

Álvarez-Silva, A. A., & Fernández-Guasti, A. (2019). The combination of mirtazapine plus venlafaxine reduces immobility in the forced swim test and does not inhibit female sexual behavior. Pharmacology, Biochemistry and Behavior, 187, 172817 doi: 10.1016/j.pbb.2019.172817

Anttila, S. A., & Leinonen, E. V. (2001). A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Reviews, 7(3), 249-264. doi: 10.1111/j.1527-3458.2001.tb00198.x

Barros, H. M., & Ferigolo, M. (1998). Ethopharmacology of imipramine in the forced swimming test: gender differences. Neuroscience & Biobehavioral Reviews, 23(2), 279-286. doi: 10.1016/S0149-7634(98)00029-3

Berlanga, C., & Flores-Ramos, M. (2006). Different gender responses to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine. Journal of Affective Disorders, 95(1-3), 119-123. doi: 10.1016/j.jad.2006.04.029

Bertrand, P. P., Paranavitane, U. T., Chavez, C., Gogos, A., Jones, M., & van den Buuse, M. (2005). The effect of low estrogen state on serotonin transporter function in mouse hippocampus: a behavioral and electrochemical study. Brain Research, 1064(1-2), 10-20. doi: 10.1016/j.brainres.2005.10.018

de Boer, T., Ruigt, G. S. F., & Berendsen, H. H. G. (1995). The α2-selective adrenoceptor antagonist org 3770 (mirtazapine, Remeron®) enhances noradrenergic and serotonergic transmission. Human Psychopharmacology: Clinical and Experimental, 10(S2), S107-S118. doi: 10.1002/hup.470100805

Bogdanova, O. V., Kanekar, S., D’Ancy, K. E., & Renshaw, P. F. (2013). Factors influencing behavior in the forced swim test. Physiology and Behavior, 118, 227-239. doi: 10.1016/j.physbeh.2013.05.012

Cochran, S. V., & Rabinowitz, F. E. (2000). Men and depression: Clinical and empirical perspectives. San Diego, California: Academic Press. ISBN 0-12-177540-2

Dalla, C., Antoniou, K., Kokras, N., Drossopoulou, G., Papathanasiou, G., Bekris, S., ... Papadopoulou-Daifoti, Z. (2008). Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission. Physiology & Behavior, 93(3), 595-605. doi: 10.1016/j.physbeh.2007.10.020

Dalla, C., Pitychoutis, P. M., Kokras, N., & Papadopoulou-Daifoti, Z. (2010). Sex differences in animal models of depression and antidepressant response. Basic & Clinical Pharmacology & Toxicology, 106(3), 226-233. doi: 10.1111/j.1742-7843.2009.00516.x

Davis, R., & Wilde, M. I. (1996). Mirtazapine: A review of its pharmacology and therapeutic potential in the management of major depression. CNS Drugs, 5(5), 389-402. doi: 10.2165/00023210-199605050-00007

Detke, M. J., Rickels, M., & Lucki, I. (1995). Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology, 121(1), 66-72. doi: 10.1007/BF02245592

Drossopoulou, G., Antoniou, K., Kitraki, E., Papathanasiou, G., Papalexi, E., Dalla, C., & Papadopoulou-Daifoti, Z. (2004). Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats. Neuroscience, 126(4), 849-857. doi: 10.1016/j.neuroscience.2004.04.044

Estrada-Camarena, E., Fernández-Guasti, A., & López-Rubalcava, C. (2003). Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology, 28(5), 830-838. doi: 10.1038/sj.npp.1300097

Estrada-Camarena, E., López-Rubalcava, C., Hernández-Aragón, A., Mejía-Mauries, S., & Picazo, O. (2011). Long-term ovariectomy modulates the antidepressant-like action of estrogens, but not of antidepressants. Journal of Psychopharmacology, 25(10), 1365-1377. doi: 10.1177/0269881111408456

Estrada-Camarena, E., Rivera, N. V., Berlanga, C., & Fernández-Guasti, A. (2008). Reduction in the latency of action of antidepressants by 17-β estradiol in the forced swimming test. Psychopharmacology, 201(3), 351-360. doi: 10.1007/s00213-008-1291-8

Fernández-Guasti, A., Olivares-Nazario, M., Reyes, R., & Martínez-Mota, L. (2017). Sex and age differences in the antidepressant-like effect of fluoxetine in the forced swim test. Pharmacology, Biochemistry and Behavior, 152, 81-89. doi: 10.1016/j.pbb.2016.01.011

Gómez, M. L., Martinez-Mota, L., Estrada-Camarena, E., & Fernandez-Guasti, A. (2014). Influence of the brain sexual differentiation process on despair and antidepressant-like effect of fluoxetine in the rat forced swim test. Neuroscience, 261, 11-22. doi: 10.1016/j.neuroscience.2013.12.035

Gray, V. C., & Hughes, R. N. (2015). Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats. Behavioural Brain Research, 281, 43-54. doi: 10.1016/j.bbr.2014.12.023

Hernández, A., & Fernández-Guasti, A. (2018). Male rats with same-sex preference show higher immobility in the forced swim test, but similar effects of fluoxetine and desipramine than males that prefer females. Pharmacology, Biochemistry and Behavior, 171, 39-45. doi: 10.1016/j.pbb.2018.05.017

Hernández-Munive, A. K., Rebolledo-Solleiro, D., Ventura-Aquino, E., & Fernández-Guasti, A. (2018). Reduced lordosis and enhanced aggression in paced and non-paced mating in diabetic female rats. The Journal of Sexual Medicine, 15(2), 124-135. doi: 10.1016/j.jsxm.2017.11.018

Holliday, S. M., & Benfield, P. (1995). Venlafaxine: A review of its pharmacology and therapeutic potential in depression. Drugs, 49(2), 280-294. doi: 10.2165/00003495-199549020-00010

Khan, A., Brodhead, A. E., Schwartz, K. A., Kolts, R. L., & Brown, W. A. (2005). Sex differences in antidepressant response in recent antidepressant clinical trials. Journal of Clinical Psychopharmacology, 25(4), 318-324. doi: 10.1097/

Kokras, N., Antoniou, K., Dalla, C., Bekris, S., Xagoraris, M., Ovestreet, D. H., & Papadopoulou-Daifoti, Z. (2009). Sex-related differential response to clomipramine treatment in a rat model of depression. Journal of Psychopharmacology, 23(8), 945-956. doi: 10.1177/0269881108095914

Koldzic-Zivanovic, N., Seitz, P. K., Watson, C. S., Cunningham, K. A., & Thomas, M. L. (2004). Intracellular signaling involved in estrogen regulation of serotonin reuptake. Molecular and Cellular Endocrinology, 226(1-2), 33-42. doi: 10.1016/j.mce.2004.07.017

Kornstein, S. G., Schatzberg, A. F., Thase, M. E., Yonkers, K. A., McCullough, J. P., Keitner, G. I., ... Keller, M. B. (2000). Gender differences in treatment response to sertraline versus imipramine in chronic depression. American Journal of Psychiatry, 157(9), 1445-1452. doi: 10.1176/appi.ajp.157.9.1445

Martenyi, F., Dossenbach, M., Mraz, K., & Metcalfe, S. (2001). Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile. European Neuropsychopharmacology, 11(3), 227-232. doi: 10.1016/S0924-977X(01)00089-X

Melo, T. G., Izídio, G. S., Ferreira, L. S., Sousa, D. S., Macedo, P. T., Cabral, A., ... Silva, R. H. (2012). Antidepressants differentially modify the extinction of an aversive memory task in female rats. Progress in Neuro-psychopharmacology and Biological Psychiatry, 37(1), 33-40. doi: 10.1016/j.pnpbp.2012.01.012

Millan, M. J., Gobert, A., Lejeune, F., Newman-Tancredi, A., Rivet, J. M., Auclair, A., & Peglion, J. L. (2001). S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. Journal of Pharmacology and Experimental Therapeutics, 298(2), 565-580.

Mize, A. L., Young, L. J., & Alper, R. H. (2003). Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780. Neuropharmacology, 44(5), 584-591. doi: 10.1016/S0028-3908(03)00044-3

Molendijk, M. L., & de Kloet E. R. (2015). Immobility in the forced swim test is adaptative and does not reflect depression. Psychoneuroendocrinology, 62, 389-391. doi: 10.1016/j.psyneuen.2015.08.028

de Montigny, C., Haddjeri, N., Mongeau, R., & Blier, P. (1995). The effects of mirtazapine on the interactions between central noradrenergic and serotonergic systems. CNS Drugs, 4(1), 13-17. doi: 10.2165/00023210-199500041-00004

Rénéric, J. P., & Lucki, I. (1998). Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology, 136(2), 190-197. doi: 10.1007/s002130050555

Rénéric, J. P., Bouvard, M., & Stinus, L. (2002). In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed. European Neuropsychopharmacology, 12(2), 159-171. doi: 10.1016/S0924-977X(02)00007-X

Rogóz, Z., Kabziἠzki, M., Sadaj, W., Rachwalska, P., & Gᶏdek-Michalska, A. (2012). Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test. Pharmacological Reports, 64(6), 1391-1399. doi: 10.1016/S1734-1140(12)70936-2

Šagud, M., Hotujac, L. J., Mihaljević-Pelleš, A., & Jakovljević, M. (2002). Gender differences in depression. Collegium Antropologicum, 26(1), 149-157.

Schmidt, M. E., Matochik, J. A., Goldstein, D. S., Schauten, J. L., Zametkin, A. J., & Potter, W. Z. (1997). Gender differences in brain metabolic and plasma catecholamine responses to alpha2-adrenoceptor blockade. Neuropsychopharmacology, 16(4), 298-310. doi: 10.1016/S0893-133X(96)00264-3

Slattery, D. A., & Cryan, J. F. (2012). Using the rat forced swim test to assess antidepressant-like activity in rodents. Nature Protocols, 7(6), 1009-1014. doi: 10.1038/nprot.2012.044

Sramek, J. J., Murphy, M. F., & Cutler, N. R. (2016). Sex differences in the psychopharmacological treatment of depression. Dialogues in Clinical Neuroscience, 18(4), 447-457.

Vega-Rivera, N. M., Fernández-Guasti, A., Ramírez-Rodríguez, G., & Estrada-Camarena, E. (2013a). Acute stress further decreases the effect of ovariectomy on immobility behavior and hippocampal cell survival in rats. Psychoneuroendocrinology, 38(8), 1407-1417. doi: 10.1016/j.psyneuen.2012.12.008

Vega-Rivera, N. M., López-Rubalcava, C., & Estrada-Camarena, E. (2013b). The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test. Neuroscience, 250, 102-111. doi: 10.1016/j.neuroscience.2013.06.058

World Health Organization. (2018). Depresión. Retrieved from:

Xing, Y., He, J., Hou, J., Lin, F., Tian, J., & Kurihara, H. (2013). Gender differences in CMS and the effect of antidepressant venlafaxine in rats. Neurochemistry International, 63(6), 570-575. doi: 10.1016/j.neuint.2013.09.019