It looks like there is a chasm between animal and human research. In animal research, chronic stress is well-known to cause a variety of mood disorders, covering virtually entire spectrum of the human-equivalents described in DSM IV/V. Specifically, animal research has even established a reliable behavior protocol for causing severe depression by subjecting the animals to a few weeks of so-called chronic unpredictable mild stress (CUMS). In other words, not only is there no role of “depression genes” in the induction of severe depression, said depression can be reliably induced at will simply by subjecting the animals to chronic stress that is several magnitudes lower than what most people experience on a daily basis. No wonder depression and suicide rates are through the roof and keep rising! In addition, the study not only offers a relatively harmless solution in the form of (bioidentical) progesterone administration, but also vindicates progesterone when it comes to mental health. Many OBGYN doctors and psychiatrists contend that progesterone may be a causative factor in depression, especially the postpartum kind, despite irrefutable evidence that progesterone levels sharply drop after pregnancy. One of the reasons give for progesterone’s “depressive” effects is its known opposition/antagonism to estrogen, and over the last decade or so medicine has everything possible to vilify the so-called WHI studies, which proved beyond doubt that estrogen therapy is really terrible for women’s neurological and mental health. Well, hopefully people will take the findings of the study below seriously and consider progesterone as an option before agreeing to use the abominations known as SSRI drugs.
The human-equivalent dose of progesterone was about 1mg/kg daily and the treatment was administered for 2 weeks, about 4 weeks after the chronic stress protocol was started the animals were already clinically depressed. The higher human-equivalent dose (2mg/kg daily) did not produce further benefit, while lower doses (<1mg/kg) were less effective, thus suggesting partially dose-dependent effects. Importantly, progesterone reversed not only various behavior and cognitive features of depression, but also the anhedonia. The latter is a notoriously difficult-to-treat symptom of depression and most SSRI are ineffective in that respect. Speaking of SSRI, the study suggests that whatever antidepressant effect SSRI drugs may have, it is due to reductions in inflammatory biomarkers such as TNF-a, and not due to increasing extracellular serotonin levels. In corroboration, chronic stress (as used in this study or otherwise) also strongly increases inflammation in the nervous system and it is this inflammation that apparently causes depression. Progesterone’s proposed anti-depressant effect was due to the reduction of said inflammation in the nervous system, but also systemically! While I do agree with those hypotheses, my opinion is that progesterone has a few other mechanisms of action resulting in a robust antidepressant effects. Namely, progesterone is a glucocorticoid receptor (GR) antagonist and blocks the effects of excess cortisol. The latter is a known causal factor in depression. Furthermore, progesterone inhibits the enzyme 11b-HSD1 and activates 11b-HSD2, which means that it also directly reduces the synthesis of cortisol while also promoting cortisol deactivation. In addition, progesterone is a strong GABA agonist and such agonists have already been demonstrated to have therapeutic effects in depression. Finally, progesterone promotes thyroid function and thus systemic metabolism, and pro-thyroid substances (especially T3) have also been demonstrated to be therapeutic in depression.
https://doi.org/10.1016/j.bbr.2025.115879
“…The rising global prevalence of depression, exacerbated by modern psychosocial stressors, underscores the imperative to elucidate pathophysiology and develop mechanistically novel therapeutics. Our study demonstrates that progesterone alleviates chronic unpredictable mild stress (CUMS)-induced depressive phenotypes through NLRP3 inflammasome inhibition, providing critical insights into neurosteroid mediated neuroprotection. The CUMS paradigm employed in this study effectively recapitulates core features of human depression. Progressive behavioral adaptations from initial hyperarousal to eventual psychomotor retardation and anhedonia-mirror clinical trajectories of chronic stress-induced emotional dysregulation. Notably, the sustained weight loss, fur deterioration, and diminished stress resilience observed in CUMS-exposed rats align with established biomarkers of rodent despair states [2,23].”
“…Our use of male SD rats circumvented potential confounders from estrogen-mediated neuroprotection [3], while the CUMS protocol prevented stressor habituation through variable stimulation-a methodological advance over single-stressor paradigms [19]. Post-CUMS behavioral deficits, including reduced sucrose preference and increased immobility in the forced swim test, were reversed by progesterone in a dose-dependent manner consistent with its previously documented neurostimulatory effects in depression models [18], thereby confirming its therapeutic efficacy against depression-relevant endophenotypes. Mechanistically, progesterone’s antidepressant effects correlate with NLRP3 inflammasome suppression. The reversal of anhedonia (SPT) and despair (FST immobility) by progesterone correlates with reduced NLRP3 activation, suggesting that neuroinflammatory mitigation underlies behavioral recovery. The CUMS-induced upregulation of NLRP3, pro-caspase-1, and cleaved caspase-1 in prefrontal and hippocampal tissues—key regions governing emotional regulation—confirms stressinduced inflammasome activation as a neuropathological hub [24,32]. Progesterone administration normalized these molecular changes and reduced serum IL-1β and TNF-α levels, indicating systemic anti-inflammatory effects. This dual central-peripheral modulation aligns with progesterone’s established capacity to: (1) suppress glial activation by inhibiting NF-κB/NLRP3 signaling in astrocytes [12,13]; (2) enhance GABAergic tone via allopregnanolone-mediated GABAA receptor potentiation [8], which counterbalances stress-induced neuroexcitation; (3) preserve neuroplasticity through dendritic spine stabilization and oxidative stress mitigation [7,27]. Notably, progesterone’s inhibition of caspase-1 activation impedes IL-1β/IL-18 maturation-a critical nexus linking neuroinflammation to depressive symptomatology [17,25]. The observed prefrontal-hippocampal specificity of pro-caspase-1 reduction may reflect regional variations in microglial reactivity, warranting future single-cell transcriptomic characterization. Our findings extend prior evidence of progesterone’s neuroprotection in ischemia and neurodegeneration [4] to stress-related mood disorders. The dose-dependent effects mirror clinical observations wherein progesterone derivatives correlate with improved neurocognitive outcomes [16]. Furthermore, the shared anti-inflammatory mechanisms between progesterone and SSRIs-notably TNF-α suppression [29]-suggest potential synergies for treatment-resistant depression.”
