Inflammation and Treatment-Resistant Depression from Clinical to Animal Study: A Possible Link?

Abstract

The aim of this study was to investigate the relationship between treatment-resistant depression (TRD) and inflammation in humans and experimental models. For the human study, a retrospective cohort study was conducted with 206 participants; half were on antidepressants for major depressive disorder. The patients were divided into healthy and depressed groups. Inflammation was assessed based on the values of the main inflammatory biomarkers (CRP, WBC and ESR). For the animal experiments, 35 adult male Wistar rats were assigned to stressed and non-stressed groups. Inflammation and stress were induced using lipopolysaccharide and chronic unpredictable mild stress. A 10 mg/kg intraperitoneal injection of fluoxetine (FLX), a known antidepressant, was simultaneously administered daily for 4 weeks. Behavioral tests were performed. The plasma levels of inflammatory and stress biomarkers were measured and were significantly higher in the stressed and non-responsive groups in both studies. This study provides evidence of the link between inflammation and TRD. We further observed a possible link via the Phosphorylated Janus Kinase 2 and Phosphorylated Signal Transducer and Activator of Transcription 3 (P-JAK2/P-STAT3) signaling pathway and found that chronic stress and high inflammation hinder the antidepressant effects of FLX. Thus, non-response to antidepressants could be mitigated by treating inflammation to improve the antidepressant effect in patients with TRD.

The Patient’s Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression

“…Therefore, although further studies with larger samples are needed, we could argue that patients with TRD and concomitant high levels of anhedonia and suicidality, like those from this sample, might need more time to feel a clear enhancement in certain symptomatic dimensions, according to the greater severity that characterizes TRD [65], the inflammatory theory arisen in the field of mood disorders, and delayed onset of statistically significant improvements in ESK-NS-treated patients with more complex, chronic forms of depression with specific prognostic factors [2,66].…”

Stress: Influences and Determinants of Psychopathology

“…Likewise, recent research has provided insight into the interaction between the nervous and immune systems [61,84,85,103], which must be carefully balanced to maintain overall stability. Immune alterations have been implicated in brain plasticity and mood changes, and chronic social stress has been shown to modulate the cytokines network [101].…”

“…Inflammation related to stress has been associated with various conditions, such as insomnia, late-life depression, anxiety, cognitive decline, and Alzheimer's disease [100]. Chronic stress and heightened inflammatory biomarkers have also been linked to a reduced response to antidepressant medications [103]. Peripheral inflammation activates several brain regions, and stress can lead to immunological responses and increased brain cytokine levels [60,61].…”

“…Peripheral inflammation activates several brain regions, and stress can lead to immunological responses and increased brain cytokine levels [60,61]. These factors are, in turn, commonly associated with certain risk factors for impaired associative, motivational, and emotional abilities, memory impairment, and cognitive loss [38,59], including Alzheimer's [37], insomnia, sleep disorders [73], depression [103], and schizophrenia [104]. There is growing evidence showing that even mild psychosocial stressors, such as fear of rejection, or social isolation can cause inflammatory activity and neuroinflammation [85,103].…”

“…These factors are, in turn, commonly associated with certain risk factors for impaired associative, motivational, and emotional abilities, memory impairment, and cognitive loss [38,59], including Alzheimer's [37], insomnia, sleep disorders [73], depression [103], and schizophrenia [104]. There is growing evidence showing that even mild psychosocial stressors, such as fear of rejection, or social isolation can cause inflammatory activity and neuroinflammation [85,103]. The neural circuits that are activated in response to these interactions are the same ones that have evolved for rewarding behaviors essential to survival.…”