PAID study design on the role of PKC activation in immune/inflammation-related depression:a randomised placebo-controlled trial protocol

Background Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression.Microglia activation can lead to an increase in the levels of proinflammatory cytokines,including TNF-α,which leads to neuronal apoptosis in the specific neural circuits of some brain regions,abnormal cognition and treatment-resistant depression(TRD).Protein kinase C(PKC)is a key regulator of the microglia activation process.We assume that the abnormality in PKC might result in abnormal microglia activation,neuronal apoptosis,significant changes in emotional and cognitive neural circuits,and TRD.In the current study,we plan to target at the PKC signal pathway to improve the TRD treatment outcome.Methods and analysis This is a 12-week,ongoing,randomised,placebo-controlled trial.Patients with TRD(N=180)were recruited from Shanghai Mental Health Center,Shanghai Jiao Tong University.Healthy control volunteers(N=60)were recruited by advertisement.Patients with TRD were randomly assigned to‘escitalopram+golimumab(TNF-αinhibitor)’,‘escitalopram+calcium tablet+vitamin D(PKC activator)’or‘escitalopram+placebo’groups.We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale(HAMD-17).The secondary outcome is defined as changes in anti-inflammatory effects,cognitive function and quality of life.Discussion This study might be the first randomised,placebo-controlled trial to target at the PKC signal pathway in patients with TRD.Our study might help to propose individualised treatment strategies for depression.Trial registration number The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

Hypothalamic-Pituitary-End-Organ Axes:Hormone Function in Female Patients with Major Depressive Disorder

Classic hypothalamic-pituitary-end-organ feedback loops–the hypothalamic-pituitary-adrenal axis(HPAA),hypothalamic-pituitary-thyroidal axis(HPTA),and hypothalamic-pituitary-gonadal axis(HPGA)–are associated with the neuroendocrine and immune systems in major depressive disorder(MDD).Female patients with MDD present with evident neuroendocrine and immunological changes.Glucocorticoid,thyroid hormone,and reproductive steroid levels fluctuate with menstrual cycles,which might lead to glucocorticoid receptor resistance,impairment of triiodothyronine conversion,and sex hormone secretion disorders.In this review,we summarize the independent and interactive functions of these three axes in female MDD patients.The similar molecular structure of steroids implies an interrelationship between the hypothalamic-pituitary-end-organ axes and the competitive inhibitory effects at the receptor level,especially when considering the HPAA and HPGA.