Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies

Abstract

Depression is a multicausal disorder and has been associated with the risk to develop cancer, dementia, diabetes, epilepsy and stroke. As a metabolic disorder depression has been associated with obesity, diabetes, insulin sensitivity, neuropeptide Y, glucose regulation, poor glycemic control, glucagone-like peptide-1, cholezystokinin, ghrelin, leptin, the endocannabinoid system, insulin-like growth factor and gastrin-releasing peptide. As a cardiovascular disease a close relationship exists between depression and blood pressure, heart rate, norepinephrine, sympathetic tone, vascular resistance, blood viscosity, plasma volume, intima thickness and atherosclerosis. Additionally blood coagulation, fibrinolysis, D-dimers, plasminogen activator inhibitor-1 protein, platelet activation, VEGF, plasma nitric oxide and its synthase are changed in depressed patients. As an endocrinological and stress disorder depression has been connected with the concentration of free T₄, TSH, CRH, arginine vasopressin, corticotrophin, corticosteroid release and ACTH. Depression as an inflammatory disorder is mediated by pro-inflammatory cytokines, interleukin-1, interleukin-6, TNF-alpha, soluble interleukin-2 receptors, interferon-alpha, interleukin 8, interleukin-10, hs-CRP, acute phase proteins, haptoglobin, toll like receptor 4, interleukin-1beta, mammalian target of rapamycin pathway, substance P, cyclooxygenase-2, prostaglandin-E2, lipid peroxidation levels and acid sphingomyelinase. Nutritional factors might influence depression risk, i.e. the consumption of folate, omega-3 fatty acids, monounsaturated fatty acids, olive oil, fish, fruits, vegetables, nuts, legumes, vitamin B6 and vitamin B12. The neurodegenerative hypothesis of depression explains decreased hippocampal volumes in depressed patients and changes of neurotrophic support by BDNF, erythropoietin, GDNF, FGF-2, NT3, NGF and growth hormone. In this context, a fast neuroprotective and antidepressant effect has also been observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications.

Proinflammatory cytokines correlate with early exercise attenuating anxiety‐like behavior after cerebral ischemia

“…The prevalence of PSA ranges between 20% within 1 month after stroke and 24% 6 months or more after stroke (Menlove et al., 2015). Most importantly, PSA not only increases the difficulties associated with the patient's care (by both family and society), but also reduces the patient's compliance with stroke rehabilitation (Lang & Borgwardt, 2013; Zhang, Yu, et al., 2013). Clinical and neurobiological data suggest that exercise may be an effective treatment strategy to ease the symptoms of anxiety disorders (Hennings et al., 2013).…”

“…The incidence of stroke increases annually by 9% and has been a leading cause of death in China. Mood disturbance is common complication of stroke and is characterized by mood abnormalities, self‐blaming, sadness, especially anxiety and depression (Lang & Borgwardt, 2013). Poststroke depression (PSD) has received most research attention (Wu et al., 2014), in contrast, poststroke anxiety (PSA) has only recently gained attention although anxiety is commoner than depression (Menlove et al., 2015).…”

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

“…Depression is associated with risk for other pathologies, including cancer and cardiometabolic disease (Lang and Borgwardt, 2013), which themselves are associated with stress. The present analysis of uCMS-exposed animals revealed upregulation and downregulation of genes related to these disorders.…”

“…Strikingly, a high percentage of patients treated with the currently available therapies do not show full remission (Lang and Borgwardt, 2013) and present treatment resistance (Blier and Blondeau, 2011). Although the pathophysiology of depression is still incompletely understood, dysregulation of monoaminergic systems, neuroplasticity, and immunological responses (Villanueva, 2013;Willner et al, 2013) are considered to contribute to the disease.…”

Biomarkers of Epileptogenesis: Psychiatric Comorbidities (?)

“…Furthermore, even depressive impairments not primarily associated with inflammatory stimuli (e.g., depression induced by stress) are readily improved by anti-inflammatory medications [174,175]. Among various components of innate immunity, the inflammatory cytokine IL-1β has been particularly strongly implicated in inflammation-induced depression [176][177][178][179]. For example, central administration of IL-1β is sufficient to produce behavioral [176] and neuroendocrine (i.e., elevated plasma corticosterone levels [180]) signs of depression in rodents.…”