The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

Abstract

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

Focus on fatty acids in the neurometabolic pathophysiology of psychiatric disorders

“…More recent hypotheses suggest broader metabolic alterations that extend beyond monoamine metabolism (Su 2008;Maes et al 2009;Assies et al 2014;Naviaux 2014;Rosenblat et al 2014;Muller et al 2015;Mocking et al 2016a). Complex interacting metabolic pathways are being hypothesized to partly underlie -and be connected with -observed coexistent biological (oxidative) stress, inflammatory, and brain network alterations.…”

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

“…[29][30][31][32]. Immune-inflammatory, O&NS, autoimmune and neuroprogressive pathways are involved in shaping depressive phenomenology, staging of depression (e.g.…”

“…Immune-inflammatory, O&NS, autoimmune and neuroprogressive pathways are involved in shaping depressive phenomenology, staging of depression (e.g. treatment resistance, recurrence, chronicity and sensitization) and the comorbidity with many (neuro)inflammatory or (auto)immune disorders [29][30][31][32]. Shared immune and O&NS pathways in part explain the robust comorbidity of depression with medical conditions, e.g.…”

Cerebral plasticity and connectopathies: mechanisms of comorbidity of neurological diseases and depression

“…Сходство между нейровоспалительными про-цессами и нарушениями систем трофических факторов и нейромедиаторов привело к гипотезе о том, что именно эти звенья патогенеза лежат в основе коморбидности де-прессий и нейродегенеративных заболеваний [20]. Одно-временно возникла нейровоспалительная и нейродегене-ративная гипотеза развития депрессии, в рамках которой постулировалось, что внешние (например, психосоциаль-ные) и внутренние (например, провоспалительные влия-ния) стрессоры запускают депрессивные расстройства, стимулируя процессы нейровоспаления [21]. Формули-ровке этой гипотезы способствовала информация о том, что большинство, если не все, антидепрессанты обладают противовоспалительными свойствами.…”