Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic–pituitary–adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for dietary n-3 PUFA in the prevention of HPA axis dysfunction associated with the development of some neuropsychiatric disorders including depression.

Background: Neuroinflammatory processes are considered a double-edged sword, having both protective and detrimental effects in the brain. Microglia, the brain's resident innate immune cells, are a key component of neuroinflammatory response. There is a growing interest in developing drugs to target microglia and control neuroinflammatory processes. In this regard, docosahexaenoic acid (DHA), the brain's n-3 polyunsaturated fatty acid, is a promising molecule to regulate pro-inflammatory microglia and cytokine production. Several works reported that the bioavailability of DHA to the brain is higher when DHA is acylated to phospholipid. In this work, we analyzed the antiinflammatory activity of DHA-phospholipid, either acetylated at the sn-1 position (AceDoPC, a stable form thought to have superior access to the brain) or acylated with palmitic acid at the sn-1 position (PC-DHA) using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo.

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Cognitive impairments reported across psychiatric conditions (ie, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder) strongly impair the quality of life of patients and the recovery of those conditions. There is therefore a great need for consideration for cognitive dysfunction in the management of psychiatric disorders. The redundant pattern of cognitive impairments across such conditions suggests possible shared mechanisms potentially leading to their development. Here, we review for the first time the possible role of inflammation in cognitive dysfunctions across psychiatric disorders. Raised inflammatory processes (microglia activation and elevated cytokine levels) across diagnoses could therefore disrupt neurobiological mechanisms regulating cognition, including Hebbian and homeostatic plasticity, neurogenesis, neurotrophic factor, the HPA axis, and the kynurenine pathway. This redundant association between elevated inflammation and cognitive alterations across psychiatric disorders hence suggests that a cross-disorder approach using pharmacological and nonpharmacological (ie, physical activity and nutrition) anti-inflammatory/immunomodulatory strategies should be considered in the management of cognition in psychiatry.

BackgroundIn patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient’s inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design.MethodsThis study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the ‘Depression with inflammation’ stratum (CRP levels > 3 mg/L); or into the ‘Depression without inflammation’ stratum (CRP levels ≤ 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit.DiscussionThe current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2829-7) contains supplementary material, which is available to authorized users.

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Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

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