Recent evidence from clinical and animal studies with anti-inflammatory agents in depression is conflicting. One possible reason is the heterogeneity of baseline inflammation levels. Since older adults are generally associated with chronic low-grade inflammation and depression is one of the most common mental disorders in this population, this meta-analysis aimed to evaluate the therapeutic and preventative effects of anti-inflammatory interventions for depression among older adults. PubMed, Cochrane Library, Embase, and PsycINFO were searched for randomized controlled trials (RCTs) up to November 18, 2024. The primary outcomes were mean change scores of depression scores and incidences of depression after treatment. Pooled standard mean differences (SMDs) and odds ratios (ORs) including 95% confidence intervals (95% CI) were calculated. Of 3116 screened articles, 31 RCTs met the inclusion criteria, with 25 studies investigating efficacy and 7 studies investigating the incidence following anti-inflammatory treatment. Anti-inflammatory interventions were statistically significantly more effective than placebo in reducing depressive scores for older adults with depression (SMD = -0.57, 95% CI = -0.98 to -0.15, p = 0.008). Sub-group analyses supported the use of omega-3 fatty acids (SMD = -0.14, 95% CI = -0.27 to -0.02, p = 0.03) and botanical drug or dietary intervention (SMD = -0.86, 95% CI = -1.58 to -0.13, p = 0.02) among older participants. While limited by substantial heterogeneity among included studies, these results reveal the moderate beneficial effects of anti-inflammatory interventions for the treatment and prevention of depression among older adults. Future high-quality RCTs are warranted to determine which anti-inflammatory interventions are most preferential for older patients with depression.

Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.

Although depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10-8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15-1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.

While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson's disease, COVID, traumatic brain injury, and Alzheimer's disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical "psychiatric medications" are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.

Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Psychodermatology pertains to the relationship between the skin and brain. This review aims to summarize the evidence of the mind body connection in four psychophysiological conditions: rosacea, atopic dermatitis (AD), acne vulgaris (AV), and psoriasis. A literature search was conducted using several English language databases. All four conditions share similar psychiatric co-morbidities, including but not limited to anxiety, depression, and suicidality. In rosacea, the upregulation of transient receptor potential vanilloid type 1, Toll like receptor 2, and Th17 cells releases downstream products that are simultaneously implicated in mood disorders. Stress exacerbates AV through the hypothalamic-pituitary-adrenal (HPA) system, which alters functioning of sebocytes and Cutibacterium acnes. In AD and psoriasis, the HPA axis influences Th1, Th2, Th22, and Th1, Th17 immune mediated responses, respectively. This leads to the secretion of pro-inflammatory cytokines which are also involved in the pathogenesis of anxiety and depression. Neurotransmitters implicated in mental illness, such as gamma-aminobutyric acid and serotonin, may also play a role in the development of AD and psoriasis. The management of cutaneous disease may mitigate psychological distress, and future research may show the corollary to also be true.

Depression is common among patients with acute coronary syndrome (ACS). Although multiple studies have confirmed that depression is an independent risk factor for poor outcomes in ACS, general awareness of this issue is still limited. Ongoing research has described detailed aspects of depression in ACS, with various mechanistic hypotheses put forward to explain the complexity of this comorbidity. Several investigations have explored management strategies in this subgroup of patients, including screening for depression, antidepressant treatment, and cardiac rehabilitation. However, evidence of long-term improvement in clinical outcomes is still scarce, and a more comprehensive understanding of the underlying mechanisms that link depression with ACS is required to further improve disease management.

Myocardial infarction (MI) can have significant physical and mental consequences. Depression is a prevalent psychiatric condition after MI which can reduce the quality of life and increase the mortality rates of patients. However, the connection between MI and depression has remained under-appreciated. This review examines the potential connection between depression and MI by overviewing the possible pathophysiologic mechanisms including dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, coagulation system dysfunction, inflammation, environmental factors, as well as, genetic factors. Furthermore, depression can be an adverse event of medications used for MI treatment including beta-blockers, statins, or anti-platelet agents. The need for early detection and management of depression in patients with MI is, therefore, crucial for improving their overall prognosis. Adherence to treatments and regular follow-up visits can ensure the best response to treatment.

Treatment refractory depression (TRD) in the elderly is a common psychiatric disorder with high comorbidity and mortality. Older adults with TRD often have complicated comorbidities and several predisposing risk factors, which may lead to neuropsychiatric dysfunction and poor response to treatment. Several hypotheses suggest the underlying mechanisms, including vascular, immunological, senescence, or abnormal protein deposition. Treatment strategies for TRD include optimization of current medication dose, augmentation, switching to an alternative agent or class, and combination of different antidepressant classes, as well as nonpharmacological adjuvant interventions such as biophysical stimulation and psychotherapy. In summary, treatment recommendations for TRD in the elderly favor a multimodal approach, combining pharmacological and nonpharmacological treatments.

The effects of acetylsalicylic acid (ASA) on mood disorders (MD) and on inflammatory parameters in preclinical and clinical studies have not yet been comprehensively evaluated. The aim of this study was to systematically summarize the available knowledge on this topic according to PRISMA guidelines. Data from preclinical and clinical studies were analyzed, considering the safety and efficacy of ASA in the treatment of MD and the correlation of inflammatory parameters with the effect of ASA treatment. Twenty-one studies were included. Both preclinical and clinical studies found evidence indicating the safety and efficacy of low-dose ASA in the treatment of all types of affective episodes in MD. Observational studies have indicated a reduced risk of all types of affective episodes in chronic low-dose ASA users (HR 0.92, 95% CI: 0.88, 0.95, p < 0.0001). An association between ASA response and inflammatory parameters was found in preclinical studies, but this was not confirmed in clinical trials. Further long-term clinical trials evaluating the safety and efficacy of ASA in recurrent MD, as well as assessing the linkage of ASA treatment with inflammatory phenotype and cytokines, are required. There is also a need for preclinical studies to understand the exact mechanism of action of ASA in MD.

Individuals with severe psychiatric disorders, such as mood disorders and schizophrenia, are at increased risk of developing other medical conditions, especially cardiovascular and metabolic diseases. These medical conditions are underdiagnosed and undertreated in these patients contributing to their increased morbidity and mortality. The basis for this increased comorbidity is not well understood, possibly reflecting shared risks factors (e.g. lifestyle risk factors), shared biological mechanisms and/or reciprocal interactions. Among overlapping pathophysiological mechanisms, inflammation and related factors, such as dysbiosis and insulin resistance, stand out. Besides underlying the association between psychiatric disorders and cardiometabolic diseases, these mechanisms provide several potential therapeutic targets.

Cardiovascular agents, including angiotensin-converting enzyme inhibitors, angiotensin II receptor inhibitors, acetylsalicylic acid, statins, and metformin, have demonstrated benefits for depression. However, there is scant evaluation of these drugs' antidepressant properties in large population settings.

This study aimed to examine cross-sectional associations between depression symptoms and the use of cardiovascular agents and metformin in populations with cardiovascular diseases or diabetes mellitus.

Participants in the Trøndelag Health Study 2006-08 (HUNT3, n = 40,516) and 2017-19 (HUNT4, n = 42,103) were included and data on their drug use from 2006 to 2019 was retrieved from the Norwegian Prescription Database. The outcome was self-reported depression symptoms defined by the Hospital Anxiety and Depression Scale. Associations between cardiovascular agents or metformin use and self-reported depression were analyzed by multi-level logistic regression in sex-stratified samples.

Among men with cardiovascular diseases, use of acetylsalicylic acid was associated with reduced depression symptoms compared with acetylsalicylic acid non-users (reference) in HUNT3 and HUNT4 [risk ratio = 0.76; 95% confidence interval 0.59-0.94, risk ratio = 0.67; 95% CI 0.52-0.82, respectively]. Similarly, male statin users had a lower likelihood of reporting depression than statin non-users in HUNT3 (risk ratio = 0.70; 95% confidence interval 0.54-0.86) and HUNT4 (risk ratio = 0.67; 95% confidence interval 0.51-0.84). Associations between statins or acetylsalicylic acid use and reduced depression symptoms were detected in women with cardiovascular diseases in HUNT4. We found no statistical support for associations between other cardiovascular agents or metformin use and a reduced or increased depression symptom risk.

Results suggest negative associations between acetylsalicylic acid or statin use and depression symptoms. However, longitudinal cohort studies and randomized controlled trials are required to confirm the antidepressant effects of these drugs.

The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO), but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme, but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with antiinflammatory properties are unlikely to act by direct inhibition of IDO, but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of 6 antiinflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other 5 dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD.  TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal antiinflammatory drugs.  The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.

With the progressive aging of the world's population, prolongation of a healthy lifespan in old age has become a medical research priority. The presence of depressive symptoms in later life is associated with poor health prognosis and increased mortality^1,2. Here we explore distinct trajectories of depressive symptoms in later life and their association with several health-related outcomes in 19,110 older individuals followed for a median of 4.7 years. Using a latent class, mixed-modeling approach we identified four distinct trajectories of depressive symptoms with scoring patterns of consistently low, moderate, emerging and persistently high. Compared to those with minimal depressive symptoms, membership of any other class was associated with specific patterns of baseline sociodemographic and medical factors. Membership of any group with depressive symptoms was associated with a higher likelihood of health events, including physical disability, cancer and major bleeding episodes. Membership of the persistently depressed class was associated with increased mortality, while a diagnosis of dementia was generally limited to the class with initially low and progressively rising symptoms. The course of depressive symptoms in older individuals can vary widely and depend on several factors. The presence of depressive symptoms, including those that do not meet criteria for major depression, can flag a poor prognosis and risk for specific health conditions. Systematic assessment of depressive symptoms may facilitate early identification of at-risk populations.

Traumatic brain injury (TBI) is an established risk factor for the development of psychiatric disorders, especially depression and anxiety. However, the mechanistic pathways underlying this risk remain unclear, limiting treatment options and hindering the identification of clinically useful biomarkers. One salient pathophysiological process implicated in both primary psychiatric disorders and TBI is inflammation. An important consequence of inflammation is the increased breakdown of tryptophan to kynurenine and, subsequently, the metabolism of kynurenine into several neuroactive metabolites, including the neurotoxic NMDA receptor agonist quinolinic acid and the neuroprotective NMDA receptor antagonist kynurenic acid. Here, we review studies of the kynurenine pathway (KP) in TBI and examine their potential clinical implications. The weight of the literature suggests that there is increased production of neurotoxic kynurenines such as quinolinic acid in TBI of all severities and that elevated quinolinic acid concentrations in both the cerebrospinal fluid and blood are a negative prognostic indicator, being associated with death, magnetic resonance imaging abnormalities, increased depressive and anxiety symptoms, and prolonged recovery. We hypothesize that an imbalance in KP metabolism is also one molecular pathway through which the TBI-induced neurometabolic cascade may predispose to the development of psychiatric sequelae. If this model is correct, KP metabolites could serve to predict who is likely to develop psychiatric illness while drugs that target the KP could help to prevent or treat depression and anxiety arising in the context of TBI.

Major depressive disorder (MDD) is a common, severe and disabling neuropsychiatric disorder with a heterogenous etiology. Among the most widely recognized etiological models, immunopathogenesis is a predominant one. Numerous studies have demonstrated aberrant levels of inflammatory markers in the peripheral blood, cerebrospinal fluid (CSF) and brain of patients with MDD. Multiple studies including meta-analyses have reported increased peripheral levels of acute phase proteins, and pro-inflammatory cytokines, particularly IL-1β, TNF-α, and IL-6 in MDD. Postmortem brain studies similarly demonstrated upregulated expressions of these pro-inflammatory cytokines. This along with evidence of monocytic, lymphocytic and microglial activation, suggest an activated inflammatory response system (IRS) in MDD. A few studies show increased levels of anti-inflammatory cytokines or defective inflammatory pathways and a deficit in T cell maturation and responses in MDD patients. This suggests the presence of a Compensatory Immune Response System (CIRS), which can counterbalance the effects of IRS in major depression. More recently, simultaneously increased levels of both the pro-and anti-inflammatory cytokines are reported in the brain of MDD patients; this indicates activity of both the IRS and CIRS in MDD. The IRS and CIRS are the evolutionarily conserved and integral elements of an overarching system. The relevance of a dysregulated IRS-CIRS system in the neurobiological construct of MDD is just beginning to be understood. Speculation is rife that the disrupted IRS-CIRS elements might determine the onset, episodes, neuroprogressive processes, treatment response as well as recovery of patients with MDD. Notably, the signatures of an activated IRS-CIRS might emerge as potential biomarkers of MDD. Herein, an attempt has been made to highlight the biology and pathobiological relevance of IRS-CIRS activation in MDD and provide an insight into the role of these components in pharmacological therapy.

Omega-3 fatty acids have been acknowledged for their number of holdings on an individual's health. Not only in physical valuation but also in managing psychiatric disorders, omega-3 fatty acids have been found to be a powerful formula. It is proclaimed that depressive patients suffer anomaly with the levels of omega-3 polyunsaturated fatty acids in the body, coupled with insignificant EPA and DHA. Enhancement in brain functioning, neuronal functions, and paying attention in interacting with the brain cells are some of the additional tasks, being performed by the supplementation of omega-3 fatty acids. The leading and primary source via dietary supplementation involves the involvement of fish and fish products. These are hypothesized to be the best and dominant source for omega-3 fatty acids. Consumption of omega-3 fatty acid is well safe, that physician highly favors intake of these supplements, remarkably in the case of pregnant women. However, treating this serious life-threatening mental disorder leads to many adverse effects when treated with antidepressants. The dose range includes 1g/d to 10g/d, which is to be incorporated by the patient. It is also tested that the combination of EPA and DHA is found to be more efficacious for a person in treating and preventing depressive symptoms. Some studies verify the supplementation of omega-3 fatty acids in diet was coequally productive and successful with minimal side effects when analyzed with antidepressants. Despite these facts, much research is still needed and presently in process for long-term safety and studying the role of omega-3 fatty acids in human health.

Depression is a common and highly disabling condition in older adults. It is a heterogenous disorder and there is emerging evidence of a link between inflammation and depression in older patients, with a possible inflammatory subtype of depression. Persistent low-level inflammation, from several sources including psychological distress and chronic disease, can disrupt monoaminergic and glutaminergic systems to create dysfunctional brain networks. Despite the evidence for the role of inflammation in depression, there is insufficient evidence to recommend use of any putative anti-inflammatory agent in the treatment of depression in older adults at this stage. Further characterisation of markers of inflammation and stratification of participants with elevated rates of inflammatory markers in treatment trials is needed.