Inflammation and depressive comorbidity in obesity: modulation by omega-3 polyunsaturated fatty acid status – NUTRIMOOD

NUTRIMOOD uses a translational, multidisciplinary approach. Clinical methods include recruitment of overweight/obese patients with MDD in France and Taiwan, comprehensive psychiatric evaluations, collection of biological samples, and measurement of erythrocyte n-3 PUFA levels (EPA and DHA). Inflammatory markers are assessed in blood, and gut microbiota composition and intestinal permeability are analyzed to evaluate gut-related mechanisms. A subgroup of patients with low n-3 PUFA status receives supplementation to assess preliminary clinical effects on depressive symptoms and antidepressant response.
Parallel preclinical studies in mice focus on gut-related inflammation and the impact of PUFA modulation on depressive-like behaviors, providing mechanistic insights. Multidisciplinary integration allows linking clinical outcomes with molecular and microbiota profiles to identify predictors of antidepressant response and novel intervention targets.

Recruitment started on December 3, 2024, with delays compared to the projected timeline due to daministrative constraints and eligibility issues (ongoing treatment, age limits, clinical severity). As of May 2025, eight patients have provided informed consent, completed clinical assessments, and biological samples were collected.
Biological assays will be performed after 25 participants are enrolled.

NUTRIMOOD uniquely combines clinical psychiatry, nutritional psychiatry, and translational research to investigate the mechanistic links between obesity, inflammation, gut alterations, PUFA status, and antidepressant response. Its focus on personalized medicine through biomarker profiling and innovative targeted interventions offers the potential to improve treatment outcomes in patients with comorbid overeweight/obesity and MDD.

Amadieu C., Leyrolle Q, (…), Aouizerate B, Capuron L. Association between kynurenine pathway metabolism, clinical severity and functional outcomes in treatment-resistant depression. British Journal of Psychiatry (in submission).

Obesity and overweight represent important public health concerns given their growing prevalence worldwide. These conditions are often associated with neuropsychiatric comorbidities. Major depressive disorder (MDD) is the most frequent, severe and disabling of those disorders, affecting about 30% of obese subjects, with strong impact on quality of life and adherence to weight loss programs. Moreover, obese subjects with comorbid MDD are more prone to show antidepressant resistance. In this context, strategies to manage MDD and antidepressant non-response in overweight/obese subjects are urgently needed. The definition of such strategies requires the elucidation of the mechanisms linking obesity to MDD and treatment resistance.
Recent data obtained by partner 1 (P1, France) suggest the involvement of inflammation in the relationship between obesity and MDD. Obesity is characterized by a chronic low-grade inflammatory state originating from the adipose tissue and the gut that could contribute to depressive symptoms and antidepressant resistance. However, MDD and treatment resistance do not develop in all subjects afflicted with chronic inflammatory conditions, such as obesity, suggesting that inflammation per se is not sufficient but may act with other factors. Partner 2 (P2, Taiwan) showed that reduced n-3 PUFA status, notably as it relates to erythrocytes levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with anti-inflammatory properties, significantly increases the risk of inflammation-related MDD. Moreover, recent findings from P1 show that lower levels of n-3 PUFAs predict reduced clinical response to conventional antidepressants in MDD patients. Convergent clinical and preclinical data suggest the role of gut alterations in the relationship between obesity-related inflammation, PUFA status and antidepressant response.
The overarching aim of NUTRIMOOD is to 1) assess the relationships between PUFA status, inflammation, gut microbiota/intestinal permeability, and treatment response in cohorts of French and Taiwanese overweight/obese subjects with comorbid MDD; 2) provide a preliminary investigation of the effect of n-3 PUFA supplementation in improving clinical symptoms in a subgroup of obese subjects with comorbid MDD and low n-3 PUFA status known to be associated with unsatisfactory response to standard antidepressants; and 3) elucidate the mechanisms involved in these effects using a translational approach focusing on gut-related inflammation in mice.
NUTRIMOOD is a multidisciplinary research program aggregating expertise in psychiatry, psychoneuroimmunology, nutrition and metabolism, biochemistry and molecular biology. It brings together partners internationally renowned for their contribution to knowledge on the relationship and pathophysiological mechanisms linking inflammation and depression (P1) and world leading experts in the emerging field of nutritional psychiatry, notably as it relates to n-3 PUFAs (P2). By improving knowledge on factors and mechanisms linking obesity and MDD, NUTRIMOOD will help defining novel and tailored strategies for the prevention and treatment of MDD in overweight/obese subjects in line with the principles of personalized medicine based on the patient biological and clinical profiles.