The aim of this clinical trial is to investigate the effects of L-serine supplementation on cognitive decline and psychosocial functioning in older adults with late-life depression (LLD). The study will evaluate changes in depressive symptoms, neural and cognitive functioning, and will assess neurophysiological, metagenomic, and biochemical alterations associated with L-serine supplementation compared with placebo.
The main research questions are:
* Does L-serine supplementation affect cognitive function, depressive symptoms, and neural functioning in individuals with late-life depression? * What biological mechanisms may underlie the effects of L-serine on cognitive decline? Participants will be randomly assigned to one of two study arms: an intervention group (total n = 42) receiving L-serine at a dose of 6 g/day for 48 weeks, and a placebo group (total n = 42) receiving 6 g/day of maltodextrin for the same duration.
All participants will be assessed at three time points: T0 (baseline, prior to trial initiation), T18 (after 18 weeks), and T48 (after 48 weeks, at the end of the trial).
At each assessment, participants will:
* complete clinical questionnaires and a neuropsychological assessment; * provide blood, fecal, and urine samples; * undergo electroencephalographic (EEG) recordings.
Age 65-85 years;
Presence of depressive symptoms, defined as a score ≥ 5 on the Geriatric Depression Scale-15 items (GDS-15) or ≥ 5 on the Patient Health Questionnaire-9 (PHQ-9).
Diagnosis of dementia;
Use of antibiotics or anti-inflammatory medications within the previous 8 weeks;
Active gastrointestinal disease;
Severe chronic medical conditions (e.g., advanced-stage cancer, severe cardiac or renal disorders, or other debilitating diseases);
Parallel
L-serine supplementation
Dietary supplementParticipants randomized to the experimental arm will receive L-serine supplementation (6 g/day), administered orally as a single stick per day for a total duration of 48 weeks.
Placebo
Other interventionParticipants randomized to the Placebo arm will receive Maltodextrine supplementation (6 g/day), administered orally as a single stick per day for a total duration of 48 weeks.
Geriatric Depression Scale - 15
The Geriatric Depression Scale - 15 items (GDS-15) is a validated clinical instrument widely used in clinical and research settings to screen for depressive symptoms in older adults.
Repeatable Battery for the Assessment of Neuropsychological Status
The Repeatable Battery for the Assessment of Neuropsychological (RBANS) is a neuropsychological battery composed of 12 subtests grouped into five domains: Immediate Memory, Visuospatial/Constructional, Language, Attention, and Delayed Memory. It yields index scores and a total scale score. Higher scores indicate better cognitive functioning, reflecting a more favorable clinical outcome.
Patient Health Questionnaire - 9
The Patient Health Questionnaire-9 (PHQ-9) is a self-administered instrument used to assess the severity of depressive symptoms based on DSM criteria. It consists of 9 items, each rated from 0 (not at all) to 3 (nearly every day), resulting in a total score ranging from 0 to 27. Higher scores reflect more severe depressive symptoms, indicating a worse clinical outcome.
Montgomery-Åsberg Depression Rating Scale
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-administered scale designed to assess the severity of depressive symptoms. It consists of 10 items, each rated on a scale from 0 to 6, yielding a total score ranging from 0 to 60. Higher scores indicate greater severity of depression, meaning a worse clinical outcome
Electroencephalogram -derived neurophysiological metrics
Electroencephalogram (EEG) recordings will be used to derive individual spectral analysis and connectivity.
Gut Microbiome Composition
Assessment of gut microbiome composition through analysis of fecal samples using high-throughput sequencing techniques (e.g., 16S rRNA gene sequencing). Microbial diversity (alpha and beta diversity) and relative abundance of bacterial taxa will be evaluated.
Immune-related biomarkers levels
Plasma and serum levels of immune-related biomarkers will be measured, including cytokines and chemokines, C-reactive protein (CRP), and NLRP3. Quantitative assessment will be performed using validated laboratory assays. Changes in biomarker concentrations over time will be evaluated.
Amino acid and metabolic biomarkers
L-serine and D-serine concentrations will be measured in blood, urine, and fecal samples using validated analytical methods. Quantitative assessment of biomarker levels and changes over time will be performed.
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