Human Microbiota Transfer Therapy for Depression (The "Moving Moods Pilot Study")

INTERVENTION: Faecal Microbiota Transplantation via enema, referred to in this study as Human Microbiota Transfer Therapy (HMTT) Participants will recieve four doses of HMTT via enema over four consecutive days. Each dose will consist of a 50mL volume of faecal suspension, combined with 10% glycerol delivered into the rectum via a syringe. Participants will be required to retain the enema for thirty minutes. The HMTT will be delivered by a study nurse in a hospital environment. Delivery and direct obsersvation by study nurse will ensure adherence to the intervention. CONDITION: Major Depressive Disorder; ; Major Depressive Disorder Mental Health ‐ Depression PRIMARY OUTCOME: Feasibility of HMTT as an adjunctive treatment for MDD in adults is considered a composite outcome which will be measured by:; • the ability to meet recruitment targets (measured by recruitment logs, comparing actual recruitment against projected targets); • participant retention and completion rates (measured by recruitment logs, attrition rates and completeness of data); • adherence to intended protocol (measured by completion of intervention as planned, missed appointments, technical difficulties arising, and completeness of study data); • adherence to intended budget (measured by a comparison of projected budget and actual budget); • participant acceptability (measured using the TransCelerate Study Participant Feedback Questionnaire, plus the addition of questions designed specifically for this study); • robustness of study methodology, including effectiveness of blinding and placebo (measured qualitatively based on feedback from researchers throughout and at the conclusion of the study, and a participant and researcher survey to assess blinding); [12 weeks] Safety of HMTT as an adjunctive treatment for MDD in adults will be measured by assessment of adverse events/reactions which will be collected through direct observations by the study nurse during administration of the intervention, and by participant report during the intervention and each visit thereafter [adverse events/reactions will be measured at weeks 0, 2, 4, 6, 8, 10, 12 and 26] ; [Data will be collected at weeks 0, 2, 8 and 12] The functional potential between baseline and follow‐up, and compared with donor samples, using whole‐genome shot‐gun metagenomic sequencing (measured at weeks 0, 2, 8 and 12) ; [Measured at weeks 0, 2, 8 and 12] INCLUSION CRITERIA: • Adults (age 18‐65) • MDD according to Structured Clinical Interview for DSM‐5 (SCID‐5) MDD module • Moderate‐to‐severe score on MADRS (i.e. score of greater than or equal to 20) • Have been on stable pharmaceutical treatment for MDD for one month prior to commencing trial SECONDARY OUTCOME: Changes in blood biomarkers of neurogenesis (e.g. brain‐derived neurotrophic factor)[measured at weeks 0, 2, 8 and 12] Changes in cardiometabolic blood parameters, including random lipid profile, random blood sugar levels and HbA1c [measured at weeks 0, 2, 8 and 12] Changes in gut permeability (e.g., lipopolysaccharide binding protein and zonulin) will be measured in plasma using immunoassays (e.g. solid phase sandwich ELISA assay). [measured at weeks 0, 2, 8 and 12] Changes in gut symptomology will be measured using the Gastrointestinal Symptom Rating Scale (GSRS) (measured at baseline, and weeks 2, 4, 6, 8 and 12)[measured at baseline, and weeks 2, 4, 6, 8 and 12] Changes in inflammation (e.g., macrophage inhibitory factor, interleukins 1b, 1ra, 6 and 10, soluble CD14, and high sensitivity C‐reactive protein) will be measured in plasma using immunoassays (e.g. solid phase sandwich ELISA assay). [measured at weeks 0, 2, 8 and 12] Changes in mental health symptomatology measured by the Montgemery‐Asberg Depression Rating Scale (MADRS) and the Depression‐Anxiety Stress Scale (DASS) (measured at screening, and weeks 2, 4, 6, 8 and 12)[measured at screening, and weeks 2, 4, 6, 8 and 12] Changes in metabolic and cardiovascular risk factors assessed via physical exam, including heart rate, blood pressure, weigh circumference, height and weight (measured at week 0, 2, 8 and 12)[measured at week 0, 2, 8 and 12] Changes in sleep quality will be measured using the Pittsburgh Sleep Quality Index [measured at baseline, and weeks 2, 4, 6, 8 and 12] Cost effectiveness will be assessed from both health sector and societal perspectives. The cost of FMT via enema will be estimated and added to the cost of lost productivity and health care resources utilised by participants over the course of the trial using the Resource Utilization Questionnaire (measured at baseline, and weeks 8 and 12)[measured at baseline, and weeks 8 and 12] Level of function will be measured using the Sheehan Disability Scale[measured at baseline, and weeks 2, 4, 6, 8 and 12] overall improvement will be assessed using the Patient Global Impression of Change[measured at baseline, and weeks 2, 4, 6, 8 and 12] Quality of life will be measured with the Assessment of Quality of Life‐8 Dimension (AQoL‐8D); this scale also allows the calculation of preference‐based outcomes also known as utilities. Utility values will be used to calculate quality adjusted life years (QALYs) a common metric used in economic evaluations (measured at baseline, and weeks 2, 4, 6, 8 and 12)[measured at baseline, and weeks 2, 4, 6, 8 and 12] The degree of microbial ‘engraftment’ by observing differences between gut microbiota composition and compared with donor samples, using whole‐genome shot‐gun metagenomic sequencing (measured at weeks 0, 2, 8 and 12)