Metformin and Atorvastatin in Major Depression: The Hearts and Minds double-blind, randomised, placebo-controlled trial.

INTERVENTION: 16 weeks of adjunctive Metformin 2000mg oral tablet daily or Atorvastatin 40mg oral tablet daily. Adherence to intervention will be monitored via counting of returned medication. CONDITION: Major Depressive Disorder; ; Major Depressive Disorder Mental Health ‐ Depression PRIMARY OUTCOME: Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on depression symptomotology using MADRS mean scores. [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 (Primary Endpoint) after starting treatment.; ] SECONDARY OUTCOME: ; Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on Anxiety symptomotology using Hamilton Anxiety Rating Scale mean scores. (HAM‐A).[Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Economic evaluation of adjunctive metformin or atorvastatin treatment compared to placebo. Incremental cost‐effectiveness (using MADRS) and cost‐utility ratios (using quality adjusted life years (QALYs) derived from utility values on AQoL‐4D) will be calculated from health sector and practical societal perspectives. Additional health care resource use will be measured using a Resource Use Questionnaire (RUQ), and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI‐GH) will provide time lost from from paid work and presenteeism. The Assessment of Quality of Life (AQoL‐4D) will provide preference based utility values used to calculate QALYs.[Comparison between baseline and Week 16 after starting treatment. ; ] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks by measuring health and disability using by World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) mean score. ; ; [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks measuring change in functioning, using the Longitudinal Interval Follow‐up Evaluation‐Range of the Impaired Functioning Tool (LIFE‐RIFT) mean score. ; [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks measuring on quality of life using Quality of life form (AQol‐4D). ; ; [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on Bipolar Depression symptomatology using Bipolar Depression Rating Scale (BDRS) mean scores.[Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on general level of functioning using Clinical Global Impression Scale mean scores (CGI‐S and CGI‐I) (Severity and improvement).[Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on response to treatment using the Patient Global Impression Scale (PGI) mean score. ; ; [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on self‐assessed Depression symptomotology using Montgomery‐Åsberg Depression Rating Scale Self‐report Version (MADRS‐S). ; [Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using animal naming (Fluency).[Comparison between baseline and Week 16 after starting treatment.] Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using letter‐number span (LNS).[Comparison between baseline and Week 16 after starting treatment. ] Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using pen and paper tasks (Brief Assessment of Cognition in Schizophrenia: Symbol Coding (BACS‐SC). [Comparison between baseline and Week 16 after starting treatment. ; ] Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using trail making tests (TMT A & B). [comparison between baseline and Week 16 after starting treatment.] Evaluation of degree to which adverse childhood experiences mediate the relationship between treatment and Depression symptomatology using the Behavioural Risk Factor Surveillance Survey Adverse Childhood Experience module (BRFF‐ACE) ; [Initial screening only. Used in exploratory analysis. ] Evaluation of degree to which cardiovascular risk biomarkers (hs‐CRP, HDL, LDL , HbA1C and blood glucose levels) mediate the relationship between atorvastatin or metformin and placebo plus usual care on severity of depression symptomatology. Evaluation will be based on blood test. [Comparison between baseline and Week 16 after starting treatment.] Evaluation of degree to which historical antidepressant use mediates the relationship between treatment and Depression symptomatology using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGHATRQ).[Initial screening only. Used in mediation analysis. ] Evaluation of degree to which presence and severity of personality disorder mediates the relationship between treatment and Depression symptomatology using the Personality Disorder Severity ICD‐11 Scale (PDS‐ICD‐11).[Initial screening only. Used in mediation analysis. ] To demonstrate the effects of atorvastatin or metformin compared with placebo on blood pressure (Systolic mm/Hg/Diastolic mm/Hg) as measured using a sphygmomanometer.[Comparison between baseline and Week 16 after starting treatment. ; ] To demonstrate the effects of atorvastatin or metformin compared with placebo on hip circumference (cm) using a tension‐controlled measuring tape. [Comparison between baseline and week 16 after starting treatment. ] To demonstrate the effects of atorvastatin or metformin compared with placebo on waist circumference (cm) using a tension‐controlled tape measure. [Comparison between baseline and week 16 after starting treatment. ] To demonstrate the effects of atorvastatin or metformin compared with placebo on weight (kg) using a calibrated digital scale. [Comparison between baseline and week 16 after starting treatment. ] To evaluate the degree to which attachment style mediates the relationship between treatment and Depression symptomatology using the Attachment Style Questionnaire (ASQ).[Initial screening only. Used in exploratory analysis. ] To evaluate the long term effects of atorvastatin or metformin, compared to placebo evaluated via mean differences in change from baseline to 6‐months post end of treatment using MADRS and other previously administered rating scale scores.[Comparison between baseline and 6 month post end of treatment follow up (Secondary Endpoint).] INCLUSION CRITERIA: 1. A DSM‐5 diagnosis of current major depressive disorder determined by the SCID‐5‐RV 2. Moderate to severe depression indexed by a MADRS score of = 20. the MADRS will be administered at baseline to confirm ongoing eligibility prior to dispensing of study IP/administration of medication; 3. Aged 18 years and above; 4. Have the capacity to consent to the study and to follow its instructions and procedures; 5. Participants will need to have been on stable pre‐existing pharmacological or psychotherapy regimens for two weeks prior to study entry; 6. Be using effective contraception if female, sexually active and of childbearing age; 7. Be able to speak, read, write, and understand the English language, 8. Participants will be required to nominate a current treating physician, Willing to consent to blood collection for safety monitoring.