Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial

TY - JOUR

T1 - Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial

AU - Gaughran, Fiona

AU - Stringer, Dominic

AU - Wojewodka, Gabriella

AU - Landau, Sabine

AU - Smith, Shubulade

AU - Gardner-Sood, Poonam

AU - Taylor, David

AU - Jordan, Harriet

AU - Whiskey, Eromona

AU - Krivoy, Amir

AU - Ciufolini, Simone

AU - Stubbs, Brendon

AU - Casetta, Cecilia

AU - Williams, Julie

AU - Moore, Susan

AU - Allen, Lauren

AU - Rathod, Shanaya

AU - Boardman, Andrew

AU - Khalifa, Rehab

AU - Firdosi, Mudasir

AU - McGuire, Philip

AU - Berk, Michael

AU - McGrath, John

N1 - Funding Information: Conflict of Interest Disclosures: Dr Gaughran reported receiving speaking honoraria from Otsuka Lundbeck outside the submitted work. Dr Landau reported receiving grants from National Institute for Health Research (NIHR) Mausley Biomedical Research Centre (BRC) and Stanley Foundation during the conduct of the study. Dr Taylor reported receiving grants from Janssen and Recordati and personal fees from Janssen, Recordati, HLS, and Sunovion outside the submitted work. Dr Rathod reported receiving grants from Janssen Education and support to attend educational meetings from Boehringer Education and Otsuka Education outside the submitted work. Dr Berk reported receiving personal fees from Janssen, Medplan Communications Canada, RANZCP Hobart, Abbott India, American Society of Clinical Psychology, Headspace GP, Servier, Lundbeck, a National Health and Medical Research Council (NHMRC) Senior Research Fellowship, Sandoz, and Milken Institute outside the submitted work. No other disclosures were reported. Funding Information: Funding/Support: The study was funded by grant 13T-006 from the Stanley Medical Research Institute and received support from the NIHR Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London and the NIHR Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust. Dr McGrath is supported by the Danish National Research Foundation (Niels Bohr Professorship). Dr McGrath is employed by The Queensland Centre for Mental Health Research, which receives core funding from Queensland Health. Dr Berk is supported by an NHMRC Senior Principal Research Fellowship. Drs Gaughran and Landau are in part supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Maudsley Charity, and, along with Dr Williams, by the NIHR ARC South London at King’s College Hospital NHS Foundation Trust. Publisher Copyright: © 2021 American Medical Association. All rights reserved.

PY - 2021/12/28

Y1 - 2021/12/28

N2 - Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions: Monthly augmentation with 120000 IU of cholecalciferol or placebo. Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P =.13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration: isrctn.org Identifier: ISRCTN12424842.

AB - Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions: Monthly augmentation with 120000 IU of cholecalciferol or placebo. Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P =.13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration: isrctn.org Identifier: ISRCTN12424842.

UR - http://www.scopus.com/inward/record.url?scp=85122376614&partnerID=8YFLogxK

U2 - 10.1001/jamanetworkopen.2021.40858

DO - 10.1001/jamanetworkopen.2021.40858

M3 - Article

C2 - 34962559

SN - 2574-3805

VL - 4

SP - e2140858

JO - JAMA Network open

JF - JAMA Network open

IS - 12

ER -