Micronutrient deficiency and depression are major global health problems. Here, we first review recent empirical evidence of the association between several micronutrients—zinc, magnesium, selenium—and depression. We then present potential mechanisms of action and discuss the clinical implications for each micronutrient. Collectively, empirical evidence most strongly supports a positive association between zinc deficiency and the risk of depression and an inverse association between zinc supplementation and depressive symptoms. Less evidence is available regarding the relationship between magnesium and selenium deficiency and depression, and studies have been inconclusive. Potential mechanisms of action involve the HPA axis, glutamate homeostasis and inflammatory pathways. Findings support the importance of adequate consumption of micronutrients in the promotion of mental health, and the most common dietary sources for zinc and other micronutrients are provided. Future research is needed to prospectively investigate the association between micronutrient levels and depression as well as the safety and efficacy of micronutrient supplementation as an adjunct treatment for depression.

Importance: When randomized trials are unavailable or not feasible, observational studies can be used to answer causal questions about the comparative effects of interventions by attempting to emulate a hypothetical pragmatic randomized trial (target trial). Published guidance to aid reporting of these studies is not available.Objective: To develop consensus-based guidance for reporting observational studies performed to estimate causal effects by explicitly emulating a target trial.Design, Setting, and Participants: The Transparent Reporting of Observational Studies Emulating a Target Trial (TARGET) guideline was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework. The development included (1) a systematic review of reporting practices in published studies that had explicitly aimed to emulate a target trial; (2) a 2-round online survey (August 2023 to March 2024; 18 expert participants from 6 countries) to assess the importance of candidate items selected from previous research and to identify additional items; (3) a 3-day expert consensus meeting (June 2024; 18 panelists) to refine the scope of the guideline and draft the checklist; and (4) pilot of the draft checklist with stakeholders (n = 108; September 2024 to February 2025). The checklist was further refined based on feedback on successive drafts.Findings: The 21-item TARGET checklist is organized into 6 sections (abstract, introduction, methods, results, discussion, other information). TARGET provides guidance for reporting observational studies of interventions explicitly emulating a parallel group, individually randomized target trial, with adjustment for baseline confounders. Key recommendations are to (1) identify the study as an observational emulation of a target trial; (2) summarize the causal question and reason for emulating a target trial, (3) clearly specify the target trial protocol (ie, the causal estimand, identifying assumptions, data analysis plan) and how it was mapped to the observational data, and (4) report the estimate obtained for each causal estimand, its precision, and findings from additional analyses to assess the sensitivity of the estimates to assumptions, and design and analysis choices.Conclusions and Relevance: Application of the TARGET guideline recommendations aims to improve reporting transparency and peer review and help researchers, clinicians, and other readers interpret and apply the results.

The messenger RNA (mRNA)–based vaccines BNT162b2 and mRNA-1273 are more than 90% effective against coronavirus disease 2019 (Covid-19). However, their comparative effectiveness for a range of outcomes across diverse populations is unknown. We emulated a target trial using the electronic health records of U.S. veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and May 14, 2021, during a period marked by predominance of the SARS-CoV-2 B.1.1.7 (alpha) variant. We matched recipients of each vaccine in a 1:1 ratio according to their risk factors. Outcomes included documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic Covid-19, hospitalization for Covid-19, admission to an intensive care unit (ICU) for Covid-19, and death from Covid-19. We estimated risks using the Kaplan–Meier estimator. To assess the influence of the B.1.617.2 (delta) variant, we emulated a second target trial that involved veterans vaccinated between July 1 and September 20, 2021. Each vaccine group included 219,842 persons. Over 24 weeks of follow-up in a period marked by alpha-variant predominance, the estimated risk of documented infection was 5.75 events per 1000 persons (95% confidence interval [CI], 5.39 to 6.23) in the BNT162b2 group and 4.52 events per 1000 persons (95% CI, 4.17 to 4.84) in the mRNA-1273 group. The excess number of events per 1000 persons for BNT162b2 as compared with mRNA-1273 was 1.23 (95% CI, 0.72 to 1.81) for documented infection, 0.44 (95% CI, 0.25 to 0.70) for symptomatic Covid-19, 0.55 (95% CI, 0.36 to 0.83) for hospitalization for Covid-19, 0.10 (95% CI, 0.00 to 0.26) for ICU admission for Covid-19, and 0.02 (95% CI, −0.06 to 0.12) for death from Covid-19. The corresponding excess risk (BNT162b2 vs. mRNA-1273) of documented infection over 12 weeks of follow-up in a period marked by delta-variant predominance was 6.54 events per 1000 persons (95% CI, −2.58 to 11.82). The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance. (Funded by the Department of Veterans Affairs and others.)

Because randomized trials of sustained dietary changes are sometimes impractical for long-term outcomes, the explicit emulation of a (hypothetical) target trial using observational data may be an important tool for nutritional epidemiology. We describe a methodological approach that aims to emulate a target trial of dietary interventions sustained over many years using data from observational cohort studies. We estimated the 20-y risk of all-cause mortality under the sustained implementation of the food-based goals of the American Heart Association (AHA) 2020 using data from 3 prospective observational studies of US men [Health Professionals Follow-up Study (HPFS)] and women [Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II)]. We applied the parametric g-formula to estimate the 20-y mortality risk under a dietary intervention and under no dietary intervention. There were 165,411 participants who met the eligibility criteria. The mean age at baseline was 57.4 y (range, 43–82 y) in the HPFS, 52.4 y (range, 39–66 y) in the NHS, and 40.2 y (range, 30–50 y) in the NHS II. During 20 y of follow-up, 13,241 participants died. The estimated 20-y mortality risks under a dietary intervention versus no intervention were 21.9% compared with 25.8%, respectively, in the HPFS (risk difference, −3.9%; 95% CI: −4.9% to −3.2%); 10.0% compared with 12.6%, respectively, in the NHS (risk difference, −2.6%; 95% CI: −3.1% to −1.8%); and 2.1% compared with 2.5%, respectively, in the NHS II (risk difference, −0.35%; 95% CI: −0.56% to −0.09%). The corresponding risk ratios were 0.85 (95% CI: 0.81–0.88) in the HPFS, 0.79 (95% CI: 0.75–0.85) in the NHS, and 0.86 (95% CI: 0.78–0.96) in the NHS II. We estimated that adherence to the food-based AHA 2020 Dietary Goals starting in midlife may reduce the 20-y risk of mortality.