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Purpose: There is growing interest in the concept of 'deaths of despair' (DoD)—defined as deaths from three causes: suicide, drug poisoning, and alcohol-related conditions—as a more comprehensive indicator of the impact of psychological distress on mortality. The purpose of this study is to investigate the degree of commonality in trends and geographic patterning of deaths from these causes in England and Wales. Methods: WHO mortality data were used to calculate age-standardised, sex-specific temporal trends in DoD mortality and in mortality from suicide, drug poisonings, and alcohol-related conditions in England and Wales, 2001–2016. Three-year average crude rates were calculated for English local authorities for 2016–2018 and associations between rates were assessed using Spearman's rank correlation. Results: Between 2001 and 2016, the DoD mortality rate increased by 21·6% (males) and 16·9% (females). The increase was largely due to a rise in drug poisoning deaths, with limited tracking between trends in mortality by each cause. DoD mortality risk was highest in middle-aged people; there were rises in all age groups except 15–24 year old males and 65 + females. There were strong positive correlations (r = 0.66(males) and 0.60(females)) between local authority-area drug poisoning and alcohol-specific mortality rates in 2016–2018. Correlations of these outcomes with suicide were weaker (r = 0.29–0.54). Conclusions: DoD mortality is increasing in England and Wales but there is limited evidence of commonality in the epidemiology of cause-specific mortality from the component causes of DoD (suicide, drug poisoning and alcohol-related conditions), indicating the need for tailored prevention for each outcome. [ABSTRACT FROM AUTHOR]