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Changes in crisis of meaning mediated the changes in PHQ-4. Meaningfulness appears to have a protective, and crisis of meaning an exacerbating effect on psychological distress, as shown here for the time of the first pandemic wave until three months later. Attention to existential experiences of meaningfulness and loss of meaning thus proves relevant to the clinical and public health context. Measures that support meaningfulness will help coping with crises of meaning, which in turn supports overcoming general mental distress. Meaningfuln