Antidepressants are pivotal in treating major depressive disorder and other psychiatric conditions. However, despite their widespread use, evidence regarding the serious adverse effects of prolonged antidepressant use and withdrawal in complex older-adult populations remains limited.

We aimed to investigate the association between phases of antidepressant treatment with emergency hospital admission and hospital admissions related to adverse drug reactions in older adults with polypharmacy in English primary care.

We conducted a case–control study using linked primary and secondary care electronic health record data from the Clinical Practice Research Databank GOLD and Aurum. We included individuals aged 65–100 years with polypharmacy (i.e. those who were prescribed five or more medicines). We used conditional logistic regression to investigate the associations between the phases of antidepressant treatment and hospital admission risks.

We found 626 199 emergency hospital admission cases and matched with 3 639 740 controls. The initiation phase of antidepressants was associated with the greatest increase in the risk of emergency hospital admission (adjusted odds ratio 2.30, 95% CI 2.23–2.38), followed by short treatment gap or early discontinuation after short-term use (adjusted odds ratio 1.41, 95% CI 1.37–1.45). We found that patients had a higher risk of serotonin-related symptoms, falls and trauma, and cardiovascular events during antidepressant use phases, and the risks tend to decrease in past exposure phases for most conditions.

Individuals who are on the initiation and short treatment gap or early discontinuation after short-term use of antidepressant treatment are associated with a higher risk of hospital admission. This study highlights the need for vigilant monitoring of antidepressant initiation and withdrawal in older-adult polypharmacy patients.