BACKGROUND: Antidepressants are commonly prescribed. There are clear national guidelines in relation to treatment sequencing. This study examines trends and variation in antidepressant prescribing across English primary care. AIM: To examine trends and variation in antidepressant prescribing in England, with a focus on: monoamine oxidase inhibitors (MAOIs); paroxetine; and dosulepin and trimipramine. DESIGN & SETTIN: gRetrospective longitudinal study using national and practice-level data on antidepressant items prescribed per year (1998-2018) and per month (2010-2019). METHOD: Class- and drug-specific proportions were calculated at national and practice levels. Descriptive statistics were generated, percentile charts and maps were plotted, and logistic regression analysis was conducted. RESULTS: Antidepressant prescriptions more than tripled between 1998 and 2018, from 377 items per 1000 population to 1266 per 1000. MAOI prescribing fell substantially, from 0.7% of all antidepressant items in 1998 to 0.1% in 2018. There was marked variation between practices in past year prescribing of paroxetine (median practice proportion [MPP] = 1.7%, interdecile range [IDR] = 2.6%) and dosulepin (MPP = 0.7%, IDR = 1.8%), but less for trimipramine (MPP = 0%, IDR = 0.2%). CONCLUSION: Rapid growth and substantial variation in antidepressant prescribing behaviour was found between practices. The causes could be explored using mixed-methods research. Interventions to reduce prescribing of specific antidepressants, such as dosulepin, could include review prompts, alerts at the time of prescribing, and clinician feedback through tools like OpenPrescribing.net.