Background Previous research has highlighted the impact of economic conditions and uncertainty on physical and mental health. The unexpected result of the Brexit referendum in 2016 triggered high levels of economic uncertainty.

Objective To examine whether prescriptions for antidepressants increased after the referendum result, benchmarking them against other drug classes.

Methods We used GP practice prescribing data to compile the number of defined daily doses per capita every month in each of the 326 voting areas in England over the period 2011–2016. We used a difference-in-differences (DID) approach to identify the effects of Brexit on antidepressant prescriptions, compared with trends in a control group (antigout and iron preparations) that were unlikely to be associated with uncertainty and depression.

Results Antidepressant prescribing continued to increase after the referendum but at a slower pace. Therapeutic classes used as controls showed a decrease. The DID approach shows that there was a relative increase of 13.4% in antidepressants compared with other therapeutic classes (DID coeff: 0.134; 95% CI 0.093 to 0.174).

Conclusion Our results are open to different interpretations and should be treated with caution. This relative increase in antidepressant prescribing after the referendum may be attributed to increased uncertainty for certain parts of the population, but does not rule out an improvement in mood for others. Alternatively, some other factor—for example, distraction, might have contributed to a decrease in the control therapeutic classes. A possible policy implication is that programmes for the promotion of mental health may need to be intensified during periods of uncertainty.