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Background Selective serotonin reuptake inhibitors (SSRIs) are a common treatment for depression and anxiety in adolescents but are associated with an increased incidence of bipolar disorder (BD). Whether this relationship is causal remains unclear.Objective We applied a quasi-experimental design to national registry data, using an instrumental variable (IV) approach (regional variation in prescribing practice) to investigate for a causal relationship between adolescent SSRI treatment and subsequent risk of BD.Methods We used national electronic health register data on individuals born 1991–1998 followed to maximum age 32 years, looking at individuals diagnosed with unipolar depression in adolescence. Using regional variation in prescribing practice as an IV, we compared risk of BD in adolescents prescribed vs not prescribed SSRIs (fluoxetine, sertraline or citalopram).Findings In non-IV analyses, adolescents who were prescribed SSRIs had an increased risk of BD, in keeping with previous research. Subsequent IV analyses, however, did not support a causal relationship between SSRI treatment and BD risk, either in the short or long term.Clinical implications These findings do not support a causal relationship between SSRI treatment and risk of BD. Rather, they suggest that the apparent relationship between SSRI treatment and later BD may be a result of unmeasured confounding.