Adolescent SSRI Use Not Causally Linked to Bipolar Disorder Risk, UK Registry Study Finds
Key Clinical Summary
- A UK quasi-experimental registry analysis found no causal link between adolescent selective serotonin reuptake inhibitor (SSRI) treatment and later bipolar disorder (BD) risk.
- Traditional observational analyses showed an association between SSRI prescription and BD, but instrumental variable (IV) methods did not.
- Results suggest prior findings may reflect unmeasured confounding rather than SSRI effect.
New research published in BMJ Mental Health leveraged national United Kingdom (UK) health registry data to investigate whether selective serotonin reuptake inhibitor (SSRI) treatment in adolescents with unipolar depression influences later bipolar disorder (BD) risk. Findings showed no causal link between SSRI use and risk for immediate or later BD diagnosis.
The study applied a quasi-experimental design using regional prescribing variation as an instrumental variable (IV) to strengthen causal inference beyond traditional observational associations.
Study Findings
The analysis included individuals born between 1991–1998 with adolescent unipolar depression, followed up to age 32. SSRIs examined were fluoxetine, sertraline, or citalopram prescribed via national electronic health records. Traditional (non-IV) comparisons replicated earlier findings: adolescents prescribed SSRIs had a statistically elevated risk of subsequent BD diagnosis, consistent with prior observational literature.
However, using regional SSRI prescribing variability as the IV, which helps account for unmeasured confounding such as depression severity, the apparent association did not hold. Neither short-term nor long-term BD risk after SSRI exposure differed significantly compared with those not prescribed SSRIs in the IV analysis.
The authors interpret this as evidence that the observed link between SSRI treatment and later BD in conventional studies likely reflects confounding by indication, where more severe depressive presentations — themselves linked to BD risk — lead to higher SSRI prescribing rates.
Clinical Implications
For clinicians treating adolescent depression, this study contributes important reassurance. SSRIs are frequently used first-line for moderate to severe depressive and anxiety symptoms, yet concerns persist about precipitating mania or BD. By isolating prescribing variation unrelated to individual severity through an IV approach, this analysis suggests SSRI treatment does not causally increase BD onset risk.
These findings may influence shared decision-making with families and patients, particularly where clinicians are weighing the benefits of evidence-based pharmacotherapy against fears of triggering bipolarity. The results underscore the importance of careful diagnostic assessment for bipolar spectrum features before SSRI initiation and highlight the limitations of conventional observational studies in psychiatric pharmacoepidemiology.
This work supports the broader application of quasi-experimental methods in psychiatry to improve causal inference, especially when randomized controlled trials are infeasible due to ethical or practical constraints.
Expert Commentary
“Consistent with previous research, we observed an association between SSRI treatment and subsequent risk of mania/hypomania,” stated Animesh Talukder, PhD candidate, Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, UK, and study coauthors. “Using more rigorous causal methods, however—specifically utilizing an IV design leveraging regional variability in SSRI prescribing practices—we found no evidence to support a causal relationship between SSRI treatment in adolescence (either short- or long-term) and subsequent mania/hypomania,” they continued, commenting on the study’s design and implications. The authors emphasized that apparent SSRI–BD associations may stem from underlying clinical factors rather than medication effects.
Conclusion
This large UK registry study challenges the notion that adolescent SSRI use causally elevates bipolar disorder risk. By applying robust quasi-experimental methods, it suggests prior associations likely reflect confounding. Further research should continue refining causal inference in psychopharmacology to guide evidence-based adolescent mental health care.
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