Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial.

Randomised, double comparison 2x2 factorial trial across 27 sites in the United Kingdom. Adults with bipolar I or II disorder experiencing an acute depressive episode and requiring new pharmacological treatment were enrolled; for the folic acid component, 92 participants were randomized to folic acid and 94 to placebo, with 16 not randomized into that component.

Folic acid was given orally at 500 microg/day versus placebo within a 2x2 factorial trial in adults with bipolar depression receiving quetiapine, with separate randomization to lamotrigine or lamotrigine placebo. The folic acid comparison was assessed over 12 weeks with longer follow-up to 52 weeks.

Folic acid did not improve depressive symptoms or remission compared with placebo. For depressive symptoms, there was no consistent benefit at 12 weeks (adjusted mean difference 0.75, 95% CI -1.16 to 2.66; p=0.441), 22 weeks (0.17, -1.97 to 2.30; p=0.878), or 52 weeks (-0.92, -3.20 to 1.35; p=0.423). A treatment interaction was seen at 12 weeks, and excluding those randomized to folic acid yielded a larger lamotrigine effect, suggesting folic acid may have attenuated lamotrigine response in the factorial design. Overall, the supplement did not provide a clear antidepressant benefit in bipolar depression.

Interpretation is complicated by the factorial design and an observed interaction with lamotrigine at 12 weeks. Not all participants were randomized into the folic acid component, and the main symptom endpoint was assessed over a relatively short 12-week primary window despite longer follow-up. Safety conclusions for folic acid alone are limited by the small number of adverse events and concurrent quetiapine-based treatment.