Adjunctive anti-inflammatory therapy was not superior to placebo for the treatment of depression in patients with bipolar disorder, according to results from a clinical trial published in Lancet Psychiatry. When combined with treatment as usual, minocycline and celecoxib did not outperform placebo in reducing patients’ depressive symptoms.
Muhammad Ishrat Husain, MRCPsych, of the Centre for Addiction and Mental Health in Toronto, Ontario, Canada, and colleagues designed a 12-week, randomized, placebo-controlled trial to test the effect of minocycline and/or celecoxib added to usual treatment in patients with bipolar disorder. The study was performed at 4 outpatient psychiatric clinics in Pakistan. Eligible participants were adults aged 18 to 65 years with bipolar disorder type I or II. All participants were experiencing a major depressive episode at the time of enrollment.
The trial utilized a 2×2 factorial design with 4 arms; patients were randomized 1:1:1:1 to receive active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. All patients received treatment as usual throughout the trial, which consisted of psychotropic medications, psychotherapy, and/or other interventions at the discretion of patients’ clinicians. The primary outcome was mean change from baseline to week 12 in 17-item Hamilton Depression Rating Scale (HAMD-17) score, with a significance threshold set at 0.45 for between group differences in mean score. Adverse events were monitored throughout the study.
A total of 266 patients were randomized to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66) over 12 weeks. From baseline to week 12, all 4 groups experienced reductions in mean HAMD-17 score. However, score reduction was not significantly different between groups. The mean adjusted difference in HAMD-17 reduction between the active minocycline and placebo minocycline arms was 1.48 (95% CI, -0.41 to 3.36; P =.123). Similarly, the mean adjusted difference between active celecoxib and placebo celecoxib groups was -0.74 (95% CI, -2.61 to 1.14; P =.443).
Overall, 34 patients experienced a serious adverse event during the trial: 31 had a manic switch; 2 reported self-harm; and 1 died in a motor vehicle accident. The rates of serious adverse events did not differ between study groups.
Neither minocycline nor celecoxib had significant antidepressant effects compared with placebo in patients with bipolar disorder. Study limitations included the short trial duration as the effects of minocycline and celecoxib may change with longer-term use.
The researchers noted, “This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression.”
Husain MI, Chaudhry IB, Khoso AB, et al. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial. Lancet Psychiat. 2020;7(6):515-527.