Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.

Abstract

BACKGROUND:

Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting.

METHODS:

This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363.

FINDINGS:

266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident).

INTERPRETATION:

We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression.

FUNDING:

Stanley Medical Research Institute.

• Authors: Muhammad Ishrat Husain, Imran B Chaudhry, Ameer B Khoso, Muhammad Omair Husain, John Hodsoll, Moin A Ansari, Haider A Naqvi, Fareed A Minhas, Andre F Carvalho, Jeffrey H Meyer, Bill Deakin, Benoit H Mulsant, Nusrat Husain, Allan H Young
• Journal: The lancet. Psychiatry (Lancet Psychiatry) Vol. 7 Issue 6 Pg. 515-527 (06 2020) ISSN: 2215-0374 [Electronic] England
• PMID: 32445690 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Anti-Inflammatory Agents, Non-Steroidal
• Placebos
• Minocycline
• Celecoxib

Topics

• Adult
• Anti-Bacterial Agents (administration & dosage, therapeutic use)
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, therapeutic use)
• Bipolar Disorder (drug therapy, psychology)
• Case-Control Studies
• Celecoxib (administration & dosage, therapeutic use)
• Depressive Disorder, Major (drug therapy, psychology)
• Diagnostic and Statistical Manual of Mental Disorders
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Male
• Middle Aged
• Minocycline (administration & dosage, therapeutic use)
• Pakistan (epidemiology)
• Placebos (administration & dosage)
• Psychiatric Status Rating Scales
• Treatment Outcome