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Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II DepressionA Randomized Clinical Trial

Educational Objective
To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.
1 Credit CME
Key Points

Question  What is the efficacy of tumor necrosis factor–antagonist infliximab in the treatment of bipolar depression?

Findings  This randomized clinical trial replicates a previous study indicating that infliximab is not significantly more efficacious compared with placebo for improving depressive symptoms in adults with a mood disorder.

Meaning  Infliximab therapy is not efficacious at improving depressive symptoms in patients with bipolar depression.

Abstract

Importance  To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms.

Objective  To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.

Design, Setting, and Participants  This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5–defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis.

Interventions  Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study.

Main Outcomes and Measures  The primary efficacy outcome was baseline-to–end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes.

Results  A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to–end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04).

Conclusions and Relevance  Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo.

Trial Registration  ClinicalTrials.gov identifier: NCT02363738

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Article Information

Accepted for Publication: January 23, 2019.

Corresponding Author: Roger S. McIntyre, MD, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst St, Toronto, ON M5T 2S8, Canada (roger.mcintyre@uhn.ca).

Published Online: May 8, 2019. doi:10.1001/jamapsychiatry.2019.0779

Author Contributions: Dr McIntyre had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McIntyre, Lee, Shekotikhina, Rosenblat, Brietzke, Soczynska, Suppes, Mansur.

Acquisition, analysis, or interpretation of data: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Cosgrove, Miller, Fischer, Kramer, Dunlap, Suppes, Mansur.

Drafting of the manuscript: McIntyre, Subramaniapillai, Lee, Pan, Shekotikhina, Soczynska, Miller, Fischer, Suppes, Mansur.

Critical revision of the manuscript for important intellectual content: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Soczynska, Cosgrove, Kramer, Dunlap, Suppes, Mansur.

Statistical analysis: McIntyre, Lee, Pan, Shekotikhina, Rosenblat, Brietzke, Mansur.

Obtained funding: McIntyre, Soczynska.

Administrative, technical, or material support: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Soczynska, Cosgrove, Miller, Fischer, Dunlap, Mansur.

Supervision: McIntyre, Subramaniapillai, Shekotikhina, Rosenblat, Cosgrove, Suppes.

Conflict of Interest Disclosures: Dr McIntyre reported receiving grants from Stanley Medical Research Institute during the conduct of the study; receiving grants from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation outside the submitted work; and receiving speaking/consultation fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva outside the submitted work. Ms Subramaniapillai reported receiving grants from Stanley Medical Research Institute during the conduct of the study. Dr Brietzke reported receiving personal fees from Daiichi Sankyo and receiving grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, Sãn Paulo Research Foundation, Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES), and L’Oreal for Women in Science Award outside the submitted work. Dr Suppes reported receiving grants from Stanley Medical Research Institute during the conduct of the study and from the National Institute on Drug Abuse, the National Institutes of Health, National Institute of Mental Health, Palo Alto Health Sciences, Pathway Genomics, and VA Cooperative Studies Program; receiving personal and nonfinancial support from CMEology, Global Medical Education, and Sunovion Pharmaceuticals Inc; and receiving personal fees from Allergan Inc, Hogrefe Publishing, Jones and Bartlett, Medscape Education, and UpToDate. Dr Miller reported receiving grants from Stanley Medical Research Institute during the conduct of the study and from Merck & Co and Sunovion outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grant 13T-012 from the Stanley Medical Research Institute.

Role of the Funder/Sponsor: The Stanley Medical Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

References
1.
Judd  LL, Akiskal  HS, Schettler  PJ,  et al.  The long-term natural history of the weekly symptomatic status of bipolar I disorder.  Arch Gen Psychiatry. 2002;59(6):530-537. doi:10.1001/archpsyc.59.6.530PubMedGoogle ScholarCrossref
2.
Insel  PA, Amara  SG, Blaschke  TF.  Introduction to the theme “precision medicine and prediction in pharmacology.”  Annu Rev Pharmacol Toxicol. 2015;55:11-14. doi:10.1146/annurev-pharmtox-101714-123102PubMedGoogle ScholarCrossref
3.
Subramaniapillai  M, Carmona  NE, Rong  C, McIntyre  RS.  Inflammation: opportunities for treatment stratification among individuals diagnosed with mood disorders.  Dialogues Clin Neurosci. 2017;19(1):27-36.PubMedGoogle Scholar
4.
Passos  IC, Vasconcelos-Moreno  MP, Costa  LG,  et al.  Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression.  Lancet Psychiatry. 2015;2(11):1002-1012. doi:10.1016/S2215-0366(15)00309-0PubMedGoogle ScholarCrossref
5.
Aas  M, Dieset  I, Hope  S,  et al.  Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses.  Brain Behav Immun. 2017;65:342-349. doi:10.1016/j.bbi.2017.06.005PubMedGoogle ScholarCrossref
6.
Rosenblat  JD, Kakar  R, Berk  M,  et al.  Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.  Bipolar Disord. 2016;18(2):89-101. doi:10.1111/bdi.12373PubMedGoogle ScholarCrossref
7.
Kappelmann  N, Lewis  G, Dantzer  R, Jones  PB, Khandaker  GM.  Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.  Mol Psychiatry. 2018;23(2):335-343. doi:10.1038/mp.2016.167PubMedGoogle ScholarCrossref
8.
Raison  CL, Rutherford  RE, Woolwine  BJ,  et al.  A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.  JAMA Psychiatry. 2013;70(1):31-41. doi:10.1001/2013.jamapsychiatry.4PubMedGoogle ScholarCrossref
9.
Felger  JC, Haroon  E, Patel  TA,  et al.  What does plasma CRP tell us about peripheral and central inflammation in depression?  [published online June 12, 2018].  Mol Psychiatry. PubMedGoogle Scholar
10.
Karabulut  KU, Egercioglu  TU, Uyar  M, Ucar  Y.  The change of neutrophils/lymphocytes ratio in migraine attacks: a case-controlled study.  Ann Med Surg (Lond). 2016;10:52-56. doi:10.1016/j.amsu.2016.07.023PubMedGoogle ScholarCrossref
11.
Sarchielli  P, Alberti  A, Baldi  A,  et al.  Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally.  Headache. 2006;46(2):200-207. doi:10.1111/j.1526-4610.2006.00337.xPubMedGoogle ScholarCrossref
12.
International Headache Society. ICHD/Guidelines. https://www.ihs-headache.org/ichd-guidelines. Accessed on April 1, 2018.
13.
Cheng  AY; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee.  Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada: introduction.  Can J Diabetes. 2013;37(suppl 1):S1-S3. doi:10.1016/j.jcjd.2013.01.009PubMedGoogle ScholarCrossref
14.
Rosenblat  JD, Gregory  JM, McIntyre  RS.  Pharmacologic implications of inflammatory comorbidity in bipolar disorder.  Curr Opin Pharmacol. 2016;29:63-69. doi:10.1016/j.coph.2016.06.007PubMedGoogle ScholarCrossref
15.
Etain  B, Lajnef  M, Brichant-Petitjean  C,  et al.  Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.  Acta Psychiatr Scand. 2017;135(4):319-327. doi:10.1111/acps.12684PubMedGoogle ScholarCrossref
16.
Walker  EA, Gelfand  A, Katon  WJ,  et al.  Adult health status of women with histories of childhood abuse and neglect.  Am J Med. 1999;107(4):332-339. doi:10.1016/S0002-9343(99)00235-1PubMedGoogle ScholarCrossref
17.
Sheehan  DV, Harnett-Sheehan  K, Raj  BA.  The measurement of disability.  Int Clin Psychopharmacol. 1996;11(suppl 3):89-95. doi:10.1097/00004850-199606003-00015PubMedGoogle ScholarCrossref
18.
Hawley  CJ, Gale  TM, Sivakumaran  T; Hertfordshire Neuroscience Research Group.  Defining remission by cut off score on the MADRS: selecting the optimal value.  J Affect Disord. 2002;72(2):177-184. doi:10.1016/S0165-0327(01)00451-7PubMedGoogle ScholarCrossref
19.
Cohen-Woods  S, Fisher  HL, Ahmetspahic  D,  et al.  Interaction between childhood maltreatment on immunogenetic risk in depression: discovery and replication in clinical case-control samples.  Brain Behav Immun. 2018;67:203-210. doi:10.1016/j.bbi.2017.08.023PubMedGoogle ScholarCrossref
20.
Baumeister  D, Akhtar  R, Ciufolini  S, Pariante  CM, Mondelli  V.  Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α.  Mol Psychiatry. 2016;21(5):642-649. doi:10.1038/mp.2015.67PubMedGoogle ScholarCrossref
21.
Coelho  R, Viola  TW, Walss-Bass  C, Brietzke  E, Grassi-Oliveira  R.  Childhood maltreatment and inflammatory markers: a systematic review.  Acta Psychiatr Scand. 2014;129(3):180-192. doi:10.1111/acps.12217PubMedGoogle ScholarCrossref
22.
Pedrotti Moreira  F, Wiener  CD, Jansen  K,  et al.  Childhood trauma and increased peripheral cytokines in young adults with major depressive: population-based study  [published online February 28, 2018].  J Neuroimmunol. 2018;319:112-116. doi:10.1016/j.jneuroim.2018.02.018PubMedGoogle ScholarCrossref
23.
Danese  A, Moffitt  TE, Harrington  H,  et al.  Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers.  Arch Pediatr Adolesc Med. 2009;163(12):1135-1143. doi:10.1001/archpediatrics.2009.214PubMedGoogle ScholarCrossref
24.
Grosse  L, Ambrée  O, Jörgens  S,  et al.  Cytokine levels in major depression are related to childhood trauma but not to recent stressors.  Psychoneuroendocrinology. 2016;73:24-31. doi:10.1016/j.psyneuen.2016.07.205PubMedGoogle ScholarCrossref
25.
Daruy-Filho  L, Brietzke  E, Lafer  B, Grassi-Oliveira  R.  Childhood maltreatment and clinical outcomes of bipolar disorder  [published online November 3, 2017].  Acta Psychiatr Scand. 2011;124(6):427-434. doi:10.1111/j.1600-0447.2011.01756.xPubMedGoogle ScholarCrossref
26.
Kane  JC, Murray  LK, Cohen  J,  et al.  Moderators of treatment response to trauma-focused cognitive behavioral therapy among youth in Zambia.  J Child Psychol Psychiatry. 2016;57(10):1194-1202. doi:10.1111/jcpp.12623PubMedGoogle ScholarCrossref
27.
Danese  A, Moffitt  TE, Pariante  CM, Ambler  A, Poulton  R, Caspi  A.  Elevated inflammation levels in depressed adults with a history of childhood maltreatment.  Arch Gen Psychiatry. 2008;65(4):409-415. doi:10.1001/archpsyc.65.4.409PubMedGoogle ScholarCrossref
28.
Goldstein  BI, Carnethon  MR, Matthews  KA,  et al; American Heart Association Atherosclerosis; Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young.  Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a scientific statement from the American Heart Association.  Circulation. 2015;132(10):965-986. doi:10.1161/CIR.0000000000000229PubMedGoogle ScholarCrossref
29.
Köhler  CA, Freitas  TH, Maes  M,  et al.  Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.  Acta Psychiatr Scand. 2017;135(5):373-387. doi:10.1111/acps.12698PubMedGoogle ScholarCrossref
30.
Köhler  CA, Freitas  TH, Stubbs  B,  et al.  Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis.  Mol Neurobiol. 2018; 55(5):4195-4206. PubMedGoogle Scholar
31.
Marrie  RA, Walld  R, Bolton  JM,  et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease.  Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.  Epidemiol Psychiatr Sci. 2017:1-10. doi:10.1017/S2045796017000579PubMedGoogle Scholar
32.
Leighton  SP, Nerurkar  L, Krishnadas  R, Johnman  C, Graham  GJ, Cavanagh  J.  Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.  Mol Psychiatry. 2018;23(1):48-58. doi:10.1038/mp.2017.205PubMedGoogle ScholarCrossref
33.
Nierenberg  AA, Østergaard  SD, Iovieno  N, Walker  RS, Fava  M, Papakostas  GI.  Predictors of placebo response in bipolar depression.  Int Clin Psychopharmacol. 2015;30(2):59-66. doi:10.1097/YIC.0000000000000058PubMedGoogle ScholarCrossref
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