Inflammation Theory in Depression Still Elusive as Infliximab Trial Poses New Questions

A study designed to see if infliximab could reduce depression symptoms did not show statistically significant results, except for participants who had a history of childhood physical abuse.

The concept of using a biologic for treating depression stems from previous research that has indicated that depression, along with risk factors such as childhood trauma, poor diet, obesity, and low levels of physical activity, share the same inflammatory pathway, marked by increased levels of markers of inflammation and stress.

But these markers have poor sensitivity and specificity. In addition, not every patient with psychiatric disorders have changed biomarkers, nor is it known if inflammation markers can one day lead to precision treatment, as some have hoped.

Nevertheless, new treatment options for patients with depression as well as bipolar disorder are few. For instance, in March the FDA approved the first new type of antidepressant in 30 years, approving a nasal spray variation of ketamine called esketamine. And treatment for bipolar depression, both type 1 and type 2, is not uniform.

In the study published Wednesday in JAMA Psychiatry, the trial examined antidepressant efficacy of adjunctive infliximab in patients with bipolar type 1 and bipolar type 2 depression and inflammatory conditions. The 12-week, randomized, double-blind, placebo-controlled parallel group trial of 60 participants took place at 2 outpatient clinics, one in the United States and one in Canada. Patients received 3 intravenous infusions of infliximab or placebo at baseline and at weeks 2 and week 6.

Two tools were used: the change in the Montgomery-Asberg Depression rating scale (MADRS), as well as the Childhood Trauma Questionnaire (CTQ), which assessed a history of childhood abuse, one of several secondary outcomes. The 28-item questionnaire measures 5 subdomains of emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect.

The researchers said it was the first study evaluating an anti-inflammatory agent in adults with bipolar disorder based on biochemical or phenotypic evidence of inflammation.

The study replicates a previous study that indicated that infliximab is not an improvement at reducing depression. But the inclusion criteria for this study published Wednesday was based on the post hoc analysis of the earlier study, which showed that infliximab did show significant antidepressant activity among patients showing pretreatment peripheral C-reactive protein (CRP) levels of 5 mg/L or more.

These participants had to meet 1 of the following conditions: CRP of 5mg/L or more; obesity and at least elevated triglyceride levels, decreased high-density lipoprotein levels, or hypertension; type 1 or type 2 diabetes; ulcerative colitis or Crohn disease; a rheumatologic disorder; daily cigarette smoking of at least 1 half pack a day; or migraine headaches.

Patients were excluded from the current study if they had a concurrent psychiatric disorder, a history of schizophrenia, were actively psychotic, had a history of substance use disorder or dependence in the past 6 months, had current or previous exposure to other tumor necrosis factors like infliximab or had anaphylaxis monoclonal antibodies.

Of the 60 participants, 29 were randomized to infliximab and 31 received the placebo.

Most of the participants were treated in Canada, with 5 from the United States. The majority of both groups were female, and in their mid-40s. Between 50% to 57% of both groups had a diagnosis of bipolar type 1.

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).

The secondary analysis showed a significant treatment × time × childhood maltreatment interaction, where the infliximab group of 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).

The authors noted that the study was not an attempt to show that infliximab is a viable treatment for most people with bipolar disorder. Rather, they said the proof of concept study could be used to boost the idea of interventions that target inflammation and mood disorders. “It remains a testable hypothesis whether persons reporting childhood physical abuse are consistently more (or less) likely to respond to treatments specifically targeting the immune and inflammatory system,” they wrote.

An accompanying editorial said that the study did not lend credence to the idea that patients with depressive symptoms who had higher levels of inflammation would be more likely to respond to infliximab. The editorial said the secondary results should be interpreted with caution, due to the small sample size that could only find large to moderate effect sizes, when most therapies for depressive disorders have small effect sizes.

What this study means is unclear, it said, including whether the results are generalizable to other monoclonal antibodies.

Other than certain oncology examples, precision medicine has failed to live up to its hype, and this study is no different, the editorial said.

References

1. McIntyre RS, Subramaniapillai M, Lee Y, et al. Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. [published online May 8, 2019]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.0779.
2. Berk M, Walker AJ, Nierenberg AA. Biomarker-guided anti-inflammatory therapies: from promise to reality check [published online May 8, 2019]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.0673.