Arch Gen Psychiatry. 2012 Sep 3;:1-11
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH
Abstract
CONTEXT Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants.
OBJECTIVES To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response.
DESIGN Double-blind, placebo-controlled, randomized clinical trial.
SETTING Outpatient infusion center at Emory University in Atlanta, Georgia.
PARTICIPANTS A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method.
INTERVENTIONS Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial.
MAIN OUTCOME MEASURES The 17-item Hamilton Scale for Depression (HAM-D) scores.
RESULTS No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups.
CONCLUSIONS This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00463580.
PMID: 22945416
Anti-Inflammatory May Benefit Treatment-Resistant Depression
Joan Arehart-Treichel
Psychiatric News October 19, 2012 Volume 47 Number 20 page 16-16 http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=1384231
A drug that targets inflammation may assist in the treatment of depression in individuals with high levels of inflammation.
Monoclonal antibody (biologic) medications are very expensive, costing $1,000 or even $2,000 a month, because they are not synthesized, but produced biologically—for example in mouse cells.
Nonetheless, in an interview with Psychiatric News, Andrew Miller, M.D., a professor of psychiatry at Emory University, made two predictions: “The cost will come down as the technology advances, just like the costs of computers and smartphones have, and biologics will eventually constitute new types of medications for psychiatric illnesses.”
He based the latter prediction partly on results of a proof-of-concept study by him, Charles Raison, M.D., an associate professor of psychiatry at the University of Arizona, and colleagues. Their study showed that a biologic medication was able to reduce depressive symptoms in some subjects who had suffered from major depression for an average of 15 years. The results were published online September 3 in the Archives of General Psychiatry.
Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines are known to be capable of sabotaging and circumventing the mechanisms of action of antidepressants. Thus Miller, Raison, and colleagues wanted to find out whether an inhibitor of the cytokine tumor necrosis factor called infliximab might be able to reduce depressive symptoms in individuals with treatment-resistant depression. Infliximab, a biologic, has been approved by the Food and Drug Administration for treating inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, and Crohn’s disease.
In this study, patients with hs-CRP levels > 5 mg/L (those who already have high cardiovascular risk) are the most likely to respond to treatment with Remicade for depression. hs-CRP is thus a clinically useful marker – if it is elevated. Unfortunately, in my experience, it often is not elevated to this level despite the presence of pro-inflammatory signs and symptoms in patients with depression. The key is that hs-CRP does not necessarily correlate with brain pro-inflammatory signaling. It is useful when it is high, but doesn’t tell anything if it is normal.
TNF levels are higher in treatment responders. But no clinical utility was found as with hs-CRP. TNF levels may vary significantly between individuals or the lab test doesn’t have high enough resolution to allow one to use this test clinically prior to determining treatment.
From my perspective, depression is generally a pro-inflammatory state that is the summation of several structural, signaling, and/or metabolic processes, with variations in presentation depending on variations on these factors. For example, generally pro-inflammatory signaling causes hypersomnia but excessive norepinephrine signaling may tip the balance toward insomnia. Each individual symptom and sign also are summations of underlying factors. Given multiple pathophysiologies underlying any single person’s depressive illness, each pathology needs to be identified and addressed in treatment. Addressing one pathology – such as the increase in tumor necrosis factor – is not sufficient to cause remission should the cascade of signaling and metabolic events with treatment do not significantly address the other pathophysiologies. For example, improving tumor necrosis factor signaling will not address nutritional deficiencies or other immune system problems underlying a depressive illness.