Treating Depression with Anti-Inflammatory Agents

Question:

"Would treating the actual cascade of immune response also treat depression, ie, target cytokines?"

Charles Raison, MD:
This is a great question with a simple answer, which is that we don’t know the answer, at least not yet. You’ve come to the right place because — along with Andrew H. Miller, MD — I am principal investigator for a government grant that has allowed us to examine whether a very potent anti-inflammatory agent called infliximab is an effective antidepressant in people who are medically healthy but have treatment-resistant depression. This week Dr. Miller and I opened a bottle of champagne surreptitiously in our offices to celebrate the fact that we had enrolled our 60th and final participant in the study. This participant will complete the study in three months after which we will very quickly know whether directly blocking the proinflammatory cytokine tumor necrosis factor (TNF)-alpha (which is the mechanism of action for infliximab) treats depression.

If infliximab treats depression, that will provide a simple and compelling answer to your question. If it doesn’t work that doesn’t necessarily mean that blocking cytokines is a failed strategy, however, because infliximab is too large a molecule to get into the brain, and it is possible that blockade of cytokine activity within the central nervous system is required for antidepressant efficacy. Of course, if infliximab does work for depression this makes a strong argument for the fact that bodily inflammation is important in and of itself in modulating brain states.

To our knowledge no other studies have been conducted that directly examine whether cytokine antagonists treat depression in people who are medically healthy. However, several studies suggest that these agents have antidepressant properties in people with diseases known to be associated with increased inflammation. For example, in a large study of patients with psoriasis, Tyring et al found that the TNF-alpha antagonist etanercept was more effective than placebo in lowering depression scores. ¹  Moreover, the changes in depression were not associated with improvements in the underlying medical condition, suggesting direct anti-inflammatory activity for the cytokine blocker. Similarly, antidepressant efficacy has been observed for infliximab in patients with Crohn’s disease. ²

Although not cytokine blockers per se, agents that inhibit cyclooxygenase (COX) have potent anti-inflammatory properties by reducing the production of prostaglandins that are key components of the inflammatory cascade. Two randomized, double-blind studies found that the addition of the COX-2 inhibitor celecoxib to a selective serotonin reuptake inhibitor (SSRI) led to a greater reduction in depressive symptoms than the addition of a placebo. ^3,4 Using a similar design, celecoxib was also found to be an effective augmenting strategy for reducing symptoms in bipolar patients in a depressed or mixed state. ⁵

For years, whenever I lectured about depression being associated with increased inflammation someone would raise a hand and sagely challenge me by asking, “Doesn’t this mean that aspirin should help depression?” I always had to admit yes without realizing that by 2006 an open trial had shown that the addition of aspirin to medically healthy patients with major depression who had failed four weeks of SSRI treatment led to a rapid and profound improvement in just over half the sample. ⁶

In summary, you’ve asked your very cogent question about six months to a year too soon. By that time we’ll know how promising the direct blockade of proinflammatory cytokines is for treating major depression. In addition, big studies are afoot in Europe that are examining whether COX-2 inhibitors really work to augment antidepressants and whether they might be antidepressants in and of themselves. Stay tuned.

References

1. Tyring S, Gottlieb A, Papp K, et al.  Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet.  2006;367(9504):29-35.
2. Persoons P, Vermeire S, Demyttenaere K, et al.  The impact of major depressive disorder on the short- and long-term outcome of Crohn's disease treatment with infliximab.  Aliment Pharmacol Ther.  2005;22(2):101-110.
3. Akhondzadeh S, Jafari S, Raisi F, et al.  Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial.  Depress Anxiety.  2009;26(7):607-611.
4. Muller N, Schwarz MJ, Dehning S, et al.  The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.  Mol Psychiatry.  2006;11(7):680-684.
5. Nery FG, Monkul ES, Hatch JP, et al.  Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study.  Hum Psychopharmacol.  2008;23(2):87-94.
6. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N.  Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study.  Int Clin Psychopharmacol.  2006;21(4):227-231.