Adding COX-2 Inhibitor Helps Relieve Severe Depression

Daniel M. Keller, PhD

March 14, 2012

March 14, 2012 (Prague, Czech Republic) — In a pilot study of 66 patients with major depression, the cyclooxygenase-2 (COX-2) inhibitor cimicoxib, when added to standard sertraline therapy, showed beneficial effects in a subgroup of 23 patients with severe depression.

Results trended in the same direction for the group as a whole but were not statistically significant, Norbert Müller, MD, PhD, DipPsych, of the Hospital for Psychiatry and Psychotherapy of Ludwig Maximilians University in Munich, Germany, reported here at the 20th European Congress of Psychiatry.

Several lines of evidence implicate inflammatory processes at work in depression, including elevated levels of interleukin-6, prostaglandin E2 (PGE2), tumor necrosis factor-α, and COX-2. PGE2 reduces noradrenaline release and stimulates the hypothalamic-pituitary-adrenal axis. Antidepressants inhibit PGE2 synthesis.

Increased levels of C-reactive protein (CRP) have been seen in severely depressed patients, with a significant correlation of CRP levels and the severity of depression. Microglial cells appear to be the source of stress-induced sensitization of a proinflammatory cytokine response in the central nervous system (CNS).

COX-2 is expressed in the CNS, and studies with celecoxib as add-on therapy in studies of 2 different antidepressant drugs have shown significant benefit in both trials on the Hamilton Depression Scale (HAMD-17) and in terms of a higher kynurenine/tryptophan ratio in responders as compared with nonresponders in 1 of them.

Only Effective in Severe Depression

In the double-blind, placebo-controlled trial reported here, 66 patients with major depression who were receiving sertraline 100 mg or 150 mg were randomly assigned to the as-yet not approved COX-2 inhibitor cimicoxib 50 mg or to placebo.

Twenty-three of the patients had a HAMD-17 score greater than 25 at baseline, indicating severe depression. Benzodiazepines and hypnotics were allowed only in the first 2 weeks of the 6-week trial.

"There's a 2.6 [point] advantage over placebo for the Hamilton-17 at week 6 but only in the subgroup of the severely depressed patients, and very similarly, a 5.8 [point] advantage over placebo for the MADRS [Montgomery-Åsberg Depression Rating Scale]," Dr. Müller told the delegates.

"So that means in the total group, you did not find a better outcome in the cimicoxib group, but in the group of the severely depressed patients, we found a difference between the cimicoxib and the sertraline [plus placebo] group," he added.

Commensurate with these findings, the group of severely depressed patients receiving cimicoxib showed a more pronounced trend toward remission (HAMD-17 < 7; MADRS ≤ 10) at 6 weeks vs severely depressed patients on placebo.

The total group showed a less robust trend toward remission. The results for neither the total group nor the severely depressed group reached statistical significance.

However, when a mixed-model, which accounts for the differences between groups over the time course of the study and not only at 6 weeks, was used, "then we find also a significant difference between the placebo and the cimicoxib group [with] a significant superiority of the cimicoxib but only in the patients with severe depression," Dr. Müller reported (P ≤ .039).

Not Approved as Adjunctive Therapy

Dr. Müller proposed that significant beneficial effects were not seen in the group as a whole because of the limited sample size and short course of the study.

Also, severely depressed patients traditionally show a low placebo effect, so the severely depressed placebo group would be unlikely to improve on their own beyond the effect of the sertraline itself, whereas less depressed placebo patients may have improved comparatively more, bringing their results more into line with the patients receiving cimicoxib.

Although selective COX-2 inhibitors have less risk of gastric bleeding than nonselective nonsteroidal anti-inflammatory drugs, the risk with COX-2 inhibitors is not zero.

Dr. Müller said that in his 6-week study, no patients had clinically apparent gastric bleeding. He also said that he would not expect any increased cardiovascular risk with use for a period shorter than 18 months.

For the future, Dr. Müller and colleagues plan a study of celecoxib added onto sertraline in depressed patients with elevated monocyte COX-2 expression as well as other proinflammatory markers to see whether it is possible to identify a group of patients who may respond better to add-on COX-2 inhibitor therapy.

At this point, he said he cannot recommend use of COX-2 inhibitors for the treatment of depression because they are not approved for this indication. However, he said he has used them off-label for some treatment-refractory patients.

Searching for Biomarkers

Session moderator Veerle Bergink, MD, a clinical psychiatrist doing research in psychoneuroimmunology at the Erasmus Medical Center Academic University in Rotterdam, the Netherlands, commented to Medscape Medical News that she agreed with Dr. Müller's assessment that the small sample size was a factor in the results for the group as a whole not reaching statistical significance.

"And of course, phenotyping is always a great difficulty in depression research," she said, "and he also commented that it was an add-on study, which is harder to prove effect of a concept."

She said it would be a big step forward if psychiatrists could identify those depressed patients who could benefit from anti-inflammatory treatments.

However, that will take larger studies, which are hard to get funded because the anti-inflammatory drugs are relatively inexpensive, so there is not a lot of interest by the manufacturers.

"I think in the end what you want is like biomarker kits to cheaply identify those patients with more simple techniques who could benefit from these treatment options," Dr. Bergink said. "It's really at the point where we are searching for the right markers."

The study was funded by Affectis Pharmaceuticals. Dr. Müller has received research support or honoraria from Affectis, AstraZeneca, Cerbomed, Janssen, Lilly Deutschland, Lundbeck, Pfizer, and Servier. Dr. Bergink does research on the large MoodInflame project funded by the European Union, for which Dr. Müller is also an investigator.

EPA 2012: 20th European Congress of Psychiatry. Presented Monday, March 5, 2012.


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