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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

Abstract

Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E2 (PGE2), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE2 production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4–10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.

Introduction

Major depression (MD) is expected to rank as the second leading cause of disease burden worldwide in the near future and was the first leading cause of disability worldwide in 1990.1 A deficiency in the serotonergic and noradrenergic neurotransmission plays an important role in the pathology of depression, but the mechanism leading to neurotransmitter disturbance is not yet understood.

Several lines of evidence suggest that an inflammatory process is involved in the pathogenesis of at least a subgroup of patients suffering from depression. An involvement of pro-inflammatory cytokines was proposed,2 which is supported by the depressiogenic properties of therapeutic doses of IFN-α,3 IFN-β,4 or IL-25 support this view. In particular the group of Maes,6 but also other researchers described an activation of the pro-inflammatory system in depression.7, 8, 9 An important mediator of inflammation is prostaglandin E2 (PGE2). An in vitro study reports increased PGE2 secretion from lymphocytes of depressed patients compared to healthy controls.10

Increased PGE2 in the saliva, the serum and the cerebrospinal fluid of depressed patients has previously been described.11, 12, 13, 14According to the stimulating effect of PGE2 on IL-6, most of the studies dealing with IL-6 report a marked increase of IL-6 in vitro production15 or serum levels in depressed patients.16, 17 On the other hand, it was shown that tricyclic antidepressants and selective serotonin reuptake inhibitors attenuate the PGE2-synthesis, probably via inhibition of pro-inflammatory cytokines.18, 19

‘Sickness behavior’ is an animal model of depression showing symptoms such as lack of drive, lack of appetite, decrease of weight, and fatigue etc.20 ‘Sickness behavior’ is mainly induced by pro-inflammatory cytokines such as IL-1 and IL-6, but also PGE2 seems to be directly involved in sickness behavior.21 Inhibition of COX-2 could therefore be hypothesized to exert antidepressant action. In fact, a clinical antidepressant effect of the COX-2 inhibitor rofecoxib has been described. Comorbid depression in patients with osteoarthritis was evaluated in 2228 patients treated with rofecoxib. At the beginning, 15% of the patients had a comorbid depressive syndrome, which decreased significantly during therapy with 25 mg rofecoxib in 3% of the patients.22 Moreover the COX-2 inhibitor celecoxib was shown to have positive effects on cognition – a core-feature of depression.23

Based on the probable involvement of COX-2 in the pathophysiology of depression and on the positive effects of COX-2 inhibitors on depressive symptoms and cognitive functioning, we performed a clinical trial using the COX-2 inhibitor celecoxib in MD.

Materials and methods

The study was conducted as a double-blind, randomized, placebo controlled, prospective parallel group trial of celecoxib add-on to reboxetine. The treatment period lasted 42 days (6 weeks) after a wash-out period of at least 3 days in pre-medicated patients. All patients suffered from MD (DSM IV: 296.2 × single depressive episode or 296.3 × recurrent depressive episode). Forty patients (20 F, 20 M) aged between 23 and 63 years were included in the study. Thirty-seven of the patients included were in-patients. Twelve males and 8 females were included in the celecoxib-group and eight males and 12 females in the placebo-group. Thirty-four patients were included in Munich and six patients in Münster. Patients suffering from psychotic depression were excluded. Each patient was included after written informed consent. The study was examined by the ethics committee of the medical faculty of the university of Munich.

The psychopathology of the patients was assessed by raters, who had undergone a training program, using the Hamilton Depression Scale, 17-item version (HamD).24 Assessment of psychopathology and other examinations were performed at weekly intervals. At baseline, no difference could be seen between the groups regarding the severity of depression.

During the wash-out and the treatment periods the patients additionally received the benzodiazepine lorazepam for acute agitation or anxiety.

Celecoxib and placebo were administered in identical capsules produced by the pharmacy of the medical faculty Munich according to the randomization scheme. The dose of reboxetine was flexible and ranged from 4 to 10 mg/day, according to clinical needs. Celecoxib was administered at a dose of 400 mg/day. Reboxetine was started with 2 mg for 2 days before administering 4 mg, celecoxib was titrated from 200 to 400 mg/day within 3 days.

In order to exclude the chance that any differences in treatment response between the groups might be due to noncompliance during reboxetine therapy or to differences in reboxetine metabolism (e.g. through reboxetine–celecoxib interactions), reboxetine plasma levels were monitored during the study. An overview on the characteristics of the patients and doses of drugs is shown in Table 1.

Table 1 Overview on characteristics of patients receiving celecoxib or placebo (mean±s.d.)

At inclusion into the study the severity of depression ranged from 15 to 38 points on the HamD scale. The drop-out rate was relatively high in both groups. Ten patients dropped out from the celecoxib group before the trial end. Five of them were excluded or refused further treatment in the study due to a lack of therapeutic efficacy, four patients were excluded due to side-effects of the treatment (increase in blood-pressure, sleep-disturbance, difficulties in miction or erection, exanthema of the skin). Regarding the point of time for drop-out, patients from the celecoxib group dropped out later: three patients after 3 weeks, five after 4 weeks and two during the last week of the trial. Of the latter two, one patient refused the last visit because he was discharged from the hospital and felt healthy.

From the placebo group, 12 patients dropped before the end of the study. Nine of them were excluded or denied further treatment due to a lack of therapeutic efficacy, three patients were excluded due to side-effects of the treatment (nausea, agitation, sinus tachychardia). Three patients dropped-out already after only 2 weeks, four after 3 weeks and five after 4 weeks.

In the celecoxib group, no cardiovascular events or side-effects were observed, neither clinically, nor by ECG surveillance.

Treatment response was defined as at least 30% improvement during the study period in the HamD scale, remission was defined as HamD score 7 after 6 weeks in the intent to treat groups.

Statistics

For statistics, analysis of variance was used for the HamD scale. The degrees of freedom for the within-subjects comparisons were corrected for deviance from sphericity (Greenhouse–Geisser). Post-hoc t-tests were used for the weekly comparison of HamD scores. An intent to treat analysis was performed using the ‘last observation carried forward’ (LOCF) procedure. Fisher's exact test was used for the comparison of the responder/non-responder groups and of the remitted/non-remitted patients. For the comparison of reboxetine plasma levels, the pair-wise t-test was used.

Results

A statistically significant decrease of the depressive symptoms was observed in both treatment groups during the trial on the HamD scores (HamD testing over time: Greenhouse–Geisser-corrected F=36 776; df 2.452; P<0.0001). The effects of reboxetine treatment, however, were not the focus of our study. The decrease, however, was much greater in the group who received the add-on medication of celecoxib (testing time * group: Greenhouse–Geisser-corrected F=3.220; df 2.434; P=0.035).

The course of the HamD scores is shown in Figure 1 (LOCF), the weekly values of the HAMD scores and number of patients in Table 2.

Figure 1
figure1

Comparison of HamD scores during therapy with celecoxib or placebo (ANOVA, estimated marginal means; advantage of celecoxib group: Greenhouse–Geisser-corrected F=3.220; df 2.434; P=0.035) *P0.05.

Table 2 Course of the HAMD scores during therapy with reboxetine and celecoxib or placebo in mean±s.d. (number of patients)

The mean decrease of the depressive symptoms between baseline and the end of the trial was 14 HamD score points or 55% in the reboxetine and celecoxib group and 8.1 points or 33% in the reboxetine and placebo group according to the LOCF criterion. Seventy-five percent of the patients in the celecoxib group were responders compared to 45% in the placebo group (according to the criterion 30% improvement). The difference showed a trend to significance (P0.053, one-tailed). Forty-five percent of the patients in the celecoxib group and 20% in the placebo group were remitted after 6 weeks (HamD7). The difference showed a trend to significance (P0.088, one-tailed), too.

The completers only showed an improvement of 17.5 scores in the celecoxib group and of 12.4 in the placebo group, that is, 69% improvement in the celecoxib group and 49% in the placebo group.

Side effects that have been attributed to the administration of celecoxib, especially gastrointestinal problems, were not observed. One patient who was receiving reboxetine and placebo dropped out of the study because of nausea. The reasons leading to study drop-out in the celecoxib (and in the reboxetine-) group are described in medical literature as typical effects of noradrenergic drugs such as reboxetine.

No statistical significant difference could be observed between both groups regarding the plasma levels of reboxetine (see Table 3) or the use of benzodiazepines (see Table 1).

Table 3 Plasma levels of reboxetine over 6 weeks for patients with major depression treated with reboxetine plus celecoxib or reboxetine plus placebo

Discussion

Reboxetine is a well-established noradrenergic antidepressant drug. 25 As expected both groups of depressive patients showed significant improvement of the depressive syndrome during the 6-weeks treatment with reboxetine. Although the reduction of 8.1 HAMD scores in the reboxetine (and placebo-) group is relatively small regarding an active antidepressant, it is in accordance with four other clinical studies of reboxetine, which show a decrease of the HAMD scores between six and 10.9.26 The small decrease is due to the high number of dropouts in the reboxetine-alone group. Partly, the patients dropped out due to side effects. An analysis of the completers of the study alone, which showed a 49% improvement, revealed an efficacy of reboxetine, which would be expected during a clinical study using an antidepressant.26

Additionally to this therapeutic effect of reboxetine, the data clearly show an advantage of the combined therapy of reboxetine and celecoxib compared to the therapy with reboxetine alone. The trend to significance regarding the patients showing response or remission supports this view. A therapeutic trial using monotherapy with a COX-2 inhibitor alone in depressive patients would have been denied by the ethical committee of the Munich faculty of medicine, as an effective pharmacotherapy for depression is established (e.g. using reboxetine). It is improbable that the advantageous effect in the celecoxib and reboxetine group is due to interfering variables such as plasma levels of reboxetine or use of benzodiazepines, because there was no statistical difference between both groups. Numerical differences in the plasma levels of reboxetine between both groups were not systematic and probably due to the dropouts.

COX-2 inhibitors have beneficial effects in schizophrenia under certain conditions.27, 28 The effects of COX-2 inhibitors in depression raise the question whether similar pathogenetic mechanisms play a role in schizophrenia and in affective disorders.29

Being aware that signs of an inflammation can be observed in patients suffering from MD, a clinical antidepressant effect of COX-2 inhibitors can be explained by their anti-inflammatory CNS-effect. It has been observed in an animal model that the functional effects of IL-1 (e.g. sickness behavior) and other pro-inflammatory cytokines in the CNS are antagonized by treatment with a selective COX-2 inhibitor.30 Animal studies show that COX-2 inhibition can lower the increase of the pro-inflammatory cytokines IL-1β, TNF-α, and of PGE2, but it can also prevent clinical symptoms such as anxiety and cognitive decline, which are associated with this increase of pro-inflammatory cytokines.31 Moreover, treatment with the COX-2 inhibitor celecoxib – but not with a COX-1 inhibitor – prevented the dysregulation of the hypothalamus-pituitary-adrenal-axis, in particular the increase of cortisol, one of the biological key features associated with depression.31, 32 This effect can be expected because PGE2 stimulates the HPA-axis in the CNS33 and PGE2 is inhibited by COX-2 inhibition. Other effects, however, might also play a role.

Additionally, COX-2 inhibitors influence – either directly or via CNS-immune mechanisms – the CNS serotonergic system. In a rat model, treatment with rofecoxib was associated with an increase of serotonin in the frontal- and the temporo-parietal cortex.34 As the lack of serotonin is one of the core points in the pathophysiology of depression, a clinical anti-depressive effect of COX-2 inhibitors would be expected due to this effect. Another important neurotransmitter involved in the pathophysiology of depression is noradrenaline. PGE2 reduces the release of noradrenaline from central noradrenergic neurons.33 Therefore it would be expected that COX-2 inhibition is associated with an increase of noradrenalin-release. Through these mechanisms, COX-2 inhibition increases both serotonergic and noradrenergic neurotransmission. Regardless of the mechanism(s) involved, the add-on treatment with celecoxib appears to have a beneficial effect on depressive psychopathology.

Many findings point to a possible role of COX-2 inhibitors in the future therapy of depression. These include our own findings, the observed mechanisms of pro-inflammatory cytokines and PGE2 in provoking depressive symptoms, as well as the antidepressive effect described for rofecoxib.34 Our results, however, should be interpreted cautiously because the data of this small pilot study require replication in a larger sample. On the other hand, although the statistical power of the sample is small, a significant difference was observed. This points to a strong clinical effect.

The observed therapeutic effect of celecoxib in MD supports the view that an inflammatory process might be involved in the pathogenesis of depressive disorders.

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Acknowledgements

This study was in part supported by Pharmacia GmbH, Erlangen, Germany.

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Correspondence to N Müller.

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Aspects of the paper have been pre-published at the 43rd annual meeting of the ‘American College of Neuropsychopharmacology’, 12–16 December, 2004, San Juan, Puerto Rico, USA.

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Müller, N., Schwarz, M., 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 11, 680–684 (2006). https://doi.org/10.1038/sj.mp.4001805

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Keywords

  • major depression
  • immunity
  • COX-2 inhibition
  • inflammation
  • psychoneuroimmunology

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