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Original Investigation | Meta-analysis

Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects A Systematic Review and Meta-analysis of Randomized Clinical Trials FREE

Ole Köhler, MD1,2; Michael E. Benros, PhD3; Merete Nordentoft, PhD3; Michael E. Farkouh, MD, MSc4,5; Rupa L. Iyengar, MPH4,6; Ole Mors, PhD1,2; Jesper Krogh, MD3
[+] Author Affiliations
1Research Department P, Aarhus University Hospital, Risskov, Denmark
2Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University Hospital, Risskov, Denmark
3Mental Health Centre Copenhagen, University of Copenhagen, Copenhagen, Denmark
4Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
5Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
6School of Medicine, St George’s University, St George’s, Grenada
JAMA Psychiatry. 2014;71(12):1381-1391. doi:10.1001/jamapsychiatry.2014.1611.
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Published online

Importance  Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents.

Objective  To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions.

Data Sources  Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles.

Study Selection  Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression.

Data Extraction and Synthesis  Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.

Main Outcomes and Measures  Depression scores after treatment and adverse effects.

Results  Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 4258) and 4 investigated cytokine inhibitors (n = 2004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, −0.34; 95% CI, −0.57 to −0.11; I2 = 90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I2 = 73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.

Conclusions and Relevance  Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.

Figures in this Article

Compelling evidence suggests that subgroups of major depressive disorder may be associated with an inflammatory state.1 Findings include elevated levels of cytokines2,3 and an increased susceptibility for autoimmune diseases and infections.4 Furthermore, treatment with proinflammatory agents induces symptoms of depression.5

Thus, studies have investigated whether the use of anti-inflammatory agents could improve the antidepressant response. Nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the selective cyclooxygenase 2 (COX-2) inhibitor celecoxib,6 and cytokine inhibitors7 have shown promising results in clinical trials. Nonsteroidal anti-inflammatory drugs and cytokine inhibitors exert anti-inflammatory effects by inhibiting proinflammatory cytokines. Cytokine inhibitors act directly on these cytokines,7 whereas NSAIDs inhibit the enzyme COX-2,6 which is responsible for cytokine production. However, sample sizes in most clinical trials were small and the results were conflicting, particularly in NSAID studies; observational trials8,9 have associated NSAIDs with worse antidepressant treatment effects. Several adverse effects associated with anti-inflammatory treatment have been well described1012 and should be considered in the evaluation of benefits and risks.

Nevertheless, the observed significant effects in small study groups support the evidence of potential antidepressant effects of anti-inflammatory treatment. Two recent meta-analyses have associated celecoxib add-on treatment13 and NSAID monotherapy14 with antidepressant effects. However, these meta-analyses13,14 did not include an assessment of potential bias for the included studies, making an overall assessment based solely on pooling of effect sizes problematic. It is important to evaluate the overall effect of anti-inflammatory intervention, including a broader range of studies, and compare a potential antidepressant effect with the risk for adverse effects. Trials with unclear or inadequate methodologic quality may be associated with risk of bias (systematic error) compared with trials using adequate methods, possibly leading to overestimation of intervention benefits and underestimation of harms.15 In addition, the width of clinical findings indicates the importance of not only investigating the effect of anti-inflammatory agents on depression13 or depressive symptoms14 and one compound13,14 but also including the entire spectrum of individuals with depressive symptoms and the entire range of anti-inflammatory agents.

The objectives of this systematic review and meta-analysis were to investigate the antidepressant effect of anti-inflammatory treatment and to assess possible adverse effects of these interventions in adults with depressive symptoms or depression. Investigations of the concomitant use of antidepressants and anti-inflammatory agents are of major public concern because anti-inflammatory agents, in particular NSAIDs, are frequently used by individuals receiving antidepressants, probably owing to the bidirectional relationship between depression and pain.16

The current meta-analysis aimed to include all evidence from clinical trials that have investigated anti-inflammatory treatment in depression, regardless of whether the anti-inflammatory treatment was used alone or as add-on therapy. We were interested in both antidepressant treatment effects and adverse events among adults.

Eligibility Criteria

Only randomized clinical trials were included in the meta-analysis (ie, the allocation of participants to intervention and comparison groups was described as randomized). We assessed studies investigating patients of both sexes older than 17 years. Patients could have either a diagnosis of depression or experience depressive symptoms that did not meet the criteria for depression. Because we were interested in the effect of anti-inflammatory treatment on depressive symptoms in general, trials were included regardless of concomitant disease among the patients or whether the trials included the measurement of depressive symptoms in otherwise healthy individuals. Depression was diagnosed according to a diagnostic system (Research Diagnostic Criteria, International Classification of Diseases, or DSM-IV). Depressive symptoms were rated with clinician-rated scales or self-report questionnaires (eg, Patient Health Questionnaire–9 and Hospital Anxiety and Depression Scale–Depression). The trials had to allocate participants to (1) an anti-inflammatory drug or a control group (eg, placebo or treatment as usual) or (2) an anti-inflammatory drug as add-on treatment (eg, a selective serotonin reuptake inhibitor [SSRI] with an anti-inflammatory drug vs an SSRI with a placebo). We defined anti-inflammatory treatment as NSAIDs, COX-2 inhibitors, proinflammatory cytokine inhibitors, and minocycline hydrochloride.

Search Methods for Identification of Trials

We searched Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, and the National Institutes of Health website Clinicaltrials.gov for studies published before December 31, 2013, using the following Medical Subject Headings (or similar headings) or text word terms: major depressive disorder, depression or depressive symptoms in combination with anti-inflammatory, anti-inflammatory agent, non-steroidal anti-inflammatory, NSAID, acetylsalicylic acid, cyclooxygenase 2 inhibitor, COX-2, antibiotics, celecoxib, infliximab, etanercept, or minocycline. Reference lists of relevant reviews were searched for additional trials. One investigator (O.K.) examined titles and abstracts to remove obviously irrelevant reports. Two investigators (O.K. and J.K.) examined the remaining full-text reports to determine the study’s compliance with inclusion criteria.

Data Extraction

Data were extracted independently (O.K., with assistance from J.K.) using a pre-piloted structured form. The extractors were not blinded to the study results, authors, or institutions. In addition to bibliographic information, data extraction included quality assessment, description of the participants, description of the intervention and control groups, psychometric data, and outcomes. We contacted authors of the articles identified by e-mail to learn details missing from the Methods and Results sections of the reports and determine the authors’ knowledge of or involvement in any current work in the area.

Outcome Measures

Primary outcome measures included (1) a significant reduction in depressive symptoms measured on a continuous scale at the end of an intervention, (2) response (ie, a binary outcome of the proportion of participants in each intervention group who were defined as having responded to treatment [50% reduction in depression severity]) measured at the end of the intervention, (3) serious adverse effects including gastrointestinal and cardiovascular events for NSAIDs and infections for all other drugs, and (4) remission in patients with depression (ie, a binary outcome of the proportion of participants in each intervention group whose condition was classified, for example, as a Hamilton Scale for Depression score <7 at the end of an intervention). Some trials had several intervention groups, which we analyzed by pooling data from the experimental groups and comparing them with data from the control group. Secondary outcome measures included (1) nonserious adverse effects, (2) depressive symptoms measured on a continuous scale at maximal follow-up, and (3) remission at maximal follow-up.

Assessment of Bias

The bias risks of the randomized clinical trials included were assessed (J.K.). Based on the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions17 and methodologic studies,1821 we extracted data regarding quality for 5 domains. Sequence generation was considered adequate if the authors described a random component. Allocation concealment was adequate if it was justified that neither participants nor investigators could foresee the assignment. Blinding of outcome assessors was adequate if the trial was characterized as double-blind; however, blinding of outcome assessors was not inferred from the term double-blind, and in cases in which the outcome was self-reported, participants were considered outcome assessors. Analyses were considered intention to treat if missing data were handled by adequate methods (mixed models, multiple imputations, or similar methods) or if no missing data were observed. For-profit bias was considered low if the trial appeared to be free of industry sponsorship or any other kind of for-profit support.

Trials were assessed as having a low risk of bias if the review of all of the individual domains was considered to show a low risk of bias. Trials assessed as having uncertain risk of bias or high risk of bias in one or more of the individual domains were considered trials with a high risk of bias.

Statistical Analysis

We estimated a standardized mean difference (SMD) for each study using the Cohen d test. The SMD is the mean difference in the depression score between the intervention and control groups divided by the pooled SD of the distribution of the score used in the study. The result is a unitless effect-size measure readily comparable to other studies using similar measures of outcome. By convention, effect sizes of 0.2, 0.4, and 0.8 are considered small, medium, and large, respectively. For dichotomous variables, we calculated the relative risks with 95% CIs. We decided a priori to use a random-effects analysis because of expected heterogeneity due to different treatment regimens and patient populations. In addition, we calculated the pooled odds ratio (OR) for response and remission in the included trials.

The χ2 test for heterogeneity provided an indication of between-trial heterogeneity. In addition, the degree of heterogeneity observed in the results was quantified using the I2 statistic,22 which can be interpreted as the percentage of variation observed between the trials attributable to between-trial differences rather than sampling error (chance). We used RevMan, version 5.2, for calculations.23

Subgroup Analysis

We decided a priori to perform subanalyses of both depression and depressive symptoms and of the selective COX-2 inhibitor celecoxib. Subgroup differences were tested using RevMan, version 5.2. This method is based on fixed-effects analysis using the inverse variance method.

Discrepancies From the Protocol

We decided to include response as an outcome. We were not able to analyze the effect of baseline cytokine levels, since only 1 trial reported baseline C-reactive protein (CRP) levels24 and 1 trial reported baseline interleukin 6 (IL-6) levels.25

Search Results and Study Characteristics

Using our search criteria, 1500 records were identified, of which 53 were assessed for abstract and full-text inspection (eFigure 1 in the Supplement). We included 10 publications comprising 14 randomized clinical trials investigating the antidepressant effects of anti-inflammatory treatment in 6262 adults.

Ten trials investigated NSAIDs, 4 as add-on treatment,6,2527 and 6 as monotherapy (Table 1).14,28 Four trials studied cytokine inhibitors, all as monotherapy.7,24,29,30 Depression was investigated by 5 studies and depressive symptoms by 9 studies. Nine trials included patients with somatic comorbidity, such as active osteoarthritis or psoriasis; 1 trial28 evaluated healthy individuals with a family history of Alzheimer-like dementia (Table 1). Length of treatment ranged between 6 and 12 weeks; only 1 study28 examined NSAID monotherapy during a 12-month period.

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Identified Clinical Trials Investigating Anti-inflammatory Treatment in Depression
Treatment Effect of Anti-inflammatory Intervention: Primary Outcomes

For the study by Tyring et al,7 we had information only for performing analyses on response (50% reduction in depression severity) and adverse effects. In 11 of the 13 available trials, anti-inflammatory treatment was found to yield antidepressant effects with a pooled effect estimate of −0.34 (95% CI, −0.57 to −0.11; P = .004) (Figure 1). However, this effect estimate was associated with high heterogeneity, reflected by I2 = 90%. The overall result from fixed-effects analysis was −0.20 (95% CI, −0.26 to −0.14; P < .001).

Place holder to copy figure label and caption
Figure 1.
Overall Results of Anti-inflammatory Intervention on Antidepressant Treatment: Depression and Depressive Symptoms

SMD indicates standard mean difference.

Graphic Jump Location

Anti-inflammatory treatment revealed superiority compared with placebo with regard to depression in 5 studies including 192 patients (SMD, −0.54; 95% CI, −1.08 to −0.01; P = .05; I2 = 68%) and depressive symptoms in 8 studies including 5255 patients (SMD, −0.27; 95% CI, −0.53 to −0.01; P = .05; I2 = 68%) (Figure 1). No significant subgroup difference between depression and depressive symptoms could be detected (P = .37).

Analyses of the 2 main anti-inflammatory treatments associated NSAIDs with a pooled-effect estimate of −0.27 (95% CI, −0.45 to −0.08; P = .004; I2 = 72% [n = 4258]) and cytokine inhibitors with −0.38 (95% CI, −0.88 to 0.12; P = .14; I2 = 85% [n = 2004]) (Figure 2). No subgroup differences could be detected (P = .67). By visual inspection of the forest plot on NSAIDs in Figure 2, the effect estimate obtained in the trial by Fields et al,28 the only study on healthy individuals, was markedly different. After excluding this study, the pooled effect estimates remained similar (SMD, −0.37; 95% CI, −0.57 to −0.18; P < .001) but with a smaller heterogeneity (I2 = 76%).

Place holder to copy figure label and caption
Figure 2.
Overall Results of Anti-inflammatory Intervention on Antidepressant Treatment: Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Cytokine Inhibitors

SMD indicates standard mean difference.

Graphic Jump Location

Analyses favored anti-inflammatory treatment over placebo regarding both remission (5 trials [186 patients]; OR, 2.73; 95% CI, 1.37-5.46; P = .004; I2 = 71%) (eFigure 2 in the Supplement) and response (5 trials [743 patients]; OR, 2.41; 95% CI, 1.12-5.20; P = .02; I2 = 51%) (eFigure 3 in the Supplement).

Adverse Effects

None of the NSAIDs could be associated with an increased risk for gastrointestinal (3 trials [1770 patients]; OR, 1.04; 95% CI, 0.61-1.79) or cardiovascular (1 trial [1696 patients]; OR, 2.00; 95% CI, 0.25-16.08) adverse effects (Figure 3) after 6 weeks of treatment. Specific drugs and dosages are reported in Table 1. Cytokine inhibitors were not significantly associated with infections after 12 weeks of treatment (3 trials [753 patients]; OR, 1.27; 95% CI, 0.89-1.82).

Place holder to copy figure label and caption
Figure 3.
Results of Adverse Effects

GI indicates gastrointestinal; OR, odds ratio.

Graphic Jump Location
Bias of Included Trials

As reported in Table 2, all effects estimated from trial reports were associated with a high risk of bias. Eleven of the 14 trials did not report adequate sequence generation. In each of the categories used (allocation concealment, intention-to-treat analysis, and for-profit bias), most trials were judged to have a high risk of bias. Blinded outcome assessment was the only domain in which all studies showed a low risk of bias.

Table Graphic Jump LocationTable 2.  Quality of Reporting, Indicating High or Low Risk of Bias for the Investigated Trials in 5 Domains
Subanalyses

All studies investigating NSAIDs included celecoxib. Celecoxib treatment in general could be associated with a trend toward superiority (10 trials [2750 patients]; SMD, −0.29; 95% CI, −0.49 to −0.08; P = .006; I2 = 73%) (eFigure 4 in the Supplement). After excluding the study by Fields et al,28 the effect estimate remained similar with decreased heterogeneity: SMD, −0.31 (95% CI, −0.47 to −0.15; I2 = 32%) (eFigure 5 in the Supplement). When analyzing only the trials on celecoxib monotherapy, the results showed borderline significance (SMD, −0.13; 95% CI, −0.30 to 0.04; I2 = 66%) (eFigure 4 in the Supplement). Trials using celecoxib as an add-on to antidepressant therapy showed significant improvement compared with placebo (4 trials [132 patients]; SMD, −0.82; 95% CI, −1.17 to −0.46; P < .001), with little heterogeneity (I2 = 0%) (eFigure 4 in the Supplement). In addition, celecoxib add-on improved both remission (4 trials [132 patients]; OR, 7.89; 95% CI, 2.94 to 21.17; P < .001; I2 = 0%) (eFigure 6 in the Supplement) and response (3 trials [92 patients]; OR, 6.59; 95% CI, 2.24 to 19.42; P < .001; I2 = 0%) (eFigure 7 in the Supplement).

To our knowledge, the present meta-analysis is the largest study on anti-inflammatory treatment for depressive symptoms to date, combining data on anti-inflammatory add-on treatment and monotherapy. Fourteen randomized clinical trials with a total of 6262 patients were evaluated. Anti-inflammatory treatment showed a beneficial effect on depressive symptoms. However, this estimate was associated with a high level of heterogeneity. The type of depression, somatic comorbidity, and type of medication or treatment (ie, monotherapy or add-on therapy) did not explain the differences noted in effect estimation. Nonsteroidal anti-inflammatory drugs were associated with a better antidepressant effect in general, with 9 of 10 trials favoring NSAIDs, whereas a statistical trend was observed favoring cytokine inhibitors among 4 studies, but the results remained heterogeneous. Subanalyses of celecoxib showed improved antidepressant effects with little heterogeneity, in particular with add-on treatment.

Our analyses did not associate NSAIDs or cytokine inhibitors with an increased risk for adverse effects. However, not all included studies reported adverse effects, complicating the assessment. Furthermore, most studies were small and most of the observed effect sizes were small to medium with high heterogeneity. In addition, all included trials showed a high risk of bias owing to their potentially compromised internal validity. The bias tended to exaggerate treatment effects, and this could also be the case in the present review.15 Moreover, the present meta-analysis was restricted to studies with short-term treatment duration, since evaluation of long-term effects was not possible. In addition, the present systematic review included only 14 trials, making detection of publication bias problematic,31 and we cannot exclude the possibility of unpublished trial results. Finally, the antidepressant effect of NSAIDs may be mediated via their effects on underlying somatic diseases. However, the antidepressant effect of NSAIDs has been shown14 to be independent of their pain-relieving effect. Hence, our results should be interpreted with caution. Nonetheless, it is possible that specific subgroups would benefit more from anti-inflammatory intervention, such as patients with low-grade inflammation24 or comorbid inflammatory diseases.14

Antidepressant Effects of Anti-inflammatory Agents

Findings on the antidepressant properties of anti-inflammatory intervention have been conflicting. Most randomized studies associated NSAIDs, in particular celecoxib, with antidepressant effects.6,2527 Other studies32 suggested that NSAIDs did not influence the clinical efficacy of antidepressants. On the contrary, observational studies of frequently used NSAIDs observed worse antidepressant treatment effects in clinical,8 animal,8 and epidemiologic9 settings. Observational studies contain the potential for confounding by indication and misclassification of concomitant exposure to antidepressants and NSAIDs compared with randomized studies. Subanalyses emphasized the antidepressant effects of selective COX-2 inhibitors9; it seems important to differentiate between single NSAIDs regarding possible antidepressant effects. All randomized studies6,2527 emphasized the adjunctive antidepressant effects of celecoxib within the first 6 to 8 weeks of antidepressant treatment, which have been suggested25 to be most pronounced among patients with increased proinflammatory markers.

To our knowledge, the present study is the first to analyze the overall effect and emphasize the potential antidepressant treatment effects of celecoxib, with and without concomitant antidepressant medication. The effect is considered large and thus clinically relevant. The potential importance of an active inflammatory state on the antidepressant effects of anti-inflammatory agents is supported by studies14,33 on selective COX-2 inhibitor monotherapy among patients with osteoarthritis. In one trial,28 12 months of monotherapy with celecoxib or naproxen in healthy individuals 70 years or older did not improve depressive symptoms. These findings on the potential antidepressant effects of celecoxib are supported by animal studies34 and 2 recent meta-analyses that investigated celecoxib as add-on treatment13 and monotherapy.14

Few studies have investigated the potential antidepressant effects of cytokine inhibitors. Findings have included improvement of depression7,29,35 and specific depressive symptoms, such as anxiety30 and fatigue,7 among patients with psoriasis7,29,30 or ankylosing spondylitis,35 which is supported by animal models.36 However, the presence of depression has been found to reduce the rate of remission with infliximab treatment in patients with Crohn disease.37 Only 4 randomized placebo-controlled trials evaluating cytokine inhibitors could be included in the present meta-analysis, showing a trend toward superiority compared with placebo. The study by Raison et al24 was the only one that did not note an overall association of infliximab with antidepressant effects; however, in the subgroup with increased CRP levels, infliximab improved the antidepressant response. Thus, our results on cytokine inhibitors must be regarded as preliminary owing to the limited number of studies. However, the findings emphasize a potential effect and support the need for studies to further specify the suggested effects of cytokine inhibitors on different subgroups (eg, patients with increased proinflammatory markers).

Adverse Effects of Anti-inflammatory Agents

The potential antidepressant treatment effects of anti-inflammatory strategies should always be balanced against the risk for adverse effects. Nonsteroidal anti-inflammatory drugs increase the risk for gastrointestinal10 and cardiovascular adverse effects,11 whereas cytokine inhibitors increase the risk for infections.12 We observed no increased risks of these important adverse effects; however, not all of the studies included in the present meta-analysis reported on adverse effects and treatment lasted only 6 to 12 weeks (Table 1), which potentially is too short to detect relevant adverse effects. Evaluation is particularly important concerning selective COX-2 inhibitors, with some withdrawn from the market because of their increased risks for cardiovascular events. Other studies have suggested that celecoxib may be safer as monotherapy compared with other selective COX-2 inhibitors38 without an increased risk when used as add-on therapy in the early phase of antidepressant treatment.6 Still, our results on celecoxib should be interpreted cautiously, since not all studies reported on adverse effects.

Other Agents With Possible Anti-inflammatory Potential

Other anti-inflammatory agents may have antidepressant effects, but no studies met the inclusion criteria for the meta-analysis. Aspirin has been associated with adjunctive antidepressant treatment effects, even at low doses.39 Statins40 and the tetracycline antibiotic minocycline41 may have antidepressant treatment effects. Minocycline is also interesting, since it crosses the blood-brain barrier more easily than other antibiotics.42 However, statins have many effects other than anti-inflammatory. No randomized placebo-controlled trials have evaluated the antidepressant effects of minocycline or aspirin. Recent reviews emphasized aspirin because of a more favorable benefit to risk ratio43 and potentially better antidepressant effects compared with those of selective COX-2 inhibitors.44

Polyunsaturated fatty acids,45 the antidiabetic drug pioglitazone,46,47 the vigilance-augmenting drug modafinil,48 and modulation of the mineralocorticoid receptor49 also improved the effects of antidepressants in randomized, placebo-controlled trials. However, the anti-inflammatory effects of these agents are speculative and were therefore not included in the present meta-analysis. Synthetic cortisol compounds have shown acute antidepressant effects,50,51 but because of cortisol’s various effects, these results cannot exclusively be ascribed to an anti-inflammatory effect.

Perspectives

Compelling evidence suggests an association between depression and inflammation, but no causal link with specific inflammation markers, such as CRP, has been established.52 Research should be prioritized to identify markers and the underlying cellular mechanisms to support identification of relevant subgroups that would benefit from anti-inflammatory treatment or potentially new antidepressant drugs with a targeted effect on inflammation. Different approaches are of particular interest. First, subgroups of depressed patients with elevated inflammatory markers (CRP and IL-6) have been associated with higher rates of treatment response.24,25 Second, patients with depressive symptoms as well as comorbid pain-related14,33 or inflammatory7,29,30 disorders responded better to anti-inflammatory treatment. Third, it should be further elucidated whether anti-inflammatory treatment effects could be linked to a reduction of specific depressive symptoms.

Finally, it is interesting that NSAIDs, particularly celecoxib, have been associated with treatment effects in schizophrenia53,54 and bipolar disorder.55 This association indicates that immune-related factors might be implicated and that anti-inflammatory treatment strategies would be relevant to evaluate in a larger spectrum of psychiatric disorders.

Our results indicate a proof-of-concept concerning the use of anti-inflammatory agents in the antidepressant treatment regimen and thus provide support for the speculated link between inflammation and subgroups of patients with major depressive disorder. In this meta-analysis, the use of NSAIDs was associated with an improved antidepressant treatment response without an increased risk for well-known adverse effects. In particular, add-on treatment with celecoxib improved antidepressant effects, remission, and response. Cytokine inhibitors were studied in few trials, and no significantly better antidepressant treatment effects were found compared with placebo.

Our findings emphasize the need for identifying subgroups that may benefit more from anti-inflammatory intervention, such as patients with elevated inflammatory markers or a somatic comorbidity. Specific agents, particularly celecoxib, showed promising results and should therefore be investigated in high-quality randomized clinical trials. Such trials should carefully report on adverse effects and include long-term follow-up.

Submitted for Publication: March 17, 2014; final revision received June 14, 2014; accepted June 24, 2014.

Corresponding Author: Ole Köhler, MD, Research Department P, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark (karkoe@rm.dk).

Published Online: October 15, 2014. doi:10.1001/jamapsychiatry.2014.1611.

Author Contributions: Drs Köhler and Krogh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Köhler, Benros, Krogh.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Köhler, Benros, Farkouh, Iyengar.

Critical revision of the manuscript for important intellectual content: Köhler, Benros, Nordentoft, Mors, Krogh.

Statistical analysis: Iyengar, Krogh.

Obtained funding: Köhler, Mors.

Administrative, technical, or material support: Köhler, Farkouh, Iyengar, Krogh.

Study supervision: Benros, Nordentoft, Mors, Krogh.

Conflict of Interest Disclosures: None reported.

Funding/Support:Pfizer conducted 5 of the included studies (A3191051, A3191052, A3191053, A3191062, and A3191063, all published as a meta-analysis13).

Role of the Funder/Sponsor: Pfizer had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Toussi  SS, Pan  N, Walters  HM, Walsh  TJ.  Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-alpha inhibitors: systematic review of the literature. Clin Infect Dis. 2013;57(9):1318-1330.
PubMed   |  Link to Article
Na  KS, Lee  KJ, Lee  JS, Cho  YS, Jung  HY.  Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;48:79-85.
PubMed   |  Link to Article
Iyengar  RL, Gandhi  S, Aneja  A,  et al.  NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med. 2013;126(11):e11-e18. doi:10.1016/j.amjmed.2013.02.037.
PubMed   |  Link to Article
Gluud  LL.  Bias in clinical intervention research. Am J Epidemiol. 2006;163(6):493-501.
PubMed   |  Link to Article
Manning  JS, Jackson  WC.  Depression, pain, and comorbid medical conditions. J Clin Psychiatry. 2013;74(2):e03. doi:10.4088/JCP.12049vs3c.
Link to Article
Higgins  JPT, Altman  DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons; 2008:187-235.
Schulz  KF, Chalmers  I, Hayes  RJ, Altman  DG.  Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408-412.
PubMed   |  Link to Article
Moher  D, Pham  B, Jones  A,  et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352(9128):609-613.
PubMed   |  Link to Article
Kjaergard  LL, Villumsen  J, Gluud  C.  Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135(11):982-989.
PubMed   |  Link to Article
Egger  M, Juni  P, Bartlett  C, Holenstein  F, Sterne  J.  How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? empirical study. Health Technol Assess. 2003;7(1):1-76.
PubMed
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Nordic Cochrane Centre. RevMan, Version 5.2. Copenhagen, Denmark: Nordic Cochrane Centre, Cochrane Collaboration; 2008.
Raison  C, Rutherford  RE, Woolwine  B,  et al.  The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation. Brain Behav Immun. 2012;26(suppl 1):S49. doi:10.1016/j.bbi.2012.07.200.W.
Link to Article
Abbasi  SH, Hosseini  F, Modabbernia  A, Ashrafi  M, Akhondzadeh  S.  Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord. 2012;141(2-3):308-314.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Hashemian  F, Majd  M, Hosseini  SM, Sharifi  A, Panahi  MVS, Bigdeli  O.  A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in the treatment of a drug-naive women with major depression. Klin Psikofarmakol Bul. 2011;21:S183-S184.
Fields  C, Drye  L, Vaidya  V, Lyketsos  C; ADAPT Research Group.  Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial. Am J Geriatr Psychiatry. 2012;20(6):505-513.
PubMed   |  Link to Article
Menter  A, Augustin  M, Signorovitch  J,  et al.  The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62(5):812-818.
PubMed   |  Link to Article
Langley  RG, Feldman  SR, Han  C,  et al.  Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010;63(3):457-465.
PubMed   |  Link to Article
Lau  J, Ioannidis  JP, Terrin  N, Schmid  CH, Olkin  I.  The case of the misleading funnel plot. BMJ. 2006;333(7568):597-600.
Link to Article
Uher  R, Carver  S, Power  RA,  et al.  Non-steroidal anti-inflammatory drugs and efficacy of antidepressants in major depressive disorder. Psychol Med. 2012;42(10):2027-2035.
PubMed   |  Link to Article
Collantes-Estevez  E, Fernandez-Perez  C.  Improved control of osteoarthritis pain and self-reported health status in non-responders to celecoxib switched to rofecoxib: results of PAVIA, an open-label post-marketing survey in Spain. Curr Med Res Opin. 2003;19(5):402-410.
PubMed   |  Link to Article
Johansson  D, Falk  A, Marcus  MM, Svensson  TH.  Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(1):143-148.
PubMed   |  Link to Article
Ertenli  I, Ozer  S, Kiraz  S,  et al.  Infliximab, a TNF-α antagonist treatment in patients with ankylosing spondylitis: the impact on depression, anxiety and quality of life level. Rheumatol Int. 2012;32(2):323-330.
PubMed   |  Link to Article
Karson  A, Demirtas  T, Bayramgurler  D, Balci  F, Utkan  T.  Chronic administration of infliximab (TNF-α inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol. 2013;112(5):335-340.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Solomon  DH, Avorn  J, Stürmer  T, Glynn  RJ, Mogun  H, Schneeweiss  S.  Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum. 2006;54(5):1378-1389.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
O’Neil  A, Sanna  L, Redlich  C,  et al.  The impact of statins on psychological wellbeing: a systematic review and meta-analysis. BMC Med. 2012;10:154. doi:10.1186/1741-7015-10-154.
PubMed   |  Link to Article
Miyaoka  T, Wake  R, Furuya  M,  et al.  Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(2):222-226.
PubMed   |  Link to Article
Tomás-Camardiel  M, Rite  I, Herrera  AJ,  et al.  Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis. 2004;16(1):190-201.
PubMed   |  Link to Article
Fond  G, Hamdani  N, Kapczinski  F,  et al.  Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr Scand.2014;129(3):163-179.
PubMed   |  Link to Article
Berk  M, Dean  O, Drexhage  H,  et al.  Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013;11:74. doi:10.1186/1741-7015-11-74.
PubMed   |  Link to Article
Appleton  KM, Rogers  PJ, Ness  AR.  Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2010;91(3):757-770.
PubMed   |  Link to Article
Sepanjnia  K, Modabbernia  A, Ashrafi  M, Modabbernia  MJ, Akhondzadeh  S.  Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology. 2012;37(9):2093-2100.
PubMed   |  Link to Article
Kashani  L, Omidvar  T, Farazmand  B,  et al.  Does pioglitazone improve depression through insulin-sensitization? results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology. 2013;38(6):767-776.
PubMed   |  Link to Article
Abolfazli  R, Hosseini  M, Ghanizadeh  A,  et al.  Double-blind randomized parallel-group clinical trial of efficacy of the combination fluoxetine plus modafinil vs fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.
PubMed   |  Link to Article
Otte  C, Hinkelmann  K, Moritz  S,  et al.  Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010;44(6):339-346.
PubMed   |  Link to Article
Arana  GW, Santos  AB, Laraia  MT,  et al.  Dexamethasone for the treatment of depression: a randomized, placebo-controlled, double-blind trial. Am J Psychiatry. 1995;152(2):265-267.
PubMed   |  Link to Article
DeBattista  C, Posener  JA, Kalehzan  BM, Schatzberg  AF.  Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: a double-blind, placebo-controlled study. Am J Psychiatry. 2000;157(8):1334-1337.
PubMed   |  Link to Article
Wium-Andersen  MK, Orsted  DD, Nordestgaard  BG.  Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study. Biol Psychiatry. 2014;76(3):249-257.
PubMed   |  Link to Article
Sommer  IE, de Witte  L, Begemann  M, Kahn  RS.  Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? a meta-analysis. J Clin Psychiatry. 2012;73(4):414-419.
PubMed   |  Link to Article
Nitta  M, Kishimoto  T, Müller  N,  et al.  Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39(6):1230-1241.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Overall Results of Anti-inflammatory Intervention on Antidepressant Treatment: Depression and Depressive Symptoms

SMD indicates standard mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Overall Results of Anti-inflammatory Intervention on Antidepressant Treatment: Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Cytokine Inhibitors

SMD indicates standard mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Results of Adverse Effects

GI indicates gastrointestinal; OR, odds ratio.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Identified Clinical Trials Investigating Anti-inflammatory Treatment in Depression
Table Graphic Jump LocationTable 2.  Quality of Reporting, Indicating High or Low Risk of Bias for the Investigated Trials in 5 Domains

References

Dantzer  R, O’Connor  JC, Freund  GG, Johnson  RW, Kelley  KW.  From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
PubMed   |  Link to Article
Howren  MB, Lamkin  DM, Suls  J.  Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71(2):171-186.
PubMed   |  Link to Article
Dowlati  Y, Herrmann  N, Swardfager  W,  et al.  A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.
PubMed   |  Link to Article
Benros  ME, Waltoft  BL, Nordentoft  M,  et al.  Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70(8):812-820.
PubMed   |  Link to Article
Friebe  A, Horn  M, Schmidt  F,  et al.  Dose-dependent development of depressive symptoms during adjuvant interferon-α treatment of patients with malignant melanoma. Psychosomatics. 2010;51(6):466-473.
PubMed
Müller  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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Warner-Schmidt  JL, Vanover  KE, Chen  EY, Marshall  JJ, Greengard  P.  Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A. 2011;108(22):9262-9267.
PubMed   |  Link to Article
Gallagher  PJ, Castro  V, Fava  M,  et al.  Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study. Am J Psychiatry. 2012;169(10):1065-1072.
PubMed   |  Link to Article
de Abajo  FJ, Garcia-Rodriguez  LA.  Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008;65(7):795-803.
PubMed   |  Link to Article
Schjerning Olsen  AM, Fosbol  EL, Lindhardsen  J,  et al.  Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123(20):2226-2235.
PubMed   |  Link to Article
Toussi  SS, Pan  N, Walters  HM, Walsh  TJ.  Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-alpha inhibitors: systematic review of the literature. Clin Infect Dis. 2013;57(9):1318-1330.
PubMed   |  Link to Article
Na  KS, Lee  KJ, Lee  JS, Cho  YS, Jung  HY.  Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;48:79-85.
PubMed   |  Link to Article
Iyengar  RL, Gandhi  S, Aneja  A,  et al.  NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med. 2013;126(11):e11-e18. doi:10.1016/j.amjmed.2013.02.037.
PubMed   |  Link to Article
Gluud  LL.  Bias in clinical intervention research. Am J Epidemiol. 2006;163(6):493-501.
PubMed   |  Link to Article
Manning  JS, Jackson  WC.  Depression, pain, and comorbid medical conditions. J Clin Psychiatry. 2013;74(2):e03. doi:10.4088/JCP.12049vs3c.
Link to Article
Higgins  JPT, Altman  DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons; 2008:187-235.
Schulz  KF, Chalmers  I, Hayes  RJ, Altman  DG.  Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408-412.
PubMed   |  Link to Article
Moher  D, Pham  B, Jones  A,  et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352(9128):609-613.
PubMed   |  Link to Article
Kjaergard  LL, Villumsen  J, Gluud  C.  Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135(11):982-989.
PubMed   |  Link to Article
Egger  M, Juni  P, Bartlett  C, Holenstein  F, Sterne  J.  How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? empirical study. Health Technol Assess. 2003;7(1):1-76.
PubMed
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Nordic Cochrane Centre. RevMan, Version 5.2. Copenhagen, Denmark: Nordic Cochrane Centre, Cochrane Collaboration; 2008.
Raison  C, Rutherford  RE, Woolwine  B,  et al.  The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation. Brain Behav Immun. 2012;26(suppl 1):S49. doi:10.1016/j.bbi.2012.07.200.W.
Link to Article
Abbasi  SH, Hosseini  F, Modabbernia  A, Ashrafi  M, Akhondzadeh  S.  Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord. 2012;141(2-3):308-314.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Hashemian  F, Majd  M, Hosseini  SM, Sharifi  A, Panahi  MVS, Bigdeli  O.  A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in the treatment of a drug-naive women with major depression. Klin Psikofarmakol Bul. 2011;21:S183-S184.
Fields  C, Drye  L, Vaidya  V, Lyketsos  C; ADAPT Research Group.  Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial. Am J Geriatr Psychiatry. 2012;20(6):505-513.
PubMed   |  Link to Article
Menter  A, Augustin  M, Signorovitch  J,  et al.  The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62(5):812-818.
PubMed   |  Link to Article
Langley  RG, Feldman  SR, Han  C,  et al.  Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010;63(3):457-465.
PubMed   |  Link to Article
Lau  J, Ioannidis  JP, Terrin  N, Schmid  CH, Olkin  I.  The case of the misleading funnel plot. BMJ. 2006;333(7568):597-600.
Link to Article
Uher  R, Carver  S, Power  RA,  et al.  Non-steroidal anti-inflammatory drugs and efficacy of antidepressants in major depressive disorder. Psychol Med. 2012;42(10):2027-2035.
PubMed   |  Link to Article
Collantes-Estevez  E, Fernandez-Perez  C.  Improved control of osteoarthritis pain and self-reported health status in non-responders to celecoxib switched to rofecoxib: results of PAVIA, an open-label post-marketing survey in Spain. Curr Med Res Opin. 2003;19(5):402-410.
PubMed   |  Link to Article
Johansson  D, Falk  A, Marcus  MM, Svensson  TH.  Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(1):143-148.
PubMed   |  Link to Article
Ertenli  I, Ozer  S, Kiraz  S,  et al.  Infliximab, a TNF-α antagonist treatment in patients with ankylosing spondylitis: the impact on depression, anxiety and quality of life level. Rheumatol Int. 2012;32(2):323-330.
PubMed   |  Link to Article
Karson  A, Demirtas  T, Bayramgurler  D, Balci  F, Utkan  T.  Chronic administration of infliximab (TNF-α inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol. 2013;112(5):335-340.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Solomon  DH, Avorn  J, Stürmer  T, Glynn  RJ, Mogun  H, Schneeweiss  S.  Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum. 2006;54(5):1378-1389.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
O’Neil  A, Sanna  L, Redlich  C,  et al.  The impact of statins on psychological wellbeing: a systematic review and meta-analysis. BMC Med. 2012;10:154. doi:10.1186/1741-7015-10-154.
PubMed   |  Link to Article
Miyaoka  T, Wake  R, Furuya  M,  et al.  Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(2):222-226.
PubMed   |  Link to Article
Tomás-Camardiel  M, Rite  I, Herrera  AJ,  et al.  Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis. 2004;16(1):190-201.
PubMed   |  Link to Article
Fond  G, Hamdani  N, Kapczinski  F,  et al.  Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr Scand.2014;129(3):163-179.
PubMed   |  Link to Article
Berk  M, Dean  O, Drexhage  H,  et al.  Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013;11:74. doi:10.1186/1741-7015-11-74.
PubMed   |  Link to Article
Appleton  KM, Rogers  PJ, Ness  AR.  Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2010;91(3):757-770.
PubMed   |  Link to Article
Sepanjnia  K, Modabbernia  A, Ashrafi  M, Modabbernia  MJ, Akhondzadeh  S.  Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology. 2012;37(9):2093-2100.
PubMed   |  Link to Article
Kashani  L, Omidvar  T, Farazmand  B,  et al.  Does pioglitazone improve depression through insulin-sensitization? results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology. 2013;38(6):767-776.
PubMed   |  Link to Article
Abolfazli  R, Hosseini  M, Ghanizadeh  A,  et al.  Double-blind randomized parallel-group clinical trial of efficacy of the combination fluoxetine plus modafinil vs fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.
PubMed   |  Link to Article
Otte  C, Hinkelmann  K, Moritz  S,  et al.  Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010;44(6):339-346.
PubMed   |  Link to Article
Arana  GW, Santos  AB, Laraia  MT,  et al.  Dexamethasone for the treatment of depression: a randomized, placebo-controlled, double-blind trial. Am J Psychiatry. 1995;152(2):265-267.
PubMed   |  Link to Article
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Anti-inflammatory Intervention in Depression
Posted on May 21, 2015
Michael Berk, Robyn L Woods and John J McNeil, on behalf of the ASPREE investigators
Deakin University and Monash University
Conflict of Interest: The ASPREE clinical trial receives funding from the National Institute on Aging (1R01AG029824-01A2) and ASPREE-D from the NHMRC (1081901).

Kohler and colleagues in this Journal suggest that anti-inflammatory treatment have promise for depressive symptoms, arguing for refinement of target populations (1). One potential and novel area is prevention. There are few evidence-based prevention strategies for depression using pharmacotherapy. However, the inflammatory biomarker C-reactive protein may predict risk for de-novo illness (2). There is also epidemiological data that anti-inflammatory agents might reduce the risk of developing depression, with statins and aspirin showing the most promising signals (3). A key issue is that it is necessary to see prevention of depression, its antecedent risks, operative pathways and management in the broader context of other non-communicable diseases. There are multiple risk factors for depression, many of which appear drive systemic inflammation, and these risk factors are associated with other non-communicable disorders (NCD’s) as diverse as bowel cancer, cardiovascular disease, osteoporosis, diabetes and dementia (4). There is concordant recognition of the need to expand the NCD umbrella to include the common mental disorders, which opens the door to a shared approach to the treatment of common mental and non-communicable disorders. ASPREE (ASPirin in Reducing Events in the Elderly) is a National Institutes of Health (NIH) and Australian National Health and Medical Research Council (NHMRC) supported 5 year randomized primary prevention trial of aspirin (100mg daily) or placebo in healthy older adults. It aims to study the impact of low-dose aspirin on the composite primary endpoint of death, physical disability or dementia to determine whether aspirin extends disability-free survival. This incorporates the impact of multiple NCD’s on the primary endpoint including depression (5). A sub-study, ASPREE-D, will determine if use of low-dose aspirin reduces the risk of depression in healthy individuals over 65 years of age. ASPREE has recruited 19,114 individuals, making it one of the largest randomized trials to date examining a psychiatric endpoint. Translation of any potential intervention into practice is dependent on the risk benefit ratio. The use of aspirin in this age group as a preventative agent will be influenced by its broader efficacy and safety impact on important secondary outcomes, including cardiovascular disease, cerebrovascular disease, cognitive impairment and cancer. For many medical disorders, the risk benefit ratio for aspirin is finely balanced. The safety bar for preventive interventions needs to be higher than for therapeutic strategies, as healthy individuals are targeted. In summary, the logistical, pragmatic and resource implications need to be shared amongst multiple disorders, reinforcing the viability of a common approach to NCD’s.

References

1. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71(12):1381-1391.

2. Pasco JA, Nicholson GC, Williams LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197:372-7.

3. Pasco, J. A., Jacka, F. N., Williams, L. J. et al. (2010) Clinical implications of the cytokine hypothesis of depression: the association between use of statins and aspirin and the risk of major depression. Psychother Psychosom 79, 323-5.

4. Berk M, Williams LJ, Jacka FN, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 12;11:200.

5. ASPREE Investigator Group. (2013) Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials 36, 555-64.

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Multimedia

Supplement.

eFigure 1. Flowchart of literature search and information through every step of the study selection

eFigure 2. Results of remission rates

eFigure 3. Results of response rates

eFigure 4. Subanalyses on celecoxib in general and further subdivided into add-on treatment and monotherapy

eFigure 5. Results on intervention with nonsteroidal anti-inflammatory drugs (NSAIDs) on antidepressant treatment, excluding the study by Fields et al1

eFigure 6. Subanalyses on studies investigating remission rates when using celecoxib add-on treatment

eFigure 7. Subanalyses on studies investigating response rates when using celecoxib add-on treatment

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