Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

doi:10.1016/j.jpsychires.2017.04.004

Journal of Psychiatric Research

Volume 92, September 2017, Pages 139-146

https://doi.org/10.1016/j.jpsychires.2017.04.004 Get rights and content

Highlights

•
Neuroinflammation has been implicated in the neurobiological pathways of schizophrenia.
•
Findings of the efficacy and tolerability of adjunctive celecoxib in treating schizophrenia have been inconsistent.
•
Adjunctive celecoxib was effective and safe in improving psychotic symptoms of first-episode schizophrenia.

Abstract

Neuroinflammation has been implicated in the neurobiological pathways of schizophrenia. This meta-analysis evaluated the efficacy and tolerability of adjunctive celecoxib as a noncompetitive anti-inflammation drug in treating schizophrenia. Data were searched, extracted, checked and entered into the RevMan (version 5.3) software by two independent investigators. Standardized/weighted mean differences (SMDs/WMDs), risk ratio (RR) and their 95% confidence intervals (CIs) were calculated, as appropriate. Included were 8 randomized controlled trials (RCTs) with a total of 626 patients with schizophrenia including 316 (50.5%) treated on celecoxib (400 mg/day) and 310 (49.5%) on placebo over 8.3 ± 2.3 weeks of treatment. Adjunctive celecoxib outperformed placebo with respect to total psychopathology [3 RCTs, n = 180; SMD: −0.47; 95%CI: −0.81, −0.14; P = 0.005; I² = 18%; 'moderate quality'], symptoms positive [3 RCTs, n = 180; SMD: −0.50; 95%CI: −0.79, −0.20; P = 0.001; I² = 0%; 'moderate quality'], negative symptoms [3 RCTs, n = 180; SMD: −0.32; 95%CI: −0.66, 0.02; P = 0.06; I² = 22%; 'moderate quality'], and general psychopathology scores [3 RCTs, n = 180; SMD: −0.35; 95%CI: −0.65, −0.06; P = 0.02; I² = 0%; 'moderate quality'] in first-episode, but not chronic patients. Additionally, superiority of celecoxib for the Positive and Negative Syndrome Scale (PANSS) total scores was moderated by higher PANSS positive scores and lower PANSS negative scores at baseline. All-cause discontinuation [RR: 1.02; (95%CI: 0.56, 1.86); P = 0.94; I² = 0%] and adverse drug reactions were similar between the two groups. Adjunctive celecoxib appears to be an efficacious and safe treatment in improving psychotic symptoms, particularly in first-episode schizophrenia.

Review registration

CRD42016054233 (http://www.crd.york.ac.uk/prospero/).

Introduction

Schizophrenia is a severe, chronic, and debilitating psychiatric disorder (Van and Kapur, 2009). Although the etiology of schizophrenia is still unclear, increasing evidence supports the hypothesis that neuroinflammation-induced glutamate deregulation and N-methyl-D-aspartate receptors (NMDARs) dysfunction (Xiang et al., 2017) can contribute to the aetiopathogenesis of schizophrenia (Akhondzadeh, 1998, Akhondzadeh, 2006, Akhondzadeh et al., 2007, Hanson and Gottesman, 2005, Müller and Ackenheil, 1998).

A systematic review found that major psychiatric disorders, such as schizophrenia, could benefit from the therapeutic effects of several anti-inflammatory drugs including cyclooxygenase (COX) inhibitors, polyunsaturated fatty acids (PUFAs), anti-TNF alpha and minocycline (Fond et al., 2014). Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) (Sommer et al., 2012) that selectively inhibits COX-2 but not COX-1 (Akhondzadeh et al., 2007). The efficacy of celecoxib has been examined in an animal schizophrenia model (Elsayed et al., 2016) and non-randomized trials (Baheti et al., 2013, Yang, 2013). However, randomized controlled trials (RCTs) (Akhondzadeh et al., 2007, Chen et al., 2008, Fu, 2016, Muller et al., 2002, Muller et al., 2004a, Muller et al., 2004b, Muller et al., 2010, Nie et al., 2008, Rapaport et al., 2005, Rappard and Muller, 2004) have yielded conflicting results.

Previous meta-analyses (Nitta et al., 2013, Sommer et al., 2012, Sommer et al., 2014) of adjunctive NSAIDs for schizophrenia were also inconclusive. Importantly, their meta-analysis included both NSAIDs, celecoxib and aspirin, which have heterogeneous effects (Nitta et al., 2013, Sommer et al., 2013). Two recent reviews on celecoxib alone for schizophrenia also lacked rigorous quantitative analyses (Andrade, 2016, Marini et al., 2016). Thus, this study examined the efficacy and tolerability of adjunctive celecoxib for schizophrenia based on RCTs with meta-analyzable data.

Section snippets

Selection criteria

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009). The inclusion criteria were identified using the PICOS acronym: Participants (P): patients with schizophrenia. Intervention (I): celecoxib plus antipsychotics (APs). Comparison (C): APs plus placebo. Outcomes (O): efficacy and safety. Study design (S): randomized, double-blind, placebo-controlled studies. Studies without meta-analyzable

Results of study search

The electronic search yielded 253 trials while 2 trials were found by hand search (Fig. 1). After excluding duplicate articles, 8 double-blinded RCTs [6 published (Akhondzadeh et al., 2007, Chen et al., 2008, Muller et al., 2002, Muller et al., 2010, Nie et al., 2008, Rapaport et al., 2005) and 2 conference papers (Muller et al., 2004a, Rappard and Muller, 2004) were eligible and included for analyses (Table 1).

RCTs, patients and treatment characteristics

Eight RCTs with a total of 626 schizophrenia patients, trial duration of 8.3 ± 2.3

Discussion

This meta-analysis found that adjunctive celecoxib (400 mg/day) did not outperform placebo in the improvement of psychotic symptoms in the overall samples. However, subgroup analyses showed that adjunctive celecoxib was superior to placebo in improving psychotic symptoms in studies with predominantly first-episode patients.

In the analyses of the three studies with predominantly first-episode patients (Chen et al., 2008, Muller et al., 2002, Muller et al., 2010), adjunctive celecoxib was

Conclusion

This meta-analysis found that adjunctive celecoxib appears to be an efficacious and safe adjunctive treatment for psychotic symptoms in first episode schizophrenia, which supports the phase-specific efficacy of celecoxib. However, high quality and large RCTs need to be conducted to confirm our findings, especially for patients with first episode schizophrenia.

Conflicts of interest

None.

Acknowledgements

The study was supported by the University of Macau (SRG 2014-00019-FHS; MYRG 2015-00230-FHS; MYRG 2016-00005-FHS) and the Affiliated Brain Hospital of Guangzhou Medical University (2016YFC0906302). The University of Macau and the Affiliated Brain Hospital of Guangzhou Medical University had no role in the study design, generating or interpreting the results and publication of the study.

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Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

Highlights

Abstract

Review registration

Introduction

Section snippets

Selection criteria

Results of study search

RCTs, patients and treatment characteristics

Discussion

Conclusion

Conflicts of interest

Acknowledgements

Schizophr. Res.

J. Psychiatr. Res.

Schizophr. Res.

J. Clin. Epidemiol.

Control. Clin. Trials

Control. Clin. Trials

Pharmacol. Biochem. Behav.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Schizophr. Res.

Biol. Psychiatry

J. Neuroimmunol.

Eur. Neuropsychopharmacol.

The glutamate hypothesis of schizophrenia

J. Clin. Pharm. Ther.

Pharmacotherapy of schizophrenia: the past, present and future

Curr. Drug Ther.

Anti-inflammatory strategies in the treatment of schizophrenia

Expert Rev. Clin. Pharmacol.

Scale for the Assessment of Negative Symptoms (SANS)

Scale for the Assessment of Positive Symptoms (SAPS)

Grading quality of evidence and strength of recommendations

BMJ

Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project)

Drug Saf.

Adjunctive celecoxib treatment with risperidone in first-episode schizophrenia: a double blind, randomized and placebo controlled trial [In Chinese]

Chin. J. Psychiatry

Cardiovascular risk associated with celecoxib or etoricoxib: a meta-analysis of randomized controlled trials which adopted comparison with placebo or naproxen

Minerva Cardioangiol.

Bias in meta-analysis detected by a simple, graphical test

BMJ

Celecoxib and omega-3 fatty acids alone and in combination with risperidone affect the behavior and brain biochemistry in amphetamine-induced model of schizophrenia

Biomed. Pharmacother.

Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review

Acta Psychiatr. Scand.

The efficacy of adjunctive celecoxib treatment with risperidone in patients with first-episode schizophrenia [In Chinese]

Contemp. Med.