A Randomized,Double-Blind Placebo-Controlled Trial on Effectiveness and Safety of Celecoxib Adjunctive Therapy in Adolescents with Acute Bipolar Mania

Abstract

Objective:

Recent studies have focused on the role of inflammatory cascades as one of the possible etiologic factors of bipolar disorder. We hypothesize that celecoxib, through its anti-inflammatory properties, may have a therapeutic role in acute bipolar mania.

Patients and Methods:

Forty-two adolescent inpatients with the diagnosis of acute bipolar mania participated in a parallel, randomized, double-blind controlled trial, and 40 patients underwent an 8-week treatment with either celecoxib (100 mg twice daily) or placebo as an adjunctive treatment to lithium and risperidone. Patients were evaluated using Young Mania Rating Scale (YMRS) at baseline and weeks 2, 4, and 8. The primary outcome measure was to assess the efficacy of celecoxib compared with placebo in improving mania symptoms.

Result:

General linear model repeated measures showed significant effect for time × treatment interaction on YMRS scores [F (2.54, 96.56) = 3.21, p = 0.03]. Significantly greater improvement was observed in YMRS scores in the celecoxib group compared with the placebo group from baseline YMRS score at week 8 (p = 0.04). Although a 35% greater response to treatment (considering a Clinical Global Impressions-Improvement score of ≤2, very much/much improved) was observed in the celecoxib group compared with the placebo group, the difference did not reach the statistical significance level (p = 0.09). No serious adverse event was reported.

Conclusions:

Celecoxib may be an effective adjuvant therapy in treatment of manic episodes (without psychotic features) of adolescents with bipolar mood disorder. The mood-stabilizing role of this drug might be mediated through its action on inflammatory cascades.

Introduction

Bipolar disorder (BD) is a chronic psychiatric illness resulting in significant function impairment and decreased quality of life. Current treatments for this disorder benefit only about half of the patients and a significant number do not respond adequately to available alternatives (Gershon and Soares 1997). In recent decades, numerous studies have provided evidence in support of the role of altered inflammatory responses in the etiopathogenesis of major mental illnesses, most notably major depressive disorder and schizophrenia (Muller and Schwarz 2008; Muller et al. 2011, 2012; Mohammadinejad et al. 2015). Some studies have shown an increase in circulating proinflammatory cytokines (e.g., IL-1, IL-6, and tumor necrosis factor [TNF-α]) in individuals with BD compared with healthy volunteers. Elevated peripheral levels of TNF-α and upregulation of its receptors (i.e., TNF-R1 and TNF-R2) are common findings during depressive and manic states and may even persist when a patient becomes euthymic (Breunis et al. 2003). In keeping with the view that a neurotoxic process occurs in mood syndromes, numerous studies have explored the potential effects of different conventional pharmacological treatments such as lithium and antipsychotics on BD in regard to production of proinflammatory cytokines as well as their gene expression.

Taken together, psychotropic medications used in the treatment of BD have the capacity to alter proinflammatory cytokines and restore inflammatory homeostasis (Soczynska et al. 2009). In addition, Brietzke et al. reported increased TNF-α and reduced IL-2 levels both in depression and mania, as well as increased IL-6 in mania and IL-4 in depression (Brietzke et al. 2009). Animal studies on rats have shown that mood stabilizers downregulate the arachidonic acid cascade, decrease phospholipase A2 (PLA2), brain cyclooxygenase-2 (COX2), and prostaglandin E2 (Rapoport and Bosetti 2002; Lee et al. 2007). Therefore, it is hypothesized that anti-inflammatory agents such as COX2 inhibitors may alleviate bipolar symptoms through their effects on COX2.

Celecoxib is a selective COX2 inhibitor that can reduce levels of proinflammatory prostaglandins and cytokines (Shi and Klotz 2008). It has also been used as an adjuvant therapy for the treatment of mood disorders (Muller et al. 2006; Nery et al. 2008; Akhondzadeh et al. 2009; Arabzadeh et al. 2015). We previously conducted several randomized clinical trials in adults, which demonstrated promising results of celecoxib adjuvant therapy in the treatment of acute bipolar mania, obsessive compulsive disorder, and depression (Akhondzadeh et al. 2009; Arabzadeh et al. 2015; Jafari et al. 2015; Mohammadinejad et al. 2015). We found that celecoxib adjunctive therapy in adults with acute bipolar mania (without psychotic features) was associated with a faster remission and higher remission rate compared with placebo. Six-week celecoxib adjunctive therapy was well tolerated and no serious adverse event was reported. The results of a double-blind, randomized placebo-controlled study suggest that adjunctive treatment with celecoxib may create a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes even though its long-term effect was not significant (Nery et al. 2008). There is preliminary evidence for elevated markers of inflammation in children and adolescents with neuropsychiatric disorders (Mitchell and Goldstein 2014). These emerging data support a role for immuno-inflammatory dysfunction in the etiopathogenesis of BD.

In the United States, celecoxib is used to relieve the pain and swelling symptoms of juvenile rheumatoid arthritis in patients ≥2 years old, and notably, there is a Food and Drug Administration (FDA) warning that nonaspirin, nonsteroidal anti-inflammatory drugs, including celecoxib, may raise the chance of heart and blood vessel side effects such as heart attack and stroke, which can be deadly (FDA drug safety communication). In this double-blind placebo-controlled trial, we aimed to assess the efficacy and safety of celecoxib adjunctive therapy on manic symptoms in acute bipolar mania in adolescents. We expected to observe a greater reduction in manic symptoms in patients who received celecoxib compared with controls.

Patients and Methods

Trial design and setting

An 8-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted in inpatients at the Roozbeh Psychiatric Hospital (Tehran University of Medical Sciences, Tehran, Iran) from May 2016 to October 2016. The study protocol was approved by the Institutional Review Board of Tehran University of Medical Sciences (IR.TUMS.REC.1394.517) and performed in accordance with the Declaration of Helsinki and its subsequent revisions. Written informed consent was obtained from all eligible patients and/or their legally authorized representatives following complete description of study details before entry into the study. Patients were informed that they were free to withdraw from the study at any time without giving a reason. The trial was registered at the Iranian registry of clinical trials (www.irct.ir; registration number: IRCT2015080423478N1).

Participants

Male and female inpatients between 12 and 18 years of age, with the diagnosis of bipolar mood disorder and a mania episode, as diagnosed by a Structured Clinical Interview for Axis I DSM-IV Disorders (SCID) and the Mini International Neuropsychiatric Interview, were eligible to participate in the trial. Diagnoses were also confirmed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (Kaufman et al. 1997). Participants also needed to have been in a moderate to severe episode of mania at the time of randomization, having a Young Mania Rating Scale (YMRS) of at least 20. YMRS is an 11-item clinical rating scale designed to assess the severity of manic symptoms and the treatment efficacy (Young et al. 1978). YMRS has been used in several clinical trials in Iran (Arabzadeh et al. 2015; Zeinoddini et al. 2015).

Patients with diagnosis of any psychotic disorder (includes mania with psychotic features) and autism spectrum disorder comorbidity were excluded. Other exclusion criteria included suicidal ideation at baseline, a history of kidney disease, cardiac disease, gastrointestinal or central nervous system bleeding, hepatitis, hepatic impairment or any other contraindication for celecoxib administration, presence of medical conditions such as hypo- or hyperthyroidism, serious threat of suicide, intellectual disability (intelligence quotient <70), alcohol or substance dependence (with the exception of nicotine or caffeine), sensitivity to any of the drugs in this study or use of medications, which could mimic manic symptoms, presence of other major psychiatric disorders, pregnancy, and lactation. Patients with unstable medical illness were also excluded. Patients were also excluded from the study if they had received antidepressants within 4 weeks of randomization. A thorough physical examination and electrocardiographic (ECG) study were performed on each patient to rule out the presence of the exclusion criteria.

Interventions

Eligible patients were randomly assigned to receive either 100 mg celecoxib (celebrex, Pfizer, Canada, 100-mg capsule) twice daily or placebo (ACER, Tehran, Iran) in the same manner for 8 weeks. All patients, regardless of their treatment group, also received lithium and risperidone (Rose Daru, Iran). Lithium was initiated at 300 mg per day and then increased to reach the therapeutic blood level of 0.8–1.1 mEq/L in 10 days. Risperidone was initiated at 1 mg per day and then increased to 3 mg per day in a week. Concomitant administration of lorazepam (0.5 mg) was permitted to manage agitation, irritability, restlessness, insomnia, or hostility. Participants were not allowed to use any psychotropic drug or undergo electroconvulsive therapy (ECT) during the trial course. Participants were discharged as soon as they were stable, and treatment continued in the outpatient setting.

Outcome

All patients were evaluated using YMRS at baseline and weeks 2, 4, and 8. Two raters with good experience in implementing the YMRS, who had good inter-rater reliability for YMRS [intraclass correlation coefficient = 0.80], were in charge of rating the patients. Furthermore, patients were assessed using the Clinical Global Impressions-Improvement (CGI-I) scale at the study end. The CGI-I is a brief, seven-point clinician-rated scale that evaluates how much the patient's current state has improved or worsened compared with patient's baseline condition and rated as follows: (1) very much improved; (2) much improved; (3) minimally improved; (4) no change; (5) minimally worsened; (6) much worsened; or (7) very much worsened. The primary outcome measure with respect to efficacy was comparing the mean decrease in YMRS scores from baseline to the study endpoint between the two treatment groups. Two groups were also compared with respect to the YMRS scores after controlling for baseline YMRS scores at the study end, remission rate (YMRS score ≤12 was defined as remission), and response to treatment. Response rate was calculated based on both YMRS scale (defined as ≥50% decrease in YMRS score from baseline) and CGI-I scale (ratings of 1 or 2, very much or much improved, respectively, defined as response). Adverse events were recorded at each visit through open-ended questioning, followed by a complete side effect checklist containing general side effects and known adverse events of lithium and celecoxib (Akhondzadeh et al. 2008). All participants were asked about any adverse event, which was not mentioned in the checklist.

Sample size

Assuming a clinically significant difference of 4 on the YMRS score between celecoxib and placebo groups with a standard deviation (SD) of 4 (based on our pilot study), a power of 85%, and a two-sided significance level of 5%, a minimal sample size of 34 was estimated. Considering an attrition rate of 10%, a total sample size of 42 (21 patients in each group) was planned.

Randomization, allocation, concealment, and blinding

A computer random number generator was used for randomizing the patients using block randomization in a 1:1 ratio and a block size of six. An independent party, who was not involved elsewhere in the trial, performed the randomization. Treatment allocation was concealed from the study participants and the physicians who rated them using sequentially numbered packages containing celecoxib or placebo capsules. The patients, research investigators, nurses, and interviewers were all blinded to the treatment allocation. Celecoxib and placebo capsules were completely identical in size, color, shape, texture, and odor.

We asked patients, raters, and nurses whether they thought the patients were on celecoxib treatment or placebo group at the study conclusion.

Statistical analyses

Analyses were conducted in accordance with the intention-to-treat principles, last observation carried forward on patients with at least one post baseline measurement. Continuous variables are expressed as mean ± SD and frequency of categorical variable is reported. Mean differences (MD) between the celecoxib and the placebo group are reported [MD, 95% confidence interval (CI)]. Independent T-test was used to compare baseline continuous variables between the two study groups. General linear model repeated measures were used to compare YMRS scores between treatment groups. If Mauchly's test of sphericity (an important assumption for repeated measure ANOVA test) was significant, Greenhouse–Geisser correction in degrees of freedom was made. Independent T-test and Cohen's d effect size were used to compare score changes from baseline to each time interval between the two groups. Analysis of covariance (ANCOVA) was used to compare YMRS scores between the two groups at each time point after adjustment for baseline YMRS scores. Categorical variables were compared using chi-square test and Fisher's exact test as appropriate. Statistical analysis was conducted using Statistical Package of Social Science Software (SPSS version 20, Chicago). Graph of the repeated measure test was drawn with a Sigma plot (version 12).

Results

Participants and baseline characteristics

A total number of 71 participants were screened for the eligibility criteria. Among them, 42 participants were included in the trial and randomized to receive either celecoxib (n = 21) or placebo (n = 21). In each group, one patient withdrew consent before week 1 and 40 inpatients completed the trial and participated in all follow-up visits and their data were analyzed (Fig. 1). Baseline characteristics of the participants were not significantly different between treatment groups (Table 1). The mean ages of the participants were 14.85 ± 1.63 years (range from 12 to 17 years) and 15.25 ± 1.71 years (range from 12 to 17 years) in the celecoxib and placebo groups, respectively. The mean dose of lithium and risperidone was not significantly different between the celecoxib and the placebo groups during the trial course (1221 ± 237 vs. 1146 ± 201 mg/day and 2.25 ± 0.78 vs. 2.30 ± 0.67 mg/day), respectively (nonsignificant). Mean serum lithium levels on weeks 2, 4, and 8 were not significantly different between the treatment groups (Table 1). Only two patients (10%) in the celecoxib group and four patients (20%) in the placebo group needed to remain hospitalized during the entire course of the study.

FIG. 1.

Flow diagram of the trial.

Table 1.

Baseline Characteristics According to the Treatment Group

Variable	Celecoxib group (n = 20)	Placebo group (n = 20)	p
Age, years, mean ± SD	14.85 ± 1.63	15.25 ± 1.71	0.45
Sex, female, n (%)	10 (50)	9 (45)	0.75
Duration of disease, years, mean ± SD	1.3 ± 0.5	1.8 ± 1.0	0.09
Age of onset, years, mean ± SD	13.5 ± 1.6	13.4 ± 1.9	0.93
History of previous hospitalization, n (%)	6 (30)	9 (45)	0.32
Presence of family history of mood disorder, n (%)	13 (65)	15 (75)	0.49
^aLithium dose, mg/day, mean ± SD	1221 ± 237	1146 ± 201	0.29
^aRisperidone dose, mg/day, mean ± SD	2.25 ± 0.78	2.30 ± 0.67	0.82
Baseline YMRS score, mean ± SD	36.75 ± 6.22	36.85 ± 6.93	0.96
Serum lithium level at week 2, mEq/L, mean ± SD	0.93 ± 0.06	0.93 ± 0.06	1
Serum lithium level at week 4, mEq/L, mean ± SD	0.93 ± 0.07	0.93 ± 0.06	1
Serum lithium level at week 8, mEq/L, mean ± SD	0.91 ± 0.05	0.92 ± 0.05	0.53
Baseline creatinine level, mean ± SD	0.79 ± 0.11	0.81 ± 0.12	0.41
Weight at baseline Kg, mean ± SD	55.60 ± 17.65	58.42 ± 18.15	0.62
Weight at week 8 Kg, mean ± SD	57.82 ± 18.35	59.19 ± 18.90	0.81

mean doses during the trial course.

SD, standard deviation; YMRS, Young Mania Rating Scale.

Outcomes

YMRS score

There was no significant difference between the celecoxib and the placebo groups regarding the baseline YMRS scores (36.75 ± 6.22 vs. 36.85 ± 6.93, respectively [MD (95% CI) = 0.10 (−4.31 to 4.11), t = 0.04, p = 0.96]). General linear model repeated measures demonstrated significant effect for time × treatment interaction on the YMRS score during the course of the trial [F (2.54, 96.56) = 3.21, p = 0.03] (Fig. 2). The Independent T-test demonstrated significantly greater reduction in YMRS scores in the celecoxib group compared with the placebo group from baseline to the study end, p = 0.04 (Table 2). ANCOVA, after controlling for the baseline YMRS score, demonstrated significantly lower YMRS in the celecoxib group compared with the placebo group at week 8 after treatment initiation, F (1, 37) = 4.65, p = 0.03. Although 25% greater remission rate was observed in the celecoxib group compared with the placebo group (17 patients [85%] vs. 12 patients [60.0%], respectively), the difference did not reach statistical significance, p = 0.07 (Table 3). Considering a CGI-I score of ≤2 (very much/much improved) to define response to treatment, 95% (19 patients) in the celecoxib group and 70% (14 patients) in the placebo group showed improvement. Although 25% greater improvement was observed in the celecoxib group compared with the placebo group, the difference did not reach statistical significance (p = 0.09). This could be due to the low power of this small study for detecting this difference (power = 0.32). Defining response to treatment as ≥50% decrease in YMRS score from baseline, 20 patients (100%) in the celecoxib group and 18 patients (90%) in the placebo group responded to treatment, p = 0.48. The mean percentage of reduction in YMRS score from baseline was 77% ± 12% and 67% ± 18% in the celecoxib and placebo groups, respectively, p = 0.06.

FIG. 2.

Repeated measure for comparison of the effects of two treatments on Young Mania Rating Scale (YMRS). Values represent mean ± standard deviation; p-values demonstrate the result of the independent t-test comparing changes in YMRS scores between the two groups at each time point. NS, nonsignificant; *p < 0.05.

Table 2.

Comparison of Score Changes from Baseline to Each Time Point Between the Two Groups Using the Independent t-Test

YMRS score	Celecoxib group (n = 20)	Placebo group (n = 20)	Mean difference celecoxib–placebo (95% CI)	Cohen's d	t (38)	p
Change from baseline to week 2, mean ± SD	7.20 ± 4.75	7.10 ± 4.32	0.1 (−2.80 to 3.01)	0.02	0.07	0.94
Change from baseline to week 4, mean ± SD	18.70 ± 6.66	14.95 ± 6.34	3.75 (−0.41 to 7.91)	0.59	1.82	0.07
Change from baseline to week 8, mean ± SD	28.20 ± 5.30	24.35 ± 6.19	3.85 (0.15 to 7.54)	0.68	2.11	0.04

SD, standard deviation; YMRS, Young Mania Rating Scale; CI, confidence interval.

p < 0.05.

Table 3.

Comparison of Outcome Indices Between the Two Groups

Outcome	Celecoxib group (n = 20)	Placebo group (n = 20)	p
Remission at week 4, n (%)	3 (15)	3 (15)	1.00
Remission at week 8, n (%)	17 (85)	12 (60)	0.07
CGI rating scale
• Very much improved (1), n (%)	11 (55)	10 (50)
• Much improved (2), n (%)	8 (40)	4 (20)
• Minimally improved (3), n (%)	1 (5)	5 (25)
• No change (4), n (%)	0 (0)	1 (5)
• Minimally worse (5), much worse (6), and very much worse (7), n (%)	0 (0)	0 (0)

CGI, Clinical Global Impressions.

Adverse events

Frequency of adverse events did not differ significantly between the two groups (Table 4). No serious adverse event and no death occurred. No one in the celecoxib group experienced cardiovascular event, which was confirmed by physical examination and normal ECG.

Table 4.

Frequency of Adverse Events Between the Study Groups

Adverse event	Celecoxib group (n = 20)	Placebo group (n = 20)	p
Constipation, n (%)	2 (10)	1 (5)	1.00
Morning drowsiness, n (%)	1 (5)	2 (10)	1.00
Daytime drowsiness, n (%)	2 (10)	0 (0)	0.48
Abdominal pain, n (%)	1 (5)	3 (15)	0.60
Diarrhea, n (%)	1 (5)	1 (5)	1.00
Tremor, n (%)	2 (10)	2 (10)	1.00
Restlessness, n (%)	2 (10)	0 (0)	0.48
Decreased appetite, n (%)	0 (0)	0 (0)	1.00
Increased appetite, n (%)	5 (25)	3 (15)	0.69
Dry mouth, n (%)	1 (5)	4 (20)	0.34

Blinding

Treatment allocation was concealed from the raters, nurses, and the participants, who were asked at the end of the trial which drug had been administered by each participant. Their guesses were not better than chance (raters: 55.0%; nurses: 50.0%; and participants: 52.5%).

Discussion

The results of the current study indicate effectiveness and safety of celecoxib as an adjuvant to lithium and risperidone in treatment of acute manic episodes in adolescents with BD. Overall, our results provide support for enhancement of the mood stabilizer effect of lithium and risperidone by concurrent treatment with celecoxib. This is consistent with the hypothesis that inhibition of the inflammatory cascades can play a potential role in treatment of mania.

Previous investigations have provided support for the assumed role of inflammatory mediators in the etiopathogenesis of mood disorders (Rosenblat et al. 2014). Mediators such as thromboxanes and prostaglandins, which are produced by PLA2 and cyclooxygenase-1 and 2 (COX1 and COX2), cause local inflammation. The inflammation in turn leads to the release of cytokines such as TNF-α, IL-1, and IL-6, which maintain the inflammatory response (Abbas et al. 2012). Several reports in the literature found an increased incidence of mood symptoms and mood episodes in relation to increased cytokine levels; specifically, prostaglandin E2 (PGE2), C-reactive protein, TNF-α, IL-1β, IL-2, and IL-6 were implicated in major depressive disorder and BD (Tsai et al. 2001, 2012; O'Brien et al. 2006; Kim et al. 2007; Ortiz-Dominguez et al. 2007; Dowlati et al. 2010). Levels of these mediators seem to increase in manic and depressive phases of this disorder reaching a plateau in the euthymic phase, although some inconsistencies exist in the current literature regarding these reported changes (Breunis et al. 2003; Boufidou et al. 2004; Cunha et al. 2008; Brietzke et al. 2009). Some medications, such as lithium and valproate, seem to exert their mood-stabilizing effect, at least in part, through their role in decreasing levels of these inflammatory mediators. Multiple investigations showed that IL-6 is suppressed in bipolar patients under treatment with lithium and valproate (Breunis et al. 2003; Kim et al. 2007; Knijff et al. 2007; Basselin et al. 2010; Chiu et al. 2013).

It was hypothesized that celecoxib might affect mood episodes by exerting its role as an anti-inflammatory drug (Nery et al. 2008; Guo et al. 2009; Stolk et al. 2010). Nery et al. administered celecoxib as an adjuvant to a mood stabilizer for patients with depressive or mixed episode of bipolar mood disorder. Celecoxib caused a rapid onset of antidepressant effect, but its effectiveness was not consistent following long-term use (Nery et al. 2008). In addition to antidepressant effects, celecoxib has been shown to have neuroprotective and antipsychotic effects (Minghetti 2004; Akhondzadeh et al. 2007; Muller et al. 2010). Muller et al. showed that celecoxib adjuvant therapy reduced the negative symptoms of schizophrenia. Interestingly, reduction in the negative score was correlated with reduction in CD19⁺ lymphocytes (Muller et al. 2004), indicating that its function could be mediated by its anti-inflammatory effect.

Our study is limited by its reliance on data from a relatively short follow-up of 8 weeks post-treatment. Future research could further investigate stability of treatment with celecoxib adjutant therapy over longer periods of time and examine whether it has any effect on incidence of future manic episodes and the latency with which they occur. Along with greater reduction in manic and depressive symptoms following celecoxib consumption, patients in the celecoxib group demonstrated faster remission compared with patients in the placebo group, which suggests a possible greater advantage for the use of celecoxib in patients suffering from acute bipolar mania.

In this study, we found no significant difference in adverse events across the two treatment protocols. Safety and tolerability of celecoxib have been demonstrated in several neuropsychiatric settings. In support of previous reports, we showed the 100–200 mg twice daily dose of celecoxib was safe for the gastrointestinal tract. Moreover, in agreement with previous reports (Muller et al. 2002, 2006; Nery et al. 2008; Chen et al. 2010; Stolk et al. 2010), no cardiac adverse event was observed in this study, which might be due to the relative small sample size, small dose, and short-term drug use. Therefore, larger well-designed studies with long-term follow-up are needed to address this issue. In addition, the results of this study cannot be generalized to mania with psychotic features or to mixed affective episodes, and the results of this study cannot be generalized to children (<12 years) with manic episodes. To the best of our knowledge, this study was the first randomized clinical trial evaluating efficacy and safety of celecoxib in adolescents with acute bipolar mania. Limitations of the present study include its relative small sample size, short-term follow-up period, and lack of inflammatory marker measurement.

Conclusions

The findings of the present study may suggest celecoxib as a safe and effective adjunctive therapy in adolescents with acute bipolar mania without psychotic features. This supports the potential role of COX2 inhibitors in the treatment of BD.

Clinical Significance

The findings of the present study may suggest celecoxib as a safe and effective adjunctive therapy in adolescents with acute bipolar mania without psychotic features. This may support the potential role of COX2 inhibitors in the treatment of BD.

Footnotes

Acknowledgment

This study was Dr. Seyed Yaser Mousavi's postgraduate thesis toward the Iranian Board of Child and Adolescent Psychiatry. The current study complies with contemporary laws and regulations in Iran.

Disclosures

No competing financial interests exist.

References

Abbas

, Lichtman

, Pillai

: Cellular and Molecular Immunology (7th ed.). San Francisco, CA: Elsevier, 2012.

Akhondzadeh

, Jafari

, Raisi

, Nasehi

, Ghoreishi

, Salehi

, Mohebbi-Rasa

, Raznahan

, Kamalipour

: Clinical trial of adjunctive celecoxib treatment in patients with major depression: A double blind and placebo controlled trial. Depress Anxiety, 26:607–611, 2009.

Akhondzadeh

, Malek-Hosseini

, Ghoreishi

, Raznahan

, Rezazadeh

: Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: A double-blind randomized placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry, 32:1879–1883, 2008.

Akhondzadeh

, Tabatabaee

, Amini

, Ahmadi Abhari

, Abbasi

, Behnam

: Celecoxib as adjunctive therapy in schizophrenia: A double-blind, randomized and placebo-controlled trial. Schizophr Res, 90:179–185, 2007.

Arabzadeh

, Ameli

, Zeinoddini

, Rezaei

, Farokhnia

, Mohammadinejad

, Ghaleiha

, Akhondzadeh

: Celecoxib adjunctive therapy for acute bipolar mania: A randomized, double-blind, placebo-controlled trial. Bipolar Disord, 17:606–614, 2015.

Basselin

, Kim

, Chen

, Ma

, Rapoport

, Murphy

, Farias

: Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. J Lipid Res, 51:1049–1056, 2010.

Boufidou

, Nikolaou

, Alevizos

, Liappas

, Christodoulou

: Cytokine production in bipolar affective disorder patients under lithium treatment. J Affect Disord, 82:309–313, 2004.

Breunis

, Kupka

, Nolen

, Suppes

, Denicoff

, Leverich

, Post

, Drexhage

: High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder. Biol Psychiatry, 53:157–165, 2003.

Brietzke

, Stertz

, Fernandes

, Kauer-Sant'anna

, Mascarenhas

, Escosteguy Vargas

, Chies

, Kapczinski

: Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord, 116:214–217, 2009.

10.

Chen

, Tzeng

, Chen

: Maintenance therapy of celecoxib for major depression with mimicking neuropsychological dysfunction. Gen Hosp Psychiatry, 32:647:e647–e649, 2010.

11.

Chiu

, Wang

, Hunsberger

, Chuang

: Therapeutic potential of mood stabilizers lithium and valproic acid: Beyond bipolar disorder. Pharmacol Rev, 65:105–142, 2013.

12.

Cunha

, Andreazza

, Gomes

, Frey

, da Silveira

, Goncalves

, Kapczinski

: Investigation of serum high-sensitive C-reactive protein levels across all mood states in bipolar disorder. Eur Arch Psychiatry Clin Neurosci, 258:300–304, 2008.

13.

Dowlati

, Herrmann

, Swardfager

, Liu

, Sham

, Reim

, Lanctot

: A meta-analysis of cytokines in major depression. Biol Psychiatry, 67:446–457, 2010.

14.

FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Available at www.fda.gov/Drugs/DrugSafety/ucm451800.htm (Accessed December 5, 2016 ).

15.

Gershon

, Soares

: Current therapeutic profile of lithium. Arch Gen Psychiatry, 54:16–20, 1997.

16.

Guo

, Li

, Ruan

, Sun

, Qi

, Zhao

, Luo

: Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain. Eur J Pharmacol, 612:54–60, 2009.

17.

Jafari

, Ashrafizadeh

, Zeinoddini

, Rasoulinejad

, Entezari

, Seddighi

, Akhondzadeh

: Celecoxib for the treatment of mild-to-moderate depression due to acute brucellosis: A double-blind, placebo-controlled, randomized trial. J Clin Pharm Ther, 40:441–446, 2015.

18.

Kaufman

, Birmaher

, Brent

, Rao

, Flynn

, Moreci

, Williamson

, Ryan

: Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry, 36:980-988, 1997.

19.

Kim

, Jung

, Myint

, Kim

, Park

: Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord, 104:91–95, 2007.

20.

Knijff

, Breunis

, Kupka

, de Wit

, Ruwhof

, Akkerhuis

, Nolen

, Drexhage

: An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: Restoration by lithium treatment. Bipolar Disord, 9:743–753, 2007.

21.

Lee

, Rao

, Rapoport

, Bazinet

: Antimanic therapies target brain arachidonic acid signaling: Lessons learned about the regulation of brain fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids, 77:239–246, 2007.

22.

Minghetti

: Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol, 63:901–910, 2004.

23.

Mitchell

, Goldstein

: Inflammation in children and adolescents with neuropsychiatric disorders: A systematic review. J Am Acad Child Adolesc Psychiatry, 53:274–296, 2014.

24.

Mohammadinejad

, Arya

, Esfandbod

, Kaviani

, Najafi

, Kashani

, Zeinoddini

, Emami

, Akhondzadeh

: Celecoxib versus diclofenac in mild to moderate depression management among breast cancer patients: A double-blind, placebo-controlled, randomized trial. Ann Pharmacother, 49:953–961, 2015.

25.

Muller

, Krause

, Dehning

, Musil

, Schennach-Wolff

, Obermeier

, Moller

, Klauss

, Schwarz

, Riedel

: Celecoxib treatment in an early stage of schizophrenia: Results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res, 121:118–124, 2010.

26.

Muller

, Myint

, Schwarz

: Inflammation in schizophrenia. Adv Protein Chem Struct Biol, 88:49–68, 2012.

27.

Muller

, Myint

, Schwarz

: Inflammatory biomarkers and depression. Neurotox Res, 19:308–318, 2011.

28.

Muller

, Riedel

, Scheppach

, Brandstatter

, Sokullu

, Krampe

, Ulmschneider

, Engel

, Moller

, Schwarz

: Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry, 159:1029–1034, 2002.

29.

Muller

, Schwarz

: COX-2 inhibition in schizophrenia and major depression. Curr Pharm Des, 14:1452–1465, 2008.

30.

Muller

, Schwarz

, Dehning

, Douhe

, Cerovecki

, Goldstein-Muller

, Spellmann

, Hetzel

, Maino

, Kleindienst

, Moller

, Arolt

, Riedel

: 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.

31.

Muller

, Ulmschneider

, Scheppach

, Schwarz

, Ackenheil

, Moller

, Gruber

, Riedel

: COX-2 inhibition as a treatment approach in schizophrenia: Immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci, 254:14–22, 2004.

32.

Nery

, Monkul

, Hatch

, Fonseca

, Zunta-Soares

, Frey

, Bowden

, Soares

: Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: A double-blind, randomized, placebo-controlled study. Hum Psychopharmacol, 23:87–94, 2008.

33.

O'Brien

, Scully

, Scott

, Dinan

: Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients. J Affect Disord, 90:263–267, 2006.

34.

Ortiz-Dominguez

, Hernandez

, Berlanga

, Gutierrez-Mora

, Moreno

, Heinze

, Pavon

: Immune variations in bipolar disorder: Phasic differences. Bipolar Disord, 9:596–602, 2007.

35.

Rapoport

, Bosetti

: Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder?. Arch Gen Psychiatry, 59:592–596, 2002.

36.

Rosenblat

, Cha

, Mansur

, McIntyre

: Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry, 53C:23–34, 2014.

37.

Shi

, Klotz

: Clinical use and pharmacological properties of selective COX-2 inhibitors. Eur J Clin Pharmacol, 64:233–252, 2008.

38.

Soczynska

, Kennedy

, Goldstein

, Lachowski

, Woldeyohannes

, McIntyre

: The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: Novel hypothesis-driven treatments for bipolar depression?. Neurotoxicology, 30:497–521, 2009.

39.

Stolk

, Souverein

, Wilting

, Leufkens

, Klein

, Rapoport

, Heerdink

: Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder. Prostaglandins Leukot Essent Fatty Acids, 82:9–14, 2010.

40.

Tsai

, Chung

, Wu

, Kuo

, Lee

, Huang

: Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord, 136:110–116, 2012.

41.

Tsai

, Yang

, Kuo

, Chen

, Leu

: Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania. J Affect Disord, 64:185–193, 2001.

42.

Young

, Biggs

, Ziegler

, Meyer

: A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry, 133:429–435, 1978.

43.

Zeinoddini

, Sorayani

, Hassanzadeh

, Arbabi

, Farokhnia

, Salimi

, Ghaleiha

, Akhondzadeh

: Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: A randomized, double-blind, placebo-controlled trial. Depress Anxiety, 32:167–173, 2015.