Celecoxib added to mood stabilizer for treating acute mania: A randomized, double -blind, placebo- controlled trial

Farhad Faridhosseini Mashhad University of Medical Sciences Ali talaei Mashhad University of Medical Sciences najmeh shahini (  najmeh.shahini@gmail.com ) golestan research cener of psychiatry , golestan university of medical sciences,gorgan ,iran https://orcid.org/0000-0001-7781-6014 meysam poorgholami Shahid Beheshti University of Medical Sciences School of Medicine mahbobeh eslamzadeh Mashhad University of Medical Sciences Samira ahrari Mashhad University of Medical Sciences majid khadem rezaeian Mashhad University of Medical Sciences


Background
In recent years, an increasing volume of evidence has shown the role of the in ammatory processes in the pathophysiology of psychiatric disorders, including schizophrenia, depression, and bipolar disorder (1-4)Bipolar disorder, characterized by recurrent episodes of mania, mixed and depression, is the most common major psychiatric disorder that is reported to have a prevalence of 0.5-4.3% in a recent systematic review of patients referred to the rst level of care (5) and this prevalence could be higher in secondary and tertiary care levels. Also, according to the recent investigation of world Health organization that was conducted in eleven countries, the prevalence of bipolar disorder have been reported 2.4% (5,6). As noted, many hypotheses have been proposed about the immunologic-in ammatory processes as part of the pathophysiology of bipolar disorder, as well as different mechanisms of action based on the pathophysiology of mood stabilizers (7,8) and it has recently been proposed that it may be better to view bipolar disorder as a multi-system in ammatory disease (9)Regarding manic episodes, also various evidence has shown the activation of the in ammatory process. For instance, in two recent studies, in ammatory immune system was signi cantly more active in patients with mania than the control group (10,11) and in one of these studies, increase in the immune activity was a predictor of re-hospitalization of patients (11). The results of a recent meta-analysis provided evidence of increased pro-in ammatory, anti-in ammatory and regulatory cytokines (12). Blood levels of IL6 in acute phase of mania was higher than the control group and compared to the period of remission of symptoms and manic patients with high levels of interferon-gamma was associated with more severe clinical symptoms (based on the Yang mania scale (13). It is also known that mood stabilizers such as lithium, sodium valproate and carbamazepine down-regulate the in ammatory pathways in rat's brain and this effect may contribute to their e cacy in bipolar disorder (14)(15)(16). The therapeutic effects of IL6 receptor antagonists have been also proposed in bipolar disorders (17). Celecoxib is an anti-in ammatory drug and selective cox-2 inhibitor. Considering the role of cox-2 enzyme in the synthesis of prostaglandin E2 and that the prostaglandin stimulates biosynthesis of pro-in ammatory cytokines such as IL6 (18), celecoxib stop this process by inhibition of cox-2 enzyme. Despite increase in the number and variety of medications, a considerable number of patients in the acute phase of mania does not respond su ciently (19,20). Thus, combined treatment strategies of mood stabilizers with augmentation of atypical antipsychotics in the treatment of acute mania is commonly used. But regarding the widespread side effects of mood stabilizers (21) and the considerable prevalence of metabolic syndrome among bipolar patients who receive atypical antipsychotics (22) and with regard to the role of the in ammatory processes in this disorder, the anti-in ammatory drug "celecoxib" with a favorable pro le of side effects without gastrointestinal adverse effects of other NSAIDs (23,24)can be added as a potentially effective and safe option to the treatment of acute mania. Therefore, in this study, we intended to evaluate the effectiveness of Celecoxib as adjunctive therapy in treatment of acute mania.  (25). The diagnosis was con rmed by a psychiatrist based on structured interview and a minimum score of 20 or above on the Young mania rating scale (YMRS). The patients did not receive any psychotrophic medications, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxide inhibitors for 4 weeks preceding entry into the trial. Patients were excluded from the study if they have suffered from known autoimmune disease and diagnosed of infectious diseases for at least 4 weeks prior to the beginning of the study. Also, patients were excluded if they met the criteria for major depressive disorder, eating disorders, personality disorders, mental retardation, mental disorder due to general medical condition, substance dependence or abuse in the previous three months, history of seizures that would contraindicate the use of the study's medication and receiving electroconvulsive therapy (ECT) and peptic ulcers or a history of gastrointestinal bleeding, and use of any medications identi ed as contra-indicated with COX-2 inhibitors. Patients were prohibited from initiating psychotherapy after entry into the study. Pregnant women or women not using medically accepted means of birth control were excluded. Patients were required to be free of all psychotropic medications for at least 4 weeks before the study entry.
The protocol was approved by the IRB of Mashhad University of Medical Sciences. The patients and their legally authorized representative provided informed consent in accordance with the procedures outlined by the local IRB and were informed that they could withdraw from the trial at any time. The trial was performed in accordance with the Declaration of Helsinki and subsequent revisions (26). The trial was registered in Iran: IRCT20200306046708N1 Interventions: The investigator was provided with a sealed randomization code for each available medication number. Blinding was to be broken only if the patient's trial medication would affect speci c emergency treatment.
Patients were randomized to receive celecoxib or placebo in a 1:1 ratio using a computer-generated code. Patients were randomly given routine treatment for mania plus celecoxib 400 mg/day (200 mg bid) (morning and evening) and routine treatment plus placebo for a 4-week, double-blind (participants, care providers, those assessing outcomes), placebo controlled study. Five patients dropped out over the trial . Three patients from the celecoxib group left the trial due to personal reasons unknown to the authors.
One of the patients in the placebo group withdrew from the study due to vomiting and another patient discontinued the trial, because of early discharge Outcome: Patients were assessed with the YMRS at baseline (0), and 9, 18, and 28 day after the start of the treatment(3). Examinations of the patients during the treatment period was performed by a trained psychiatrist trained in the use of YMRS. There was more than 50% reduction in YMRS scores as compared to the baseline, as a response to treatment.

Side effects
Side effects were systematically recorded althrough the study and were assessed using a checklist administered by a resident psychiatrist at baseline and 9, 18, and 28 days after the start of treatment.

Statistical analysis
A two-way repeated measures analysis of variance (time-treatment interaction) was used. The two groups as a between-subjects factor (group) and 4 weekly measurements during treatment as the withinsubjects factor (time) were considered; this was done for YMRS total scores. In order for interaction to be eliminated, then baseline score was considered as the covariate in the analysis. The two groups at baseline were compared and the outcome of the two groups at 9,18, and 28 days from the start of trial was also compared using an unpaired student's t-test with a two-sided P value. The results are presented as mean±standard deviation (SD). Data were analyzed using commercially available statistical packages (SPSS 11.5. Chicago, IL). In order to compare the demographic data and frequency of side effects between the protocols, Fisher's exact test (two-sided) was performed. All statistical tests were two-sided and were considered statistically signi cant at P≤0.05.
Patients with an informed consent entered the study and stated that they could withdraw from the study whenever they did not

Demographic characteristics
Patients (58) were initially examined, among whom4 did not fall within the inclusion criteria and 9 were eliminated due to the exclusion criteria. Therefore, 45 patients were enrolled in the study; 23 were assigned to the celecoxib group and 22 were assigned to the placebo group. The characteristics of the two study groups are summarized in Table 1. Three patients from the celecoxib group left the trial due to personal reasons unknown to the authors. One of the patients in the placebo group withdrew from the study due to vomiting and another patient discontinued the trial, because of early discharge (Figure 1) E cacy: ROUTNE TREATMENT +Celecoxib vs. ROUTNE TREATMENT + Placebo There were no signi cant differences between the two groups at week 0 (baseline) on the young mania rating scale (t: 0.29, df:38, P:0.76). Table 2  Table 2 mean ±SD in two groups in the course of study The difference between the two treatments was not signi cant as shown by the effect of the group; the We considered Age and numberof episode as a cofonding factor but the result were no changes Effect size in this study was from 36.8 (CI95%:34.7-38.9) to 22.5 (CI95%:19.9-25.1)

Clinical complications and side effects
About 5 category of side effects were observed over the period of the trial. The difference between the celecoxib and placebo groups in the frequency of side effects was not signi cant. In this study, the disturbances were examined and there was no signi cant difference between the two groups in terms of these disturbances. Table2

Discussion
To the best of our knowledge, this study is the second clinical 4-week study suggesting the potential use of celecoxib as adjuvant to routine therapy in the treatment of acute mania.
It has been suggested that the clinical e cacy of routine treatments may be enhanced by concurrent administration of agents with anti-in ammatory effects, such as celecoxib (20). There is no doubt that routine treatment are effective in the treatment of acute mania (24) As expected in both groups of patients, during the 4 weeks of treatment, a signi cant improvement was shown on YMRS. The results of a recent meta-analysis provided evidence of increased pro-in ammatory, anti-in ammatory and regulatory cytokines (12). Blood levels of IL6 in acute phase of mania was higher than the control group and compared to the period of remission of symptoms and manic patients with high levels of interferongamma was associated with more severe clinical symptoms (based on the Yang mania scale) (13). In agreement with the hypothesis of this study, the celecoxib group had signi cantly greater improvement over a 4-week trial.
Because of there was one similar clinical trial research study to evaluate the e cacy of celecoxib in alleviating symptoms of acute mania so the closest research was used Arabzadeh et al in 2015 were done the e cacy of Celecoxib adjunctive therapy for acute bipolar mania :A signi cant difference was observed in the change in YMRS scores at the end of study that this result was similar with our study (27) The results of this study provide support for the enhancement of the treatment by concurrent with celecoxib (25) . Indeed, this study shows that celecoxib as an adjuvant agent for acute mania produces improved outcomes in the form of greater reductions of mania, better response, and higher remission rate like other study The results of this study provide statistically signi cant support for the enhancement of the antidepressant effect of the SSRI by concurrent treatment with celecoxib (25) . It has been suggested that celecoxib is a potential adjunctive treatment strategy for OCD in a trial reported by Sayyah et al (28) Therapy with 400 mg/day of celecoxib was well tolerated and no clinically important side effects were observed. Clinical characteristics of the patients, such as sex,number of episode, did not differ between the groups and cannot explain the differences in the therapeutic outcome.
Limitations of this study, including the relatively small sample size and only a xed dose of celecoxib, should be taken into account and this shows the need for further research. In addition, as with all NSAIDs, there is a risk of stomach problems when taking celecoxib. Although this is a very rare side effect with celecoxib. It is still possible and the risk increases with prolonged use  response ratio in two groups