Jitteriness/anxiety syndrome caused by coadministration of celecoxib, a selective COX‐2 inhibitor, with escitalopram and trazodone in a patient with depression and spondylolisthesis

Abstract Antidepressant‐induced jitteriness/anxiety syndrome is characterized as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, and (hypo)mania, which appear immediately after initiation or increased dosage of an antidepressant. This report describes a case of the jitteriness/anxiety syndrome caused by the coadministration of celecoxib with escitalopram and trazodone in a patient with depression and spondylolisthesis. The depression of a patient, a woman in her 60 s, had been in remission at least for 5 years under treatment using escitalopram and trazodone. Immediately after coadministration of celecoxib because of her buttock and limb pain, she showed anxiety, agitation, akathisia, insomnia, irritability, aggressiveness, impulsivity, and hypomania. These symptoms disappeared after the discontinuation of celecoxib. The present case suggests that coadministration of celecoxib with escitalopram and trazodone can cause the jitteriness/anxiety syndrome, presumably via a pharmacokinetic interaction of celecoxib with these antidepressants and/or the effects of celecoxib on serotonergic neurotransmission.

On day 5 before admission to our department, she was administered celecoxib 200 mg/day because of exacerbation of the pain. At 3 days before admission, she presented a sense of restlessness, an inability to sit, anxiety, depressed mood, suicidal thought, suicidal behavior such as wringing of her neck, hyperventilation, dyspnea, chilling sensation of the body, and insomnia. On day 2 before admission, she visited the Department of Orthopedic Surgery. Celecoxib administration was stopped. Subsequently, her symptoms continued. She was therefore admitted to our department.
On admission, she was found to have no disturbance of consciousness, neurological abnormality including myoclonus, hyperreflexia, or tremor, or autonomic hyperactivity including diaphoresis or hyperthermia. Her laboratory blood tests, chest X ray, and electrocardiogram showed no abnormality. Conservative treatments including intravenous hydration were performed. By 4 days after admission, her depressive and anxiety symptoms had improved, but she showed hypomanic symptoms such as elevated mood, talkativeness, hyperactivity, and aggressiveness toward medical staff members or other patients. All symptoms had disappeared by 6 days after admission. She was discharged on 10 days after admission without complications. No drug except celecoxib was changed throughout this episode despite her various and unsettled symptoms.

| DISCUSS ION
The patient in this case showed anxiety, agitation, akathisia, insomnia, irritability, aggressiveness, impulsivity, and hypomania after coadministration of celecoxib with escitalopram and trazodone.
These symptoms disappeared completely several days after discontinuation of celecoxib. She had 8 of 10 symptoms of the jitteriness/ anxiety syndrome. 2,3 Therefore, she was diagnosed as having this syndrome.
Because of the course of her symptoms, the diagnoses of serotonin syndrome, akathisia, and mixed features in major depression were all considered, but eventually excluded. Serotonin syndrome was ruled out because the patient had neither autonomic hyperactivity (e.g., hyperthermia, diaphoresis) nor neuromuscular abnormalities (e.g., myoclonus, hyperreflexia, tremor), which are unique features of the serotonin syndrome, although serotonin syndrome may have the same pathophysiology and predisposing factors in common with the jitteriness/anxiety syndrome. 1,5 Several symptoms observed in this case fulfilled the criteria of akathisia of Sachdev, 6 where a diagnosis of akathisia is defined if at least one subjective symptom such as inner tension and a feeling of restlessness is identified with one objective symptom such as purposeless leg movement and inability to sit. However, akathisia itself is involved in the symptom cluster of the jitteriness/anxiety syndrome. 1-3 Furthermore, this patient had depressive and hypomanic symptoms, which could not be explained solely by akathisia.
The mixed features in major depression were ruled out according to the criteria of DSM-5 7 ; her depressive and manic symptoms during the present episode lasted, respectively, for only 6 and 2 days. Additionally, she had never showed (hypo)manic or mixed episode. Her depression was in remission at least 5 years immediately before the coadministration of celecoxib. However, the possibility that the patient had potential bipolarity, and this played a predisposing role in the development of the jitteriness/anxiety syndrome cannot be ruled out. Second, one in vivo study has shown that orally administered celecoxib can reach the central nervous system in humans. 13 Furthermore, Faridhosseini et al. performed a systematic review and meta-analysis of the efficacy of celecoxib coadministration with antidepressants for the treatment of depressive mood episodes. 14 Subsequently, they showed that the coadministration of celecoxib is effective for improving depressive symptoms. 14 Regarding the mechanism of these effects of celecoxib on depressive episode, findings from several studies suggest that celecoxib administered in combination with antidepressants increases the extracellular serotonin concentrations in the medial prefrontal cortex of mice. 14,15 Consequently, the celecoxib effects on increased serotonergic transmission might be related to the jitteriness/anxiety syndrome observed in this case.

ACK N OWLED G M ENTS
We sincerely appreciate the cooperation of the patient and her family.

FU N D I N G I N FO R M ATI O N
None.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

A PPROVA L O F TH E R E S E A RCH PROTO CO L BY A N I N S TITUTI O N A L R E V I E WER B OA R D
This case report was approved by the Ethical Review Committee of the Yamagata University Faculty of Medicine.

I N FO R M E D CO N S E NT
Written informed consent was obtained from the parent for the publication of this case report.

A N I M A L S TU D I E S
N/A.