A Randomized Double Blind Placebo Controlled Study Of Celecoxib Add-On In Obsessive Compulsive Disorder
- Conditions
- Mixed obsessional thoughts and acts,
- Registration Number
- CTRI/2022/01/039407
- Lead Sponsor
- King George Medical University
- Brief Summary
EXECUTIVE SUMMARY
Obsessive-compulsive disorder (OCD) is characterised by a varied spectrum of symptomsthat include intrusive ego-dystonic thoughts, rituals, preoccupations, and compulsions(1).Lifetime prevalence in the general population is estimated at 1 to 3 percent making it the4th most common psychiatric illness in India and a leading cause of disability(2). Acombination of pharmacotherapy plus psychotherapy remains the mainstay of treatment forOCD. Despite multiple treatment options being available for treatment of OCD, responseto treatment is far from satisfactory, 20% patients do not respond to any treatment(2).Various aetiologies have been explored in OCD patients which, currently, mainly focus onneurotransmitter imbalance and altered functioning of neuro-circuitry pathways(1). In thelast 1 decade pathophysiology of OCD has been further explored to find novel aetiologicalfactors associated with pathophysiology of OCD. Genetic aetiology of OCD is one suchfield being explored in the current times. Mixed results have been found across candidategene studies. Polymorphism rs6265 (Val66Met) in Brain Derived NeurotrophicFactor(BDNF) gene has shown to have positive correlation with OCD.(3) Serum levels ofBDNF have also been studied which revealed decreased serum BDNF levels in OCDpatients as compared to controls, making BDNF a potential biomarker for OCD(4).Immune dysfunction has also been implicated as an important part of pathophysiology ofOCD. Blood levels of IL-1ß, IL-6 and TNF-α have been found to be significantly elevatedin patients with OCD, indicating neuro-inflammatory pathology in OCD(5). NSAIDs haveshown promising results when used along with SSRIs as an adjunct in treatment of OCDpatients(6,7). However, only a few studies have been done in this area. Hence, the role ofanti-inflammatory medications in management of OCD needs to be explored further. Inview of this, this study intends to study the role of anti-inflammatory medications in themanagement of OCD along with biomarker assays.
REVIEW OF LITERATURE
A study was conducted by Yuan Wang, Carol A. Mathews et al in 2011 to assess the BDNFserum levels in patients with OCD. They examined BDNF plasma levels in 22 drug-naïveOCD patients, 52 drug-treated OCD patients, and 63 healthy controls. Individuals in allgroups with a current or lifetime history of depression were excluded. They found thatBDNF levels were significantly lower in OCD patients (both drug naïve and treatedpatients) when compared to healthy controls, hypothesising that BDNF is involved in thepathophysiology of OCD, and may be a peripheral marker indicating neurotrophicimpairment in OCD. A short course of treatment duration (2 weeks) used in this study mightbe the reason why no significant difference was found between the drug naïve group andtreated patients of OCD. A period of 2 weeks might not be sufficient to identify drug-associated changes in BDNF levels(4).
Another study by Reshma Jabeen Taj M J, Suhas Ganesh et al explored the role of BDNFat the genetic level where individuals diagnosed to have OCD (n = 377) and controls (n =449) were genotyped for polymorphism rs6265 (196 G/A, Val66Met). The allele ‘A’frequency was found to be significantly higher in the controls, as compared to casessuggesting a protective effect. The contamination/washing symptom dimension score wassignificantly lower in carriers of ‘A’ allele which remained significant even after testingfor confounding effects on linear regression. The results support findings from previousstudies on a possible protective effect of the ‘Met’ allele at the Val66Met locus in OCD(3).
Evrim Özkorumak Karagüzel, Filiz Civil Arslan et al recently conducted a study in 2018to assess the significance of inflammatory markers in OCD. Blood levels of interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha was assessed along with cognitivefunctions in 42 patients with OCD. They found blood levels of IL-1ß, IL-6 and TNF-α weresignificantly higher in patients with OCD than the healthy control. There was significantdifference in IL-1ß, IL-6 but not in TNF-α between autogenous/reactive subtypes andhealthy controls. It concluded that inflammatory processes contribute to thepsychopathology of OCD by compromising cognitive functions.(5)
A study, preliminary randomized double–blind clinical trial, was done by done by MehdiSayyaha, Hatam Boostani et al in 2011 to assess the role of and anti-inflammatorymedication Celecoxib (Selective COX-2 inhibitor) as an adjunct to Fluoxetine in OCDpatients. The study group comprising of 25 patients were given fluoxetine 20 mg/day pluscelecoxib 400 mg/day (200 mg BID). The control group, including 25 patients, were givenfluoxetine 20 mg/day plus placebo. At the end of 8 weeks they found that the combinationof fluoxetine and celecoxib decreased the symptoms of obsessions and compulsionssignificantly more than fluoxetine plus placebo.(6)
More recently, in 2015 Shalbafan, P. Mohammadinejad et al conducted another study toexplore the role of Celecoxib (Selective COX-2 inhibitor) add on therapy to Fluvoxaminein patients with OCD. 50 patients received either celecoxib (200 mg twice daily) or placeboas an adjuvant to fluvoxamine 100 mg/day for the first 4 weeks of the study followed by200 mg/day for the remaining 6 weeks. After statistical analysis they concluded that morerapid response was seen in the celecoxib group than the placebo group (p < 0.001) and therewas no significant difference in adverse event frequencies between the two groups.
HYPOTHESIS AND OBJECTIVES
HYPOTHESIS
Celecoxib (Selective COX-2 inhibitor) as an add-on to Fluoxetine will improve the clinicaland functional outcome in Obsessive Compulsive Disorder.
OBJECTIVE
- To study the clinical and functional outcome of Celecoxib add-on therapy tofluoxetine treatment in Obsessive Compulsive Disorder
- To study the association of clinical and functional outcome with serum Interleukin-6(IL- 6) and Brain Derived Neurotropic Factors (BDNF) in patients with obsessivecompulsive disorder, if any.
METHODOLOGY:
Study design: It is a Randomised Double Blind Placebo Control Trial studyStudy population: Patients with OCD as mentioned in the selection criteriaSampling technique: Randomized sampling Source of sample: Will be collected from Adult psychiatry OPD of a tertiary carehospital
Randomization method: Computer generated block randomization table Blinding:Double blinding (Patients + Investigators) Sample size: Sample size is calculated through Priori analysis using “G\*Power:
Statistical Power analyses 3.1.9.7†application. When used with the following variable of Statistical test: ANOVA- Repeated measures, within and between interactions Effect size f = 0.20 No. of groups : 2 No. of measurements : 5 type I error α = 5% corresponding to 95% confidence level type II error β = 10% for detecting results with 90% power of study So the required sample size n = 40 for entire study Considering a drop out rate of about 10%, the expected number of initial participantsis 44.
Selection Criteria
- Age: 18 years to 50 years
- Informed consent from the patient
- Diagnosed with OCD (ICD-10 DCR)
- Symptomatic (Y-BOCS Score >=21)
- Drug naïve (Drug free period for at least 12 weeks)
Exclusion Criteria
- Any other psychiatric comorbidity(Except nicotine dependence)
- Any medical condition requiring priority management or where use of COX-2
inhibitors is contraindicated
- Patient receiving a course of any immunosuppressive therapy or NSAID in adequate
dose for consecutive 5 days or more in the past 8 weeks.
- Established non-response to Fluoxetine (Adequate dose for adequate duration)
- Intellectual disability (assessed clinically)
- Pregnancy and breastfeeding
Drop Out Criteria:
- Clinically significant derangement in routine blood investigations at baseline
- Occurrence of any clinically significant side effects after the initiation of therapy
- Worsening of OCD symptoms during the course of the study
• Withdrawal of consent during the course of therapy th st nd
• Missing either the last (4 ) follow up visit or missing >2 visits out of the 1 , 2 and3rd follow up visit
• Missing >20% of doses as per self-report/pill count
PROCEDURE
Symptomatic patients (old or new) attending Adult Psychiatry OPD, Department ofPsychiatry, KGMU, on specified OPD days clinically diagnosed as Obsessive CompulsiveDisorder will be assessed on the selection criteria. Patients will be screened using MINI 7.0.2.to rule out other psychiatric co-morbidity. All patients of OCD will be screened on ICD-10DCR criteria with YBOCS>=21. Patients fulfilling the selection criteria will be recruited inthe study. A written informed consent will be taken from the patients prior to inclusion in thestudy. Following enrolment, the socio-demographic and clinical details of the patient will berecorded using Semi- Structured Proforma. Baseline clinical variables will be measured usingscales i.e. Dimensional YBOCS for severity of symptoms, DASS-21 to assess psychiatric co-morbidities, ACE-III for cognition, SOFAS for functioning, QOL-BREF for quality of life.Venous blood sampling will be done for routine blood investigations, to be taken to thepathology lab by the attendant, and the sample for estimation of IL-6 and BDNF will be sentto Centre For Advanced Research(CFAR), KGMU and preserved. All subjects will bestarted on Tab Fluoxetine 40mg/day. Patients will be randomly allocated into two treatmentgroups, A and B, using a computer generated randomization table and depending on thegroup each subject will receive either Celecoxib(case group) or placebo(control group),identical capsule, as twice daily prescription, for 12 weeks. Clinical investigator, responsiblefor clinical evaluation and drug dispensing, will be blind to the allocation of patients to thestudy or control group. The drugs will be made available in a pre-labelled containers. Thestudy drugs (Fluoxetine and Celecoxib) will be procured from reputed production firm from asingle batch. All patients will be followed for treatment adherence and clinical assessment atweek 2 (14 days ± 2 days), week 4 (28 days ± 2 days), week 8 (56 days ± 2 days) and week12 (84 days ± 2 days). Dose of Fluoxetine will be maintained at a maximum tolerable dose,subjected to a maximum of 80mg/day by week 4. The appropriate scales will be applied bythe investigator on each visit for assessment and monitoring i.e. Y-BOCS Scale, DimensionalYBOCS, DASS-21, ACE-III, QOL- BREF, SOFAS. Adherence will be assessed by verbalreport. Serum samples will again be collected and preserved at 12 weeks (last follow-up visit)for serum IL-6 and BDNF estimation and sent to CFAR, KGMU and analysis of pre-treatment and post-treatment samples will be done for patients completing the follow-up.Data collection and statistical analysis will be done using appropriate tools. All necessaryCOVID-19 related precautions will be taken during the study and it will be ensured that theparticipants and their attendants do not have any symptoms of the same.
TOOLS:
- Semi-structured proforma - including socio-demographic and clinical history detailsof patients.
- Mini International Neuropsychiatric Interview (MINI) 7.0.2 for screening ofpsychiatric illness in patient and care giver(8)
- International Classification of Disease-10 Diagnostic Criteria for Research(9)
- Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (10)
- Dimensional Yale-Brown Obsessive Compulsive Scale(11)
- Depression, Anxiety and Stress Scale -21 (DASS-21) (12)
- Addenbrooke’s Cognitive Examination - ACE-III (13)
- WHOQOL-BREF- World Health Organisation Quality of Life BREF(14)
- SOFAS- Social and Occupational Functioning Assessment Scale(15)
REFERENCES
1- Sadock, B. J., Sadock, V. A., & Md, R. P. (2014). Obsessive-Compulsive and Related disorders :Obsessive Compulsive disorder. In Kaplan and Sadock’s synopsis of psychiatry (Eleventh ed., pp.418– 427). LWW.
2- Janardhan Reddy Y C, Sundar A S, Narayanaswamy JC, Math SB. Clinical practice guidelines forObsessive-Compulsive Disorder. Indian J Psychiatry 2017;59, Suppl S1:74-90
3- Taj M J RJ, Ganesh S, Shukla T, Deolankar S, Nadella RK, Sen S, Purushottam M, Reddy YCJ,Jain S, Viswanath B. BDNF gene and obsessive compulsive disorder risk, symptom dimensions andtreatment response. Asian J Psychiatr. 2018 Dec;38:65-69. doi: 10.1016/j.ajp.2017.10.014. Epub 2017Oct 18. PMID: 29079096.
4- Wang Y, Mathews CA, Li Y, Lin Z, Xiao Z. Brain-derived neurotrophic factor (BDNF) plasmalevels in drug-naïve OCD patients are lower than those in healthy people, but are not lower than thosein drug- treated OCD patients. Journal of affective disorders. 2011 Sep 1;133(1-2):305-10.
5- Karagüzel EÖ, Arslan FC, Uysal EK, Demir S, Aykut DS, Tat M, Karahan SC. Blood levels ofinterleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha and cognitive functions in patientswith obsessive compulsive disorder. Compr Psychiatry. 2019 Feb;89:61-66. doi:10.1016/j.comppsych.2018.11.013. Epub 2018 Dec 21. PMID: 30594753.
6- Sayyah M, Boostani H, Pakseresht S, Malayeri A. A preliminary randomized double-blind clinicaltrial on the efficacy of celecoxib as an adjunct in the treatment of obsessive-compulsive disorder.Psychiatry Res. 2011 Oct 30;189(3):403-6. doi: 10.1016/j.psychres.2011.01.019. Epub 2011 Feb 18.PMID: 21329988.
7- Shalbafan M, Mohammadinejad P, Shariat SV, Alavi K, Zeinoddini A, Salehi M, Askari N,Akhondzadeh S. Celecoxib as an Adjuvant to Fluvoxamine in Moderate to Severe Obsessive-compulsive Disorder: A Double-blind, Placebo-controlled, Randomized Trial. Pharmacopsychiatry.2015 Jul;48(4- 5):136-40. doi: 10.1055/s-0035-1549929. Epub 2015 May 6. PMID: 25959196.
8- Sheehan D. The MINI international neuropsychiatric interview,(Version 7.0. 2) for DSM-5. 2016.Heinemann LA, Potthoff P, Schneider HP.
9- WHO. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria forResearch: World Health Organisation; 1993.
10- Scahill, L., Riddle, M.A., McSwiggin-Hardin, M., Ort, S.I., King, R.A., Goodman, W.K.,Cicchetti, D. & Leckman, J.F. (1997). Children’s Yale-Brown Obsessive Compulsive Scale: reliabilityand validity. J Am Acad Child Adolesc Psychiatry, 36(6):844-852.
11- Rosario-Campos MC, Miguel EC, Quatrano S, Chacon P, Ferrao Y, Findley D, Katsovich L,Scahill L, King RA, Woody SR, Tolin D. The Dimensional Yale–Brown Obsessive–CompulsiveScale (DY- BOCS): an instrument for assessing obsessive–compulsive symptom dimensions.Molecular psychiatry. 2006 May;11(5):495-504.
12- Lovibond SH, Lovibond PF. Manual for the depression anxiety stress scales. PsychologyFoundation of Australia; 1996.
13- Noone, Peter. (2015). Addenbrooke’s Cognitive Examination-III. Occupational medicine (Oxford,England). 65. 418-20. 10.1093/occmed/kqv041.
14- Whoqol Group. Development of the World Health Organization WHOQOL-BREF quality of lifeassessment. Psychological medicine. 1998 May;28(3):551-8.
15- Morosini PL, Magliano L, Brambilla LA, Ugolini S, Pioli R. Development, reliability andacceptability of a new version of the DSMâ€IV Social and Occupational Functioning Assessment Scale(SOFAS) to assess routine social funtioning. Acta Psychiatrica Scandinavica. 2000 Apr;101(4):323-9
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 44
Informed consent from the patient Diagnosed with OCD (ICD-10 DCR) Symptomatic (Y-BOCS Score more than or equal to 21) Drug naive (Drug free period for at least 12 weeks).
- Any other psychiatric comorbidity(Except nicotine dependence) Any medical condition requiring priority management or where use of COX-2 inhibitors is contraindicated Patient receiving a course of any immunosuppressive therapy or NSAID in adequate dose for consecutive 5 days or more in the past 8 weeks.
- Established non-response to Fluoxetine (Adequate dose for adequate duration) Intellectual disability (assessed clinically), Pregnancy and breastfeeding.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To study the severity of Obsessive Compulsive Disorder with Celecoxib add-on therapy to fluoxetine Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
- Secondary Outcome Measures
Name Time Method To study the cognition patients of Obsessive Compulsive Disorder with Celecoxib add-on therapy to fluoxetine To study the associated anxiety and depressive symptoms in patients of Obsessive Compulsive Disorder with Celecoxib add-on therapy to fluoxetine
Trial Locations
- Locations (1)
King George Medical university
🇮🇳Lucknow, UTTAR PRADESH, India
King George Medical university🇮🇳Lucknow, UTTAR PRADESH, IndiaShivangini SinghPrincipal investigator9535070299shivangini1103@gmail.com