EXECUTIVE SUMMARY

Obsessive-compulsive disorder (OCD) is characterised by a varied spectrum of symptoms that 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 the 4th most common psychiatric illness in India and a leading cause of disability(2). A combination of pharmacotherapy plus psychotherapy remains the mainstay of treatment for OCD. Despite multiple treatment options being available for treatment of OCD, response to 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 on neurotransmitter imbalance and altered functioning of neuro-circuitry pathways(1). In the last 1 decade pathophysiology of OCD has been further explored to find novel aetiological factors associated with pathophysiology of OCD. Genetic aetiology of OCD is one such field being explored in the current times. Mixed results have been found across candidate gene studies. Polymorphism rs6265 (Val66Met) in Brain Derived Neurotrophic Factor(BDNF) gene has shown to have positive correlation with OCD.(3) Serum levels of BDNF have also been studied which revealed decreased serum BDNF levels in OCD patients as compared to controls, making BDNF a potential biomarker for OCD(4). Immune dysfunction has also been implicated as an important part of pathophysiology of OCD. Blood levels of IL-1ß, IL-6 and TNF-α have been found to be significantly elevated in patients with OCD, indicating neuro-inflammatory pathology in OCD(5). NSAIDs have shown promising results when used along with SSRIs as an adjunct in treatment of OCD patients(6,7). However, only a few studies have been done in this area. Hence, the role of anti-inflammatory medications in management of OCD needs to be explored further. In view of this, this study intends to study the role of anti-inflammatory medications in the management 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 BDNF serum levels in patients with OCD. They examined BDNF plasma levels in 22 drug-naïve OCD patients, 52 drug-treated OCD patients, and 63 healthy controls. Individuals in all groups with a current or lifetime history of depression were excluded. They found that BDNF levels were significantly lower in OCD patients (both drug naïve and treated patients) when compared to healthy controls, hypothesising that BDNF is involved in the pathophysiology of OCD, and may be a peripheral marker indicating neurotrophic impairment in OCD. A short course of treatment duration (2 weeks) used in this study might be the reason why no significant difference was found between the drug naïve group and treated 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 BDNF at 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 cases suggesting a protective effect. The contamination/washing symptom dimension score was significantly lower in carriers of ‘A’ allele which remained significant even after testing for confounding effects on linear regression. The results support findings from previous studies 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 2018 to assess the significance of inflammatory markers in OCD. Blood levels of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha was assessed along with cognitive functions in 42 patients with OCD. They found blood levels of IL-1ß, IL-6 and TNF-α were significantly higher in patients with OCD than the healthy control. There was significant difference in IL-1ß, IL-6 but not in TNF-α between autogenous/reactive subtypes and healthy controls. It concluded that inflammatory processes contribute to the psychopathology of OCD by compromising cognitive functions.(5)

A study, preliminary randomized double–blind clinical trial, was done by done by Mehdi Sayyaha, Hatam Boostani et al in 2011 to assess the role of and anti-inflammatory medication Celecoxib (Selective COX-2 inhibitor) as an adjunct to Fluoxetine in OCD patients. The study group comprising of 25 patients were given fluoxetine 20 mg/day plus celecoxib 400 mg/day (200 mg BID). The control group, including 25 patients, were given fluoxetine 20 mg/day plus placebo. At the end of 8 weeks they found that the combination of fluoxetine and celecoxib decreased the symptoms of obsessions and compulsions significantly more than fluoxetine plus placebo.(6)

More recently, in 2015 Shalbafan, P. Mohammadinejad et al conducted another study to explore the role of Celecoxib (Selective COX-2 inhibitor) add on therapy to Fluvoxamine in patients with OCD. 50 patients received either celecoxib (200 mg twice daily) or placebo as an adjuvant to fluvoxamine 100 mg/day for the first 4 weeks of the study followed by 200 mg/day for the remaining 6 weeks. After statistical analysis they concluded that more rapid response was seen in the celecoxib group than the placebo group (p < 0.001) and there was 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 clinical and functional outcome in Obsessive Compulsive Disorder.

OBJECTIVE

• To study the clinical and functional outcome of Celecoxib add-on therapy to fluoxetine 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 obsessive compulsive disorder, if any.

  METHODOLOGY:

  Study design: It is a Randomised Double Blind Placebo Control Trial study Study population: Patients with OCD as mentioned in the selection criteria Sampling technique: Randomized sampling
  Source of sample: Will be collected from Adult psychiatry OPD of a tertiary care hospital

  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 participants is 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 and 3rd follow up visit

• Missing >20% of doses as per self-report/pill count

PROCEDURE

Symptomatic patients (old or new) attending Adult Psychiatry OPD, Department of Psychiatry, KGMU, on specified OPD days clinically diagnosed as Obsessive Compulsive Disorder 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-10 DCR criteria with YBOCS>=21. Patients fulfilling the selection criteria will be recruited in the study. A written informed consent will be taken from the patients prior to inclusion in the study. Following enrolment, the socio-demographic and clinical details of the patient will be recorded using Semi- Structured Proforma. Baseline clinical variables will be measured using scales 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 the pathology lab by the attendant, and the sample for estimation of IL-6 and BDNF will be sent to Centre For Advanced Research(CFAR), KGMU and preserved. All subjects will be started on Tab Fluoxetine 40mg/day. Patients will be randomly allocated into two treatment groups, A and B, using a computer generated randomization table and depending on the group each subject will receive either Celecoxib(case group) or placebo(control group), identical capsule, as twice daily prescription, for 12 weeks. Clinical investigator, responsible for clinical evaluation and drug dispensing, will be blind to the allocation of patients to the study or control group. The drugs will be made available in a pre-labelled containers. The study drugs (Fluoxetine and Celecoxib) will be procured from reputed production firm from a single batch. All patients will be followed for treatment adherence and clinical assessment at week 2 (14 days ± 2 days), week 4 (28 days ± 2 days), week 8 (56 days ± 2 days) and week 12 (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 by the investigator on each visit for assessment and monitoring i.e. Y-BOCS Scale, Dimensional YBOCS, DASS-21, ACE-III, QOL- BREF, SOFAS. Adherence will be assessed by verbal report. 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 necessary COVID-19 related precautions will be taken during the study and it will be ensured that the participants and their attendants do not have any symptoms of the same.

TOOLS:

• Semi-structured proforma - including socio-demographic and clinical history details of patients.

• Mini International Neuropsychiatric Interview (MINI) 7.0.2 for screening of psychiatric 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 for Obsessive-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 and treatment response. Asian J Psychiatr. 2018 Dec;38:65-69. doi: 10.1016/j.ajp.2017.10.014. Epub 2017 Oct 18. PMID: 29079096.

  4- Wang Y, Mathews CA, Li Y, Lin Z, Xiao Z. Brain-derived neurotrophic factor (BDNF) plasma levels in drug-naïve OCD patients are lower than those in healthy people, but are not lower than those in 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 of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha and cognitive functions in patients with 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 clinical trial 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 for Research: 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: reliability and 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–Compulsive Scale (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. Psychology Foundation 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 life assessment. Psychological medicine. 1998 May;28(3):551-8.

15- Morosini PL, Magliano L, Brambilla LA, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM‐IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social funtioning. Acta Psychiatrica Scandinavica. 2000 Apr;101(4):323-9