Latest Advances In The Treatment Of Obsessive Compulsive And Related Disorders

1. Latest Advances In The Treatment Of Obsessive Compulsive And Related Disorders NA Fineberg, J Reid, R Ruparelia, R Sachdev, E Cinosi, D Mpavaenda Highly Specialised Service for Obsessive Compulsive and Related Disorders, Hertfordshire Partnership University NHS Foundation Trust, University of Hertfordshire, Rosanne House , Welwyn Garden City, Hertfordshire AL8 6HG March 2017

2. Declaration ofinterests I have received sponsorship for: • Consultancy work from Servier, Lundbeck, Glaxo-Smith Kline, Astra-Zeneca and Bristol-Myers Squibb. • Research support from Servier, Lundbeck • Educational work and lectures from Shire, Otsuka, Janssen, Lundbeck, Bristol-Myers Squibb, Wyeth, Servier.

3. Aims of lecture • Re-conceptualization of OCRDs • What are the first-line treatments? • Does pharmacotherapy improve health-related quality of life? • How long should treatment continue? • Can we predict treatment outcomes? • Management of treatment-refractory OCD • Novel targets and treatments

4. DSM-5: Obsessive-Compulsive and Related Disorders. APA, May 4th 2011 Contains diagnoses listed in DSM-IV under Anxiety Disorders, Somatoform Disorders and Impulse-Control Disorders Not Elsewhere Classified. 300.3 Obsessive-Compulsive Disordera Specify if: Tic-related 300.7 Body Dysmorphic Disordera Specify if: With muscle dysmorphia 300.3 Hoarding Disordera Specify if: With excessive acquisition 312.39 Hair-Pulling Disorder (Trichotillomania) 698.4 Skin Picking (Excoriation) Disorder a Specify if: With good or fair insight With poor insight With absent insight/delusional beliefs

5. Evidence-based treatment for OCRDS.Grant J, Chamberlain S, Odlaug B. Clinical Guide to OCRDs, Oxford, 2014 Apart from OCD, psychological therapies not rigorously tested against matched control. Apart from OCD, pharmacotherapies tested in small un-replicated trials.

6. Anxiety Disorders Guidelines covering OCD • International Consensus Group on Depression and Anxiety (2000, 2003) • World Federation of Societies of Biological Psychiatry (2002, 2008, 2012) • World Council on Anxiety Disorders (2003) • National Institute for Clinical Excellence (UK) (2006; Evidence Update 2013) (and BDD) • British Association for Psychopharmacology (2005, 2014) • American Psychiatric Association (2007, Guideline Watch update 2013) • ICOCS; Standards of Care (2016)

7. First - Line Treatments in OCD • Behaviour therapy; exposure and response prevention (>16h; in vivo) B. Pharmacotherapy; serotonin reuptake inhibitors (SSRI > clomipramine); higher doses; extended duration-minimum 12 weeks; adjunctive DA antagonists C. Combination of A+B BUT Approx. 40% fail to respond Response is usually partial Relapse is common Better treatments are needed Fineberg NA, Brown, A, Reghunandanan S, Pampaloni I. Evidence-Based Pharmacotherapy of Obsessive-Compulsive Disorder. Int J Neuropsychopharmacol. 2012 Jan 9:1-19

8. Pharmacological and psychotherapeutic interventions for obsessive-compulsive disorder in adults, children and adolescents: a systematic review and network meta-analysis.Skapinakis P, Caldwell DM, Hollingworth W, Bryden P, Fineberg NA, et al. Lancet Psychiatry. 2016 Aug;3(8):730-9. Most psychotherapy trials included patients who were taking medications. In adults, psychotherapies, clomipramine, SSRIs or combinations of these are all effective. There were few studies in children and adolescents; psychotherapies as monotherapy or combined with SSRIs were more likely to be effective. Future RCTs should improve their design, in particular for psychotherapy or combined interventions.

9. STEPPED CARE MODEL Who is responsible for care? STEP 6 Inpatient care or intensive treatment programmes (national). STEP 5 Multidisciplinary teams with specific expertise in management of OCD (regional). STEP 4 local multidisciplinary care (GP or psychiatrist). STEP 3 GPs and primary care team, primary care mental health worker, family support team. STEP 2 GPs, practice nurses, school health advisors STEP 1 Individuals, public organisations, NHS

10. Has the management of paediatric OCD improved following the introduction of NICE guidelines?Nair A et al., Arch Dis Child 2014 Dec 30. epub Referrals received Jan 2000 - 2002 (T1 cohort, n=79) compared with Jan 2009 – 2011 (T2 cohort, n=143). Data collected as part of routine assessment in the HSS OCD clinic *p<0.05, **p<0.01, ***p<0.001, significant difference between cohorts.

11. ‘Research-enhanced health care’ Clinical state and circumstances Clinical expertise Patient preferences and actions Research evidence Haynes et al.BMJ 2002; 324: 1350

12. Which dose?

13. 0 Placebo n=113 Escitalopram 10 mg n = 114 -2 Escitalopram 20 mg n=114 Paroxetine 40 mg n=116 -4 * p<0.05, **p<0.01; difference versus placebo -6 Adjusted mean change from baseline Y-BOCS total score * -8 * * * * -10 * * * ** * ** ** ** -12 ** ** -14 0 4 8 12 16 20 24 Treatment week (LOCF) Fixed – dose escitalopram study: primary analysisStein DS et al Curr. Med. Res. and Opinion 2007

14. Patients in remission (Y-BOCS < 10)Stein DS et al Curr. Med. Res. and Opinion 2007 * * ** * * * * * Stein et al. Poster presented at APA 2006 * p<0.05 vs PBO, ** p<0.01 vs PBO

15. Placebo-controlled comparator studies of fixed-doses of SSRI a Marginally significant benefit for medium and higher doses on primary analysis (total YBOCS, p=0.059); significant on ‘responder’ analysis (p<0.05). b Response on 60mg occurred earlier (wk3) compared to 20mg and 40mg (wk 7)

16. Does SSRI improve health related disability and quality of life?

17. OCD; mean baseline SF-36 scores in combined escitalopram database (n = 921) and three other trial databases compared to published U.S. norms (Hollander E et al, J Clin Psychiatry, Epub June 2010)

18. OCD: Mean change in SF-36 score from baseline to 24 weeks in patients (n=455) receiving fixed-dose treatment with escitalopram, paroxetine, or placebo(LOCF)Hollander E et al, J Clin Psychiatry, epub June 2010 *p<0.05, **p<0.01, ***p<0.001 vs. placebo (ANCOVA).

19. Does combining medication and CBT improve outcomes?

20. Augmenting SRI in OCD with ERP vs Risperidone: A Randomized Clinical Trial. Simpson HB et al, JAMA 2013.1932 Epub 100 SSRI partial/non-responders: SSRI+Risperidone (n=40); SSRI+ERP (n=40); SSRI+ placebo (n=20). ERP=17 twice-weekly 90-min. sessions, daily homework (at least 1 hour self-directed exposure daily), and between-session telephone check-ins. No psychological therapy control for ERP. N=86 (86%) completed the trial. YBOCS Change in Symptom Severity During Augmentation

21. Can we predict outcomes on an individual basis?

22. Early improvement as an indicator of treatment response in OCD? Implications for early-treatment decision-making. Da Conceicao DL 2013, J Psychiat Res Nov;47(11):1700-7 A pragmatic naturalistic 12-week SRI trial with 128 subjects. Early improvement (>= 20% reduction in baseline Y-BOCS) at 4 weeks was the best predictor of treatment response (>=35% Y-BOCS improvement) at 12 weeks (OR = 1.05, p < 0.0001). Only 20% of patients who did not improve at 4 weeks were responders after 12 weeks. But, only 55% who showed early improvement ended up responders at 12 weeks.

23. Five-year course of obsessive-compulsive disorder: predictors of remission and relapse. • Eisen JL et al., J Clin Psychiatry. 2013 Mar;74(3):233-9. • 213 adults with DSM-IV OCD • Recruited between 2001-6 • OCD symptoms assessed annually over 5-year follow-up • 39% participants entered either partial (22.1%) or full (16.9%) remission. • Obsessions regarding harm nearly twice as likely to remit (P < .05) • Other positive predictors of remission included lower OCD severity • (P < .0001) and shorter duration of illness (P < .0001) • - Primary hoarding sig less likely to remit (2 of 21 participants (9.5%). • 59% participants who remitted subsequently relapsed. • Participants with obsessive-compulsive personality disorder more than twice as likely to relapse (P < .005). • Participants also more likely to relapse if they experienced partial remission versus full remission (70% vs 45%; P < .05)

24. Long-term course of paediatric OCD: 3 years of prospective follow-up. Mancebo MC et al Compr Psychiatry. 2014 Oct;55(7):1498-504. • 60 youth and their parents • Annual follow-up interviews for 3years - 80% patients achieved either partial (53%) or full (27%) remission • Better functioning at intake and a shorter latency to initial OCD treatment were associated with faster onset of remission (P<.001). • 21% of those who remitted subsequently relapsed (mean 88wk f-up) CONCLUSIONS • Remission is more likely among youth versus adults with OCD. • Treatment early in the course of illness and before substantial impact on functioning predicts a better course.

25. How long to remain on treatment?

26. Esc vs placebo:Time to relapseFineberg et al. Eur Neuropsychopharmacol.2007 Kaplan - Meier Esc N=163: Relapses 38 (23.5%) PBO N=157: Relapses 81 (52.6%) Hazard ration = 2.74 Log rank test: P<0.001 *** ESC N=163; Relapses: 38 (23.5%) PBO N=157; Relapses: 81 (52.6%) Hazard ratio = 2.74 N=320 (ESC 163, PBO 157 )

27. Meta-analysis of SSRI relapse prevention studies in adults with OCDFineberg et al Int Clin Psychopharmacol 2007

28. Mean SF-36 scores at lastassessment for relapsed (n=119) and non-relapsed (n=201) patients (relapse-prevention study). (Hollander E et al, J Clin Psychiatry, Jun;71(6):784-92. 2010.) p<0.05, **p<0.01, ***p<0.001 vs. placebo (ANCOVA)

29. How to treat resistant OCD?

30. Review diagnosis Check adherence First-line treatment SSRI, maximal dose, 12 weeks SRI-resistant OCD: a pharmacological algorithmObsessive-Compulsive and Related Disorders. Reghunandanan S, Fineberg NA, Stein DS. OUP. 2015 in press (1) Switch SSRI or clomipramine, maximal dose, 12 weeks Repeat (1) Increase dose beyond formulary limits Add second generation antipsychotic Add haloperidol Intravenous SSRI or clomipramine Combine clomipramine and SSRIs NOVEL AGENTS

31. Higher-dose SSRI monotherapy for resistant OCD?Ninan et al J Clin Psych 2006 • 66 OCD non-responders to 16 weeks of sertraline, randomly assigned: • 12 weeks high-dose sertraline (250-400 mg/day, mean = 357mg, N = 30) outperformed sertraline 200mg/day (N = 36) on YBOCS, NIMH Global OC Scale, CGI-I. • Responder rates not significantly different between groups, either on completer analysis ( 34% vs. 52%) or endpoint analysis (33% vs. 40%). • Both treatments showed similar adverse event rates. • Higher than labelled SSRI doses may be a treatment option for OCD patients who fail to respond to standard acute treatment.

32. American Psychiatric Association. (2007).Practice Guideline For The Treatment of Patients With Obsessive-compulsive Disorder. Arlington (VA): Koran LM et al; American Psychiatric Association (APA); 96 p. GUIDELINE WATCH (MARCH 2013): Koran LM, SimpsonHB

33. Antipsychotic augmentation in OCD Veale D, Miles S, Smallcombe N et al. BMC Psychiatry 2014; 14: 317

34. D2R and D3R ( but not 5HTR) affinity predicts effectiveness of antipsychotic in OCD: a mixed model meta-regression analysis on 13 RCTs. Ducasse D et al, 2014 Psychopharmacology (Berl). 2014 Sep;231(18): 3765-70 Effectiveness SMD YBOCS Log Ki D3 Log Ki D2 NB: Studies are small in size and number (N=13), with varied methodologies and entry criteria

35. Does intensive CBT (ERP plus cognitive restructuring) improve severe, refractory OCD? A 24 week naturalistic study of 52 inpatients Follow-up comparisons between consecutive measurements demonstrated significant falls in total Y-BOCS scores from admission to 12 weeks (P<.001) and between the 12-week and 24-week assessments (P<.001)

36. Novel treatment targets in OCD

37. 5-HT, DA, NE Glu Symptoms and cognitive deficits conceptualised as disordered structure, connectivity and function in large-scale neural networks. ArnstenAF, Casey BJ. Biological Psychiatry, 2011 Jun 15

38. Resistant OCD: Small-sized RCTs showing EFFICACY vs. placebo MONOTHERAPY AUGMENTATION Adapted from Fineberg NA, et al., Aust N Z J Psychiatry, 2013

39. Resistant OCD: Small-sized RCTs showing NO EFFICACY vs. placebo MONOTHERAPY + CBT AUGMENTATION

40. ArnstenAF, Casey BJ. Biological Psychiatry, 2011 Jun 15. PMID: 21640860 In OCRD, convergent evidence suggests insufficient top-down control in pre-frontal loops coupled with excess habit generation in dorsal striatum

41. Somatic treatments in highly refractory OCD ECT: Insufficient evidence to recommend ECT for OCD, given potential associated risks (APA Practice Guidelines on OCD; Koran et al 2007) . rTMS:RCTs (Mantovaniet al., 2010; Gomes et al., 2012) and a meta-analysis including 282 subjects (Berlim et al 2013) suggest promising results for OFC/SMA in comparison to sham rTMS. Though promising, rTMS remains experimental. DBS: stimulating ventral striatum/ventral capsule or sub-thalamic nucleus may produce therapeutic effects by modulating the cortico-striatal neurocircuitry that is widely proposed to mediate OCD (Bourne et al 2012). Though promising, DBS remains experimental. Ablative neurosurgery: (ant. cingulotomy, ant. capsulotomy) remains the last resort for very severely ill patients who do not respond to expert delivered trials of pharmacotherapy and CBT of optimal dosage/content, duration, and mode of delivery as assessed by experienced experts in specialty treatments for OCD. (Lopez AC et al JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.1193).

42. RCTs OF rTMS IN RESISTANT OCD Pooled Hedges' g for pre-post Y-BOCS = 0.59 (p = 0.006). N=10; n=282. Response rates = 35% and 13% for active and sham rTMS, respectively (OR = 3.4, p = 0.002). Non-DLPFC targets (OFC, SMA) the most promising on subgroup analysis BUT Studies are small with differing sample characteristics, duration, stimulation site, frequency etc Berlim et al., Journal of Psychiatry Research 2013

43. Conclusions • Treatment effect on SRI partial and dose and time dependent • Long-term SSRI protects against relapse • Combining SSRI + ERP may confer added benefit • Limitations of existing treatment • Novel strategies required • Outcome predictors? • Circuitries? • New compounds? • CRT/Habit-reversal psychotherapy? • Brain Stimulation?

44. THANK YOU

45. COMPARATIVE RCTs OF rTMS IN RESISTANT OCD Excludes studies of rTMS exclusively targetting the DLPFC

46. Cognitive remediation therapy (CRT); a role in OCRD? Developed for ED, CRT targets attention to detail and set-shifting, encourages flexible behaviour, motivation and perceived ability to change. • In ED, CRT improved QoL and dropout rates when combined with CBT. Cognitive inflexibility predicted a better response to CRT. Dingemans AE et al.,Psychother Psychosom 2014. • In OCD, CRT improved OC symptoms as well as executive skills and cognitive flexibility in pilot studies. Buhlmann U et al, Psychiatry Res.2006. Park HS et al., Psychiatry Clin Neurosci.2006 Individual CRT maybe a beneficial adjunct to TAU in disorders characterized by cognitive inflexibility - or possibly excessive habit

47. Antipsychotic Augmentation in Treatment-Resistant OCDDoldM et al., Int J Neuropsychopharmacol2015 Pooled Hedges’s g for pre-post Y-BOCS = -0.64, 95% CI -0.87 to -0.41; P = <.01; N = 14, n = 478 Response rates: 29.8% vs. 12.5%; RR = 1.98, 95% CI: 1.34 to 2.92; P = <.01; N = 14, n = 491