1. Long-term effectiveness and cost- effectiveness of cognitive behavioural therapy for treatment resistant depression in primary care A follow-up of the CoBalT trial Chris Williams on behalf of the CoBalt Trial Team led by Nicola Wiles, Bristol

2. Background Cognitive behavioural therapy (CBT) is an effective treatment for depression New episodes Severe and chronic depression Non-responders to antidepressant medication (CoBalT: 12 month follow-up) CBT teaches patients skills to help them better manage their mood Potential for benefit beyond end of therap y Little evidence of long-term effectiveness Most trial outcomes 6-12 months and many small (n<75) CBT for relapse prevention – benefits only lost after 4 years Cost-effectiveness data also lacking

3. Research Objectives Amongst primary care patients with treatment resistant depression: is CBT (+ usual care that includes pharmacotherapy) effective in reducing depressive symptoms and improving quality of life over the long-term (approximately 4 yrs), compared with usual care alone? is this strategy cost-effective?

4. CoBalT trial and inclusion in long-term follow-up UK multi-centre trial: 73 general practices (Bristol, Exeter and Glasgow) Eligible patients 18-75 years Adhered to adequate dose of antidepressant medication for at least 6 weeks Significant depressive symptoms (Beck Depression Inventory score ≥ 14 and met ICD-10 criteria for depression) Randomised (n = 469) 12-18 sessions of individual face-to-face CBT in addition to usual care (incl. antidepressants) Continue with usual care from their family doctor Eligible for long-term follow-up (n = 430) Given consent to be randomised into CoBalT Had not withdrawn from the study by 12 months Given written informed consent indicating that they were willing to be re-contacted

5. Study Outline: Follow-up of participants Contacted all practices ◦died ◦not appropriate to contact (excluded) ◦moved – new address given or traced Questionnaire mailing ◦Additional information for economic evaluation gathered by telephone ◦Double check of data from primary care medical records for random sample (n=50)

6. Outcomes Main (primary) outcome : Beck Depression Inventory (BDI-II) score Secondary outcomes: Response ◦At least 50% reduction in symptoms compared to baseline Remission of symptoms ◦BDI-II score of < 10 Percentage reduction in BDI-II score PHQ-9 Anxiety GAD-7 Quality of Life (SF-12)

7. Response to long-term mailing Eligible to take part in long-term follow-up study n = 430 Deceased n = 3 Potential participants (at original/new address) n = 396 Stage 1: Contact with GP practices Excluded by GP n = 10 Unable to trace n = 21 Stage 2: Mailing Completed Questionnaire n = 275 (69%) Declined n = 27 (7%) No response n = 94 (24%) Full-length n = 249 Short version n = 26 Target FU = 60% of 430 Achieved = 64%

8. CONSORT Randomised N = 469 CBT (+ UC) n = 234 Usual care (UC) n = 235 3 month follow-up (94%) Allocation 6 month follow-up (90%) Followed up n = 222Followed up n = 219 Followed up n = 209Followed up n = 213 9 month follow-up (81%) 12 month follow-up (84%) Followed up n = 188Followed up n = 191 Followed up n = 198 46 month follow-up (59%) CBT group: 64% UC group: 54% Followed up n = 149 Completed BDI-II n = 136 Completed PHQ-9 n = 148 Died n = 3 Excluded n = 3 Withdrew by 12mths n = 17 No consent to FU n = 2 Unable to trace n = 10 Declined contact n = 7 Non response n = 43 Followed up n = 126 Completed BDI-II n = 112 Completed PHQ-9 n = 126 Died n = 2 Excluded n = 7 Withdrew by 12mths n = 15 No consent to FU n = 3 Unable to trace n = 11 Declined contact n = 20 Non response n = 51

9. Length of follow-up and time since end of therapy Follow-up: median: 45.5 months since randomisation [IQR: 42.5, 51.1] Range: 38.4, 61.6 months For those who had at least 12 sessions of CBT (n = 105) average 39.7 months (SD 5.2) since end of therapy

10. Baseline characteristics of CoBalT participants BDI-II score (mean): 30.9 (severe range) Duration of current episode of depression (>2 years): 59% ICD-10 severe depressive episode: 24% Physical and psychological co-morbidity common Secondary diagnosis of an anxiety disorder: 75% At follow-up musculoskeletal problems: n =115 high blood pressure: n = 53 Asthma/chest problems: n = 48 Diabetes: n = 34

11. Psychological Therapy since 12 month follow-up Intervention (n=149) Usual care (n=126) Difference(95%CI) n%n% Used any computerised or internet based CBT package 21.3%32.4%-1.0%(-4.3%, 2.2%) Any counselling or 'talking therapy' 3120.8%3427.0%-6.2%(-16.3%, 3.9%) At least one session of CBT32.0%1411.1%-9.1%(-15.0%, -3.2%) At least six sessions of CBT10.7%97.1%-6.5%(-11.1%, -1.8%) At least twelve sessions of CBT10.7%43.2%-2.5%(-5.8%, 0.8%)

12. Means and differences in mean BDI-II scores over 46 months 6 month follow-up12 month follow-up nMean(SD)nMean(SD) Intervention20618.9(14.2)19717.0(14.0) Usual care21324.5(13.1)19821.7(12.9) Total N419395 n Difference in means* 95%CIp value 6 month follow-up 419 -5.7(-7.9, -3.4) 12 month follow-up 395 -4.9(-7.3, -2.6) *adjusted for design variables (incl. baseline BDI score) & month of follow-up 46 month follow-up nMean(SD) 13619.2(13.8) 11223.4(13.2) 248 46 month follow-up248-3.6(-6.6, -0.6) Repeated measures 1062 -4.7(-6.4, -3.0)<0.001

13. ‘Response’ over 46 months (50% reduction) 6 month follow-up12 month follow-up Nn%Nn% Intervention20695(46.1)197109(55.3) Usual care21346(21.6)19862(31.3) Total N419395 n OR*95%CIp value 6 month follow-up 419 3.24(2.08, 5.03) 12 month follow-up 395 2.76(1.81, 4.20) *adjusted for design variables (incl. baseline BDI-II score) & month of follow-up 46 month follow-up nn% 13659(43.4) 11230(26.8) 248 46 month follow-up2482.09(1.19, 3.67) Repeated measures 1062 2.65(1.97, 3.55)<0.001

14. Remission (BDI-II<10) over 46 months 6 month follow-up12 month follow-up Nn%Nn% Intervention20657(27.7)19778(39.6) Usual care21332(15.0)19836(18.2) Total N419395 n OR*95%CIp value 6 month follow-up 419 2.27(1.37, 3.77) 12 month follow-up 395 3.27(2.02, 5.31) *adjusted for design variables (incl. baseline BDI score) & month of follow-up 46 month follow-up Nn% 13638(27.9) 11220(17.9) 248 46 month follow-up2481.77(0.93, 3.39) Repeated measures 1062 2.49(1.84, 3.38)<0.001

15. Costs to the Health Service (NHS) and PSS Perspective – Health Service (NHS) and personal social services (PSS) Use of health care services all primary and community care GP, nurse, other HCP, community etc. antidepressant medication hospital (mental health-related) A&E, outpatient visits, inpatient stays Personal social services social worker, day centres, home help Data from postal questionnaire and medical records (random sample)

16. Mean annual cost per participant Cost (£) US $1534 US $768

17. Adjusted annual QALY gain 0.052 Equivalent to an extra 19 days in full health per year Annual QALY gain over 46 months

18. Results: Annual cost per QALY gain Intervention n=116 Usual Care n=98 Difference Health Service (NHS) and PSS cost £542£604-£62 Intervention£343- Total cost£885£604£281 QALYs0.5960.5440.052 Cost per QALY gain=£281/0.052 = £5,374

19. Summary CBT as an adjunct to usual care is an effective treatment for primary care patients with TRD over the long-term reduced depressive symptoms improved quality of life average of 40 months after the end of therapy and Good value for money from the perspective of a healthcare provider

20. Implications for clinical practice This is an effective intervention for a population of people not responding to antidepressants alone Clinicians need to discuss referral for CBT with all those for whom antidepressants are not effective Initiatives to improve access to psychological treatments have (mainly) increased provision of ‘low intensity’ treatments Many patients receive less than the 12-18 sessions of ‘high-intensity’ CBT as delivered in CoBalT Translating findings into patient benefit will require more investment future innovation how to best use technology to increase efficiency in delivery and maintain these benefits

21. Conflict of interest declaration CW is President of BABCP- the lead body for CBT in the UK, and a CBT researcher and trainer. He is also author of a range of CBT-based resources that address anxiety, depression and other disorders. These are available commercially as books, cCBT products, and classes. He receives royalty, and is shareholder and director of a company that commercialises these resources.