Treatment of Major Depression In Adolescents. Ian M Goodyer OBE MD FRCPsych FMedSci University of Cambridge

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1 Treatment of Major Depression In Adolescents Ian M Goodyer OBE MD FRCPsych FMedSci University of Cambridge

2 DSM: Unipolar Major Depression Irritability/anger Depressed mood Anhedonia Cognitive disturbance Self-perceptions Suicide mood + 4 (or more) Sleep disturbance others Weight/appetite disturbance Psychomotor disturbance Fatigue, lack of energy, tiredness Psychotic features 3-4 symptoms (mild) ; 5-6 symptoms (moderate) ; 7+ symptoms (severe) plus impairment

3 Randomised Controlled Trials: Treatment of Adolescent depression Study (TADS):2004. Adolescent Depression and Psychotherapy Trial (ADAPT): Treatment of Resistant Depression in Adolescents (TORDIA): Improving mood with psychotherapy and cognitive therapy (IMPACT):2017.

4 TADS:RCT Design 2084 screened 1008 interviewed 549 Baseline assessment Fluoxetine + CBT 107 (92) Fluoxetine Only N=109 (91) CBT Only N=111 (87) Medication Placebo N=112 (89) March et al JAMA 2004;292:

5 TADS: Adjusted Mean (SE) Scale Scores March et al JAMA 2004;292:

6 % of patients in remission by treatment group comb flux CBT Pill placebo % response CDRS-R N 439 adolescents with MD, 12 week outcomes

7 TADS Outcomes 1 Year of Naturalistic Follow-Up March J et al American Journal of Psychiatry 2009; 166:

8 TADS: Summary Treatment with fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment advised for major depression in adolescents March JS et al Arch Gen Psychiatry (10):

9 ADAPT: Adolescent Depression and Psychotherapy Trial 510 NHS outpatients assessed 261 excluded (109 not depressed, 48 DNA, 39 drug concerns, 38 refused, 6 too ill, 1 previous treatment, 20 other) 85 bypassed BII (34 in CAMHS, 29 on SSRI, 22 urgent meds required) 249: 164 had a brief psychosocial intervention 2/3 sessions 34 improved, 4 refused 126 BII non-responders 211 research interview 104 specialist clinical care + Fluoxetine 20mg-60mg 208 randomised 2 refused, 1 improved 104 specialist clinical care + Fluoxetine 20mg-60mg+CBT

10 Clinician Rated Depression Scale CDRS-R Weeks SSRI CBT+SSRI Average treatment effect = 1.43, 95% CI-0.71, +3.52, p = 0.19 Goodyer et el BMJ Jul 21;335(7611):142

11 Self Report Depression Symptoms- MFQ Weeks SSRI CBT+SSRI Average treatment effect = 1. 27, 95% CI-1.26, +3.80, p = 0.32 Goodyer et el BMJ Jul 21;335(7611):142

12 Clinical Global Impression Over Study Period weeks Maximum clinical benefits may not be seen until 28 weeks after treatment begins Goodyer IM et al (2008) Health Technol Assess. 12(14):iii-iv, ix-60

13 ADAPT Summary No added value for CBT in treating unipolar depression over and above that of specialist clinical care and fluoxetine. Overall treatment effectiveness at 28 weeks around 60%. Treatment resistance 10%-20% Patients in the Trial were moderate-severely ill. Not an effectiveness trial for fluoxetine

14 Treatment resistant depressions Brent DA et al: The TORDIA Study JAMA February 27; 299(8):

15 TORDIA: RCT Design 334 treatment resistant patients no response to 12 weeks Different SSRI paroxetine, citalopram, fluoxetine, mg N=85 Different SSRI + CBT N=83 Venlafaxine ( mg) N=83 Venlafaxine + CBT N=83

16 Clinical response 12 weeks post new treatment CGI % New SSRI NS+CBT Venlaf Ven + CBT entry ; N=223 completion; ITT analysis (LR): CBT p=0.03 qualified by a site x CBT interaction p= 0.003

17 TORDIA: Clinical response 72 weeks post new treatment Response apparent by 6 weeks. ~30% - no remission and 25% relapse. Vitiello B, et al J Clin Psychiatry Mar;72(3):388-96

18 Tordia Summary Treatment resistance to an SSRI can respond to combination therapy such as another SSRI +CBT. Venlafaxine not a medication of choice. Response by about 6 weeks with little gain from then.

19 Treatment of Depressed Adolescents Severe depressions occur in 1%-2% Non remission by 12 months ~30% Treatment non response rate ~ 10%-20% No robust clinical or psychosocial predictors of treatment response, resistance or recurrence risk Less good response in those with a history of childhood maltreatment, mild mania at presentation, current depression in mothers.

20 Improving Mood With Psychoanalytic Psychotherapy And Cognitive Behaviour Therapy: THE IMPACT STUDY The IMPACT Consortium Ian M Goodyer Chief Investigator University of Cambridge

21 What were our objectives Whether psychological treatment was good enough to maintain reduced depressive symptoms 12 months after treatment. If so would this be cost effective as well as clinically effective. Would specialist treatment of CBT be superior to short term psychoanalytic therapy (STPP) in achieving the objectives. Would CBT and/or STPP be superior to the reference treatment of brief psychosocial intervention (BPI)

22 Principles of Brief Psychosocial Intervention Collaborative care. Information exchange. Selected behavioural activation Rehabilitation and recovery. Improving and maintaining mental and physical hygiene, engaging in pleasurable activities, maintaining schoolwork and peer relations and diminishing solitariness.

23 Short Term Psychoanalytic Psychotherapy Aims to increase the coherence of the young person s mental models of attachment relationships Thereby improve capacity for affect regulation and thereby the making and maintaining of positive relationships. Techniques based on the relationship with the therapist. Exploration of the 'internal world experiences: current preoccupations, memories, day-dreams, nocturnal dreams and phantasies. Attending to unconscious phenomena is specific to psychoanalytic psychotherapy. The patient s experience of the therapist receiving, holding in mind, and thinking about projected material is a central feature of the therapy.

24 Cognitive Behaviour Therapy Cognitive Behaviour Therapy (CBT) is based on the classical form originally developed for adults with depression. Pervasive information processing biases which increase vulnerability to depression in the context of environmental stress. These biases maintain and amplify core mood symptoms of depression. The focus of CBT is to identify the information processing biases that maintain depression and low mood and to amend these through a process of collaborative empiricism between the therapist and client. CBT was adapted for this study by increasing focus on engagement, use of behavioural techniques and parental involvement,

25 Therapy Duration BPI : 12 sessions, (8 individual + 4 family/parent), over 20 weeks. STPP: 28 sessions (+ 7 parent sessions) over 28 weeks. CBT: Up to 20 sessions over 30 weeks (parent involvement if indicated).

26 Professionals Delivering Therapy BPI : Child and Adolescent Psychiatrists (80%) including Fellows and Child and Adolescent Mental Health Nurses (20%). CBT: Clinical psychologists or other professionals with post qualification training in CBT STPP: Child/Adolescent Psychotherapists and trainees in their last year.

27 Design Reassessments At the nominal 6,12,36 52 and 86 week MDD N=470 Randomised to One of 3 Treatment arms MR-IMPACT ME-IMPACT Genetic Assay Cognitive Assay Cortisol Assay BPI 12 sessions/20 weeks N= 155 End of study = 132 Cognitive Behaviour Therapy 20 sessions/20 weeks N=154 End of study = 130 STPP 28 sessions /30 weeks N=156 End of study = 119 Goodyer IM et al Trials Jul 13;12:175

28 Participant Characteristics Characteristic BPI (n=155) Freq. (%) CBT (n=154) Freq. (%) STPP (n=156) Freq. (%) Mean Age in yrs 15.6 (1.4) 15.6 (1.4) 15.6 (1.5) Females 115 (74) 114 (74) 119 (76) White 121 (82) 131 (86) 130 (86) SSRI before trial entry 29 (19) 32 (21) 28 (18) Mean (MFQ) depression score 46.2(10.6) 46.2(10.3) 45.4(10.8) Interviewer rated symptoms Psychosocial impairment Scale 8.4 (2.5) 8.7 (2.3) 3. (2.5) 18.9(6.0) 18.4(6.0) 18.3(6.3)

29 Participant Characteristics at Baseline Characteristic BPI (n=155) Freq. (%) CBT (n=154) Freq. (%) STPP (n=156) Freq. (%) Recent Self harm Lifetime Self Harm Recent Suicidal Attempts Lifetime Suicide Attempts Comorbidity (1+) Disruptive Behaviour Disorders 26(17) 25(16) 34(22) 87(56) 75(49) 84(54) 3(2) 2(1) 7(5) 57(37) 48(31) 55(35) 71(46) 80(52) 74(47) 20 (13) 20 (13) 16 (10)

30 Median Time (weeks)from Randomisation To Starting Therapy BPI CBT STPP Region Median (95% c.i.) Median (95% c.i.) Median (95% CI) East Anglia 4.3 (3.3 to 5.6) 7.3 (5.1 to 10.1) 4.7 (3.9 to 5.7) North London 2.9 (2.0 to 3.7) 4.0 (3.0 to 4.7) 3.9 (2.7 to 4.4) North West 4.0 (3.1 to 4.6) 4.0 (2.9 to 4.9) 4.4 (3.1 to 6.1)

31 Duration Of Therapy In Weeks Treatment Med Max Mean SD N BPI CBT STPP Number of therapy sessions attended BPI CBT STPP Median (IQR) a 6 (4,11) 9 (5,14) 11 (5,23) Planned

32 Treatment differentiation BPI CBT STTP CB Domain PI Domain Graphs by Trial Arm Measures taken by 2 raters independently listening to a fixed time series from 279 audiotapes randomly selected from the 3 arms stratified by age, centre and phase of therapy (early,2-4, later >4 sessions). Measured using the CPPS reliability = 0.82 & 0.8 per scale. CBT > STPP on (CB) sub-scale score (95% CI 1 73 to 2 09,p <0 0001). STPP > CBT mean on (PI) sub-scale score (95% CI 1 01 to 1 3, p <0 0001). BPI < CBT on CB sub-scale (mean diff. = -0 93, 95% CI to -0 75, p<0 0001) BPI< STPP on the PI sub-scale (mean diff. =-1 30, 95% CI to -1 11, p<0 0001). 81% of BPI, 80% of STPP and 74% of CBT sessions met criteria

33 Prevalence of Depressive Symptoms At Entry BPI CBT STPP

34 Depression Scores Over The Study Mean MFQ Score End of treatment Baseline 6 week 12 week 36 week 52 week 86 week BPI CBT STPP

35 Depression Sum Scores Over The Study Score ns Weeks BPI CBT STPP

36 Individual Differences in Symptom Change Average Symptom Change over time Individual Symptom Change over time MFQ Weeks MFQ Weeks Female Male Individual differences in symptom change is evident

37 Suicide Attempts & NSSI Baseline Suic Atmpt NSSI No between treatment group differences

38 SSRI Prescribing Over The Study BPI CBT STPP <36 wk >=36 wk

39 Cost Effectiveness in UK Pounds UK Pounds BPI (n=90) CBT (n=92) STPP (n=91) 0 Treatment Follow Up Total

40 Summary There are no superiority effects of CBT over STP. All 3 treatments are statistically as effective as each other. All three therapies show reduced symptoms a year after treatment. BPI offers an additional patient choice for psychological therapy. No cost effectiveness advantage between the 3 treatment groups.

41 Causality Cannot fully discount the possibility that all the observed decline in symptoms and improvement in well-being was a function of time. Fluoxetine may accelerate the decline in symptoms across the cohort independent of psychological treatment. The absence of a no treatment control group limits the assertion that any therapy was causally effective.

42 Clinical Assessment, Treatment and Monitoring A B Assess Predictors/Moderators of Likely Treatment Response 1.History of childhood maltreatment. 2. Current depression in a parent. 3. Comorbidities at presentation 4. Expectations of treatment 5. Compliance and response to past treatments. Confirm Clinically Depressed Ascertain diagnosis, obtain self report symptom scores E Treatment Progress 1. Some improvements with any treatment by 6 weeks weeks expect remission in about 50% of cases. 3. By weeks expect remission in a further 20-30%. 4. Expect 10%-20% drop out by 12 weeks. 5. Expect 10%-20% treatment resistance. 6. No improvement by 6-12 weeks- repeat box D. Collaborative Discussion 1.Enter collaborative discussion with patient and family about depression and treatment options. 2. Explain about depression and answer all relevant questions. 3. Explain treatment options including associated risks. 4. Get a planned therapeutics protocol C agreed with adolescent. 5. Offer a timeline for first line treatment. Therapeutic Activation 1.First line monotherapy can be psychological. 2.Can be combination psychosocial + fluoxetine. 3. Complex cases may need combination therapy with fluoxetine as apriority + psychosocial treatment. D Therapeutic review : 3-4 weeks 1. Is patient allied with therapist and treatment 2. Assess for side effects : consider treatment reluctance, non-compliance and nonattendance as possible signs of adverse effects to treatment. 3. Further collaborative discussion about progress. 4. Continue or revisit current treatment plan.

43 Future Research Treatment response. The maintenance of positive effects. Non-response. Whether BPI is of utility in community and primary care settings. Fluoxetine effects.

44 Acknowledgements This research was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number: 06/05/01). The views expressed in this publication are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS, or the Department of Health. The ongoing research is funded by the Wellcome Trust, Royal Society and Friends of Peterhouse.