Transcript Treatment of Adolescent Depression

Treatment of Adolescent
Depression
Dr Paul Wilkinson
University Lecturer and Honorary Consultant in Child
and Adolescent Psychiatry
NICE Fellow
IPT Supervisor
University of Cambridge / CPFT
• Depression is important
• 15% incidence during childhood/adolescence
• Great functional impairment, suicide
• Variable prognosis
• Treatable
Contents
• 1. Specific Treatments for Depression
– Physical
– Psychological
– Social
– Combination treatments
– Specialist clinical care
• 2. What Should We Actually Do?
1. Specific Treatments for
Depression
Physical
Psychological
Social
1a Physical
Physical Treatments
• Medication
– Therapeutic medication (antidepressants)
– Stop depressogenic medication
• Good diet
• Exercise
• Sleep hygiene
• ECT in extreme cases
Antidepressants and Adolescent
Depression
Tricyclics
• Minimal effectiveness (Cochrane review)
• A lot of side-effects
• Suicidality effects not well-studied
• Only used as 3rd/4th line by specialists
Selective Serotonin Reuptake Inhibitors
• Bridge meta-analysis, 2007:
– Response rate 61% vs 50%
• Number needed to treat: 10 (95% CI, 7-15)
– Standardised mean difference: 0.25
• Hetrick meta-analysis, 2007:
– Relative risk of ‘remission’ = 1.31 (95% CI 1.17-1.41)
SSRIs – all the same thing?
• Great heterogeneity between SSRIs
– Hetrick: I2 = 57.5%, p = 0.02
– Minimal heterogeneity within each class of SSRI
• ?Due to different pharmacological actions of
SSRIs
• ?Due to systematic methodological
differences between studies
– Eg age, bias
n
CDRS-R Drug vs
Placebo (CI)
Response RR vs
placebo (CI)
Fluoxetine
527
5.34 (3.38 – 7.31)
1.86 (1.49 – 2.32)
Paroxetine
646
0.96 (-0.34 – 2.26)
1.09 (0.95 – 1.26)
Sertraline
364
3.56 (0.42 – 6.69)
1.17 (1.00 – 1.36)
Citalopram/
Escitalopram
435
2.13 (-0.69 – 4.95)
1.30 (1.02 – 1.67)
• One RCT since, on escitalopram
– N=312, difference in CDRS-R = 3.3 (p= 0.022)
– Would make meta-analysis ‘significant’ for citalopram/escitalopram
Clinical Significance
• Fluoxetine-placebo difference in CDRS-R = 5.34
– Scale range = 17 – 113
– Not impressive!
• Relative risk of response = 1.86
• Difference in response rates (TADS) = 26%, NNT=4
• 61% vs 35%
• BUT, studies excluded severe depression/suicidality
Response
SSRI
Placebo
Depression Severity
Response
SSRI
Placebo
Depression Severity
Placebo Effect
• Telling depressed patients they are taking a pill
that might get them better will instil hope
– And can lead to recovery in itself
• ? SSRI-no treatment difference greater than SSRIplabebo difference (D Nutt)
• Eg (response rates):
– SSRI 70%
– Placebo 55%
– No treatment 20%
Other Antidepressants
• Venlaxine
– 2 RCTs, 182 in venlafaxine group
– No evidence of efficacy
• Mirtazepine
– 2 RCTs, 259 patients
– No evidence of efficacy
Do Antidepressants Work?
Conclusions
• Good evidence for fluoxetine
– Limited clinical significance
?Due to mild/moderate depression only
• Limited evidence for other antidepressants
– Despite similar sample size
• Would other antidepressants be significantly
better than placebo for severe depression?
Do Antidepressants Harm?
Physical Side-Effects
• More common in antidepressants than
placebo
• For SSRIs, often mild, transient
– Nausea, diarrhoea
– Tiredness
– Headache
– Impotence
Psychiatric Adverse Events
• Anecdotal reports: teenagers put on SSRIs changed
dramatically
– Self-harm / suicidality
– Aggression
• Could be because depressed teenagers do get
suicidal and aggressive
• Need placebo-controlled studies to see if an actual
effect of SSRI
Meta-Analyses
• Bridge et al (JAMA, 2007):
– Suicidal ideation/attempt (depression studies):
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New-generation antidepressant: 3%
Placebo: 2%
Difference (95% CI): 1% (-0.1% – 2%), p = 0.08
Number needed to harm = 112
– Anxiety disorder studies: 1% vs 0.2%, p = 0.2
– OCD studies: 1% vs 0.5%, p = 0.6
TADS
• 12 weeks (JAMA, 2004):
– Suicidality reduced in all groups
– Fluoxetine not significantly different to plac
– Significantly more psychiatric adverse events in
fluoxetine (21%)
– than placebo (10%) or FLU/CBT (15%)
• 36 weeks (Arch Gen Psych, 2007):
– Significant suicidality in:
• FLU: 11%; CBT: 5%; FLU + CBT: 5%
• Pairwise p < 0.05 only for FLU vs CBT
Problems With RCTs and Suicidality
• Bias may make antidepressants seem better
and safer than they really are
• Retrospective reporting of suicidality
• No actual suicides in the RCTs
• Hard to generalise results as trial patients:
– Less severe depression
– Less co-morbidity
– Suicidal adolescents excluded
Observational Studies 1
• Decrease in youth suicides as SSRI use
increased
• Increased suicides as SSRI use decreased after
2003
• Only in Netherlands/USA. No effect on
suicides in UK
• Gibbons, 2007
• Wheeler, 2008
Observational Studies 2
• Lower suicide rates in areas with higher SSRI use
• Suicidality much higher before than after starting
SSRI
• Suicide rates higher before starting treatment than
after
•
Simon, BMJ, 2008
SSRIs and Harm - Conclusions
• In depressed patients with low suicidality:
– SSRIs probably cause a small number (1-2%) to
develop increased suicidality
• Observational research suggests that SSRIs
may reduce popn suicide rates
– More people have reduced than increased
suicidality
– ? by the effects of treating depression
1b Psychological Therapy
Cognitive-Behavioural Therapy
• Improve dysfunctional thoughts and
behaviours
Cognitive-Behavioural Therapy
• Improve dysfunctional thoughts and
behaviours
Emotions
Thoughts
Behaviours
Physiological
symptoms
CBT - Evidence
• Early RCTs showed good evidence for
effectiveness compared with control
• Later meta-analyses showed smaller CBTcontrol differences
– Eg Klein et al, JAACAP 2007
– Standardised Mean Difference = 0.34
(moderate = 0.4/0.5)
– P = 0.01
Why Less Effective Now?
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Newer studies less biased
smd if CONSORT > 17
smd if active control
smd if intention-to-treat
= 0.14, p < 0.01
= 0.11, p < 0.01
= 0.26, p < 0.05
• Strong influence from one study, TADS
– No difference between CBT and placebo
• A fair comparator?
• More severe depression
Who is CBT Best For?
• Earlier studies: CBT better for mild depression
• TADS (Curry et al, JAACAP 2006)
– CBT better than placebo (and = to FLU/CBT)
– in adolescents from high income families
• ??? a proxy for intelligence / level of education
Interpersonal Psychotherapy
• Recommended by NICE as a 1st line treatment
for adolescent depression
• Short-term 1:1 psychological therapy
• Designed for depression
Cognitive
Behavioural
Therapy
Core Beliefs
Dysfunctional Conditional
Assumptions
Negative
Automatic
Thoughts
Behaviours
Emotions
Physiological
Symptoms
Interpersonal Therapy
Emotions / Affect
Interpersonal
Relationships
Techniques
• Use specific strategies to improve (or end)
relationships
• Help with the grief of lost relationships
– And help transition to new life
• Recognise emotions/affect and their effects on
relationships
• This can be enough to get remission
– Depression multifactorial
Interpersonal Inventory
• Intense exploration of current and past
relationships
• Leads to a clear IP formulation and focus area
• Unique to IPT
Evidence for Adolescent IPT
• 3 RCTs – all show IPT better than control
• Mufson et al, Arch Gen Psych 2004
– Good methodology: intention-to-treat
– Active control (school counsellors)
– smd = 0.5, p = 0.04
IPT vs CBT
• IPT simpler than CBT: better or worse?
• No good comparisons in adolescents
• Most recent meta-analysis in adults
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7 trials, 741 participants
No significant difference
Poor methodology in primary studies
Jakobsen et al, 2011
Other Psychotherapies
• Family Therapy
– No better than control treatment in 4 RCTs
– Probably a necessary adjunct to individual therapy
in some families
• Psychodynamic therapy
– Equivalent to family therapy in 1 RCT
– Being tested in new IMPACT study
• No RCTs for other therapies, counselling
Other Psychotherapies 2
• But we need something for the 30-40% of
patients who don’t respond to CBT
• Medication/IPT (if available) may help some
• What about the others?
– May need a less directive therapy
– May not verbalise well and need a creative therapy
– May have deeper attachment issues, needing dynamic
therapy
– No evidence does not mean evidence they don’t work
1c Social Treatment
• Why is the patient depressed now?
• Make a proper formulation
• Physical/psychological/social factors
• Address modifiable social factors
– Bullying
– Needing extra help at school
– Housing
– Abuse
– Benefits
1d Combination / Comparison of
Treatments
Antidepressants vs Psychological
Treatment
• 2 studies compare SSRI vs CBT monotherapy
• TADS: fluoxetine superior to CBT
– N = 221
– Difference in CDRS = 6 (p = 0.01)
• Melvin et al, CBT superior to sertraline
– N < 50
– OR = 6.9 (CI: 1.1 – 41.8)
– CBT better than combined treatment (ns)
CBT Plus Medication
• TADS showed CBT plus fluoxetine better than
fluoxetine alone
– Only for mild/moderate depression
• TORDIA (treatment resistant depression)
– Switch to CBT plus new med better than new med
alone on some outcome measures
• Not replicated in other studies
• No sig difference in meta-analysis
– Dubicka et al, 2010
SSRIs, CBT and Suicidality
• TADS, ADAPT, TORDIA, Melvin et al, Clarke et al
• Tested combined CBT/SSRI vs SSRI
• None found combination treatment significantly
reduced suicide attempts compared to SSRI alone
• Meta-analysis (Dubicka et al, 2010):
– No difference in suicidality
• Suicidality reduced with fluoxetine treatment
– With or without CBT
1e Specialist Clinical Care
ADAPT Trial
• RCT of adolescent depression:
– SSRI vs SSRI plus CBT
• All cases got ‘specialist clinical care’
• No difference in outcome between arms
– ie SSRI + CBT = SSRI + SSC
• Unlike TADS
– No SCC in fluoxetine only arm
• Maybe SCC is very effective
• What is SCC?
SCC
• SCC manualised for IMPACT Trial (Raph Kelvin)
– SCC vs CBT vs STPP
• Deliverable by all CAMHS trained professionals
• Many of us do it already
SCC Components
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Psychoeducation
Good formulation
Action-oriented
Goal-focused
Attention to negative life events
Encouragement to take part in positive
activities
• Liaison with other agencies (eg schools)
SCC – Should we Use It?
• Cheaper in the short-term than CBT/IPT
• IMPACT will tell us if it is an effective
monotherapy
• Common sense tells us we should use the
principles of it alongside other therapies, in
particular medication
2 What Should We Use?
NICE Guidelines, 2005
• Moderate-severe adolescent depression
• First-line treatment – either:
– CBT
– IPT
– Family therapy
• Second-line – either:
– Additional/alternative psychological therapy
– Antidepressants
• Fluoxetine 1st line; citalopram/sertraline 2nd line
• Should be given alongside specific psychological therapy (eg CBT)
Personal Opinion
• These are out-of-date
• They neglect patient choice
• They ignore poor availability of treatment
• TADS: fluoxetine more effective than CBT
• SSRIs cause side-effects; so does psychological
therapy
• Fluoxetine plus CBT not better than fluoxetine
plus SCC
• Should we be making the choice of CBT over
medication for our patients?
• I offer informed choice: SSRI or specific
psychological therapy
– Inform families of side-effects and waiting-lists
• And all should get SCC as part of therapy
What Works for Whom?
• Can we tailor treatment for specific patients?
• Virtually no evidence
• CBT more effective for moderate than severe
depression
• CBT works better for rich families
• SSRI-placebo difference greater for moderate
than mild depression in adults
• (Much) more research needed!
CONCLUSIONS
• The following are effective in some depressed patients:
– Fluoxetine
– CBT
– IPT
• Common sense tells us we should use SCC as part of
the treatment for all patients
• Antidepressants cause side-effects
– Make some people more suicidal
– Make more people less suicidal
• We need better studies to help us to decide which
treatment to give individual patients
– Until then, let’s let our patients and their families choose
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References
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Brent, D., Emslie, G., Clarke, G., Wagner, K. D., Asarnow, J. R., Keller, M., . . . Zelazny, J. (2008). Switching to
another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRIresistant depression: the TORDIA randomized controlled trial. Jama, 299(8), 901-913.
Curry, J., Rohde, P., Simons, A., Silva, S., Vitiello, B., Kratochvil, C., . . . March, J. (2006). Predictors and
moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad
Child Adolesc Psychiatry, 45(12), 1427-1439.
Dubicka, B., Elvins, R., Roberts, C., Chick, G., Wilkinson, P., & Goodyer, I. (2010). Combined Treatment With
Cognitive Behavioural Therapy In Adolescent Depression: Meta-Analysis. B J Psych, 197(6):433-40.
Goodyer, I., Dubicka, B., Wilkinson, P., Kelvin, R., Roberts, C., Byford, S., . . . Harrington, R. (2007).
Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT). A Randomised Controlled Trial of
SSRIs with and without cognitive behaviour therapy in adolescents with major depression. BMJ,
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Goodyer IM, Tsancheva S, Byford S et al. (2011) Improving Mood with Psychoanalytic and Cognitive
Therapies (IMPACT): A pragmatic effectiveness superiority trial to investigate whether specialised
psychological treatment reduces the risk for relapse in adolescents with moderate to severe unipolar
depression: study protocol for a randomised controlled trial. Trials, 12:175
Klein, J. B., Jacobs, R. H., & Reinecke, M. (2007). Cognitive-Behavioral Therapy for Adolescent Depression:
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March, J., Silva, S., Petrycki, S., Curry, J., Wells, K., Fairbank, J., . . . Severe, J. (2004). Fluoxetine, cognitivebehavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents
With Depression Study (TADS) randomized controlled trial. Jama, 292(7), 807-820.
Melvin, G. A., Tonge, B. J., King, N. J., Heyne, D., Gordon, M. S., & Klimkeit, E. (2006). A comparison of
cognitive-behavioral therapy, sertraline, and their combination for adolescent depression. J Am Acad Child
Adolesc Psychiatry, 45(10), 1151-1161.
Mufson, L., Dorta, K. P., Wickramaratne, P., Nomura, Y., Olfson, M., & Weissman, M. M. (2004). A
randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen
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TADS. (2007). The Treatment for Adolescents With Depression Study (TADS). Long-term Effectiveness and
Safety Outcomes. Archives of General Psychiatry, 64(10), 1132-1144.
Vitiello, B., Emslie, G., clarke, G., Wagner, K. D., Asarnow, J., Keller, M., . . . Brent, D. (2011). Long-Term
Outcome of Adolescent Depression Initially Resistant to Selective Serotonin Reuptake Inhibitor Treatment:
A Follow-Up Study of the TORDIA Sample. Journal of Clinical Psychiatry, 72(3), 388-396.
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Questions
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