Rational Psychopharmacology in Children and Youth Professor Stan Kutcher Dr. David Gardner Dalhousie University, Halifax, NS, Canada CACAP, Toronto, Nov 12 & 13, 2009
Objective Give a [C&A Psychiatrist] a fish and you feed her for a day. Teach a [C&A Psychiatrist] to fish and you feed her for a lifetime. Chinese Proverb
Our objective to improve your ability to use psychotropics in the care of your patients. To do this we need your help.
Outline Thursday: 12 – 1 pm Stan: The Social Context David: The Impressive Size of Effect Discussion Friday: 12 – 1 pm David: Lies, Damn Lies, and Statistics Stan: Discussion
Assessment and monitoring: R.I.P.
Rational Psychopharmacology in Youth: to be or not to be
Brain Teasers Would you take this? Benefit: improves mood transiently Non‐benefit: – Weight gain (long‐term use) – Worsens risk factors for CVD and diabetes (same) – Drug seeking behaviour (cravings) – Anaphylaxis (rare)
Brain Teasers Would you take this? Benefit: improves mood transiently Non‐benefit: – Weight gain (long‐term use) – Worsens risk factors for CVD and diabetes (same) – Drug seeking behaviour (cravings) – Anaphylaxis (rare)
Prescribing Psychotropics in Children & Youth A Comment from the Social Context
What we would like to have Rich and substantial data set of level I evidence pertaining to efficacy; effectiveness; tolerability; safety – easily accessible and with clear consensus on what to use, when to use it and how to use it – for all pediatric mental disorders and significant mental symptoms causing functional impairment PLUS well regulated therapeutics in all domains
What we have • Highly prevalent, chronic mental disorders with substantial morbidity and mortality • Weak to non‐existent level 1 therapeutic knowledge • Hostile “camps”; competing “ideologies”; vested interests; confused public; inflaming media • Unrealistic expectations – 100% effective; 100% tolerable; 100% safe
Medications and Children: Issues • “Vulnerable” population (ethical framework – consent; assent; knowledge; understanding) and social context (family, institution) • Developmental neurobiology • Ecological models of explaining “disturbances” in child behavior (social, family, etc.) • Underdeveloped basic, clinical sciences, translation • Underdeveloped diagnostics
The movie star “expert” “I still think that if you analyze most of the school shootings, its not gun control. Its (psychotropic) drugs at the bottom of it”
» John Travolta (quoted in the International Herald Tribune. Thursday June 21, 2007)
What about the very young? • A number of disabling mental disorders can be diagnosed in the pre‐ school years (eg: Autism; ADHD; psychosis) • Medication treatments may be beneficial for both short and long term outcomes
Clinical Reality – the ethical framework • Any treatment prescribed is framed in a “social contract” between physician and patient • Principle of Beneficence/Principle of Nonmaleficence (benefit:risk) • Third party interest – medications – psychotherapies
Prescribing in an Imperfect World – Rational Therapeutics for “Best Outcomes”
Challenges to Rational Prescribing Physician Factors Overwhelming number of medications Nature and amount of information – lack of evidence + regulatory labeling Adequacy of training Pressure of work
Public Factors Popular demands that are inconsistent with scientific evidence Poor adherence Unrealistic expectations of therapeutic effect Poorly informed about risk:benefit issues
Collaborative, rational drug therapy decision‐making Pharmacopathophysiolic reasoning
Patient preference
Rational Drug Choice
Evidencebased
Experiencebased
Back to Basics • Lets be clear about what we know and how well we know it • Lets use what we know in a manner that is most likely to help and least likely to harm • Lets practice in such a manner as to improve the possibilities of a positive outcome and decrease the possibilities of a negative outcome • Lets be thoughtful, humble and constructively critical Rational Therapeutics
Over to David
Brain Teasers Which Antidepressant is Most Dangerous? Outcome: suicide attempt A. B. C. D.
More than doubles the risk Increases the risk by 136% Increases the risk by 0.15% Leads to a new suicide attempt in 1 person for every 667 treated?
Which Antidepressant is More Dangerous? New suicidality
A. B. C. D.
Antidepressant
0.26%
No antidepressant
0.11%
More than doubles the risk Increases the risk by 136% Increases the risk by 0.15% Leads to a new suicidality in 1 person for every 667 treated?
The Impressive Size of Effect
Q: Are children and youth more/less susceptible to the benefits/harms of psychotropics vs. adults?
A: ?
Effect Size Medications for GAD Hidalgo et al. J Psychopharmacology 2007
The effect size of SSRIs on GAD was 1.38 (SD 0.45, p<0.0001) in studies (k=2) of children and adolescents. In adults, it was 0.39 (SD 0.06, p<0.0001). Rynn et al. Am J Psychiatry 2001: Sertraline for GAD in children. Hamilton Anxiety Rating Scale (Ham-A) Walkup et al. NEJM 200X. Fluvoxamine for anxiety disorders in children and adolsecents. Pediatric anxiety rating scale (PARS).
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85.
Effect size = 1.1
RISPERIDONE IN CHILDREN WITH AUTISM AND SERIOUS BEHAVIORAL PROBLEMS N Engl J Med 2002;347:314‐21.
Turner et al
Publication bias
NEJM Jan 2008
Effect size estimates of published trials (journals) vs. FDA submitted (all) trials
Interpreting Hedge’s g effect size: • 0.2: small clinical effect • 0.5: medium clinical effect • 0.8: large clinical effect
g: Hedge’s g (=difference in means/SDp) Turner et al. NEJM Jan 2008
Effect Size Expressions “Cohen’s d” “Hedges’s g” “Glass’s ∆” Generic form: Effect size =
mean1 – mean2 standard deviation
Cohen’s d: pooled SD Hedges’s g: pooled SD* Glass’s ∆: control group SD * “unbiased estimator of SD”
Interpreting Cohen’s d Effect Size Effect size
Clinical interpretation
0
No effect
0.2
Small clinical effect
Difference in heights of 15 and 16 year old girls
0.5
Medium clinical effect
Difference in heights of 14 and 18 year old girls
Large clinical effect
Difference in heights of 13 and 18 year old girls, or difference in IQ between PhDs and ‘typical college freshmen’
0.8
Lay example Complete overlap; no difference in means
What Professor Cohen Said “The terms ‘small’, ‘medium’, and ‘large’ are relative . . . to each other . . . the definitions are arbitrary . . . these proposed conventions were set forth throughout with much diffidence, qualifications, and invitations not to employ them if possible.” “The values chosen had no more reliable a basis than my own intuition.” Turner & Rosenthal. BMJ Feb 2008
Table:Interpretations of effect sizes Effect Size
Percentage of control group who would be below average person in experimental group
Rank of person in a control group of 25 who would be equivalent to the average person in experimental group
0.0
50%
13
0.1
54%
12
0.2
58%
11
0.3
62%
10
0.4
66%
9
0.5
69%
8
0.6
73%
7
0.7
76%
6
0.8
79%
6
0.9
82%
5
1.0
84%
4
1.2
88%
3
1.4
92%
2
1.6
95%
1
1.8
96%
1
Melatonin for Insomnia in Children with ADHD Weiss MD et al. J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):512-9.
• R, DB, x‐over trial (10 days per phase, 5 day w/o) • 19 children – ADHD – Stimulant‐treated – >60 min initial insomnia
• Interventions: – Melatonin 10 mg (20 min pre hs) – Placebo (20 min pre hs)
Effect size on sleep onset latency:
0.61
Melatonin for Insomnia in Children with ADHD Weiss MD et al. J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):512-9.
Time (minutes)
Effect Size = 0.61
75 60
45
73%
50%
27% 50%
30 15 Placebo
Melatonin
CBT for Depression (MDD) in Adolescents Klein J et al. J Am Acad Child Adolesc Psychiatry. 2007 Nov;46(11):1403-13.
• Meta‐analysis – 11 trials
• Assessed the effect of research and analysis methods on CBT effect size estimates • Effect size: – Difference in post‐therapy means • CBT group • Control group
– Pooled SD (Hedges’)
Effect size
0.53
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85.
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85. Ped. Anx. Rating Scale at 8 weeks (ITT) Mean scores
SD
Fluvoxamine
9.0
7.0
Placebo
15.9
5.3
Effect size =
Step 1 (X1 – X2) : 15.9 – 9.0 = Step 2 (SDP) : (7.0+5.3)/2 =
6.9 6.15
= 1.1
Effect size estimates of published trials (journals) vs. FDA submitted (all) trials
Interpreting Hedge’s g effect size: • 0.2: small clinical effect • 0.5: medium clinical effect • 0.8: large clinical effect
g: Hedge’s g (=difference in means/SDp) Turner et al. NEJM Jan 2008
Illustrated comparison of effect sizes 0.41 and 0.31
Visualized here are the two effect sizes of antidepressant effectiveness; one influenced by industry’s selective publishing practices and the other not. Can you tell the difference? Would Turner be published in NEJM if he presented his data this way? Illustrations accurately show effect sizes of 0.41 and 0.31 using contrived data that approximate usual AD RCT findings using HDRS measures
Illustrated comparison of effect sizes 0.41 and 0.31
ES = 0.41
ES = 0.31
The avg person treated with an AD is doing better than 66% taking placebo
The avg person treated with an AD is doing better than 62% taking placebo
Illustrations accurately show effect sizes of 0.41 and 0.31 using contrived data that approximate usual AD RCT findings using HDRS measures
A 32% difference in Effect Size Looks like this! Effect size = 0.31
Effect size = 0.41
End of Day 1
Lies, Damn Lies, and Statistics in Psychiatry David
How do you interpret research results? Which drug is better for symptoms of schizophrenia?
Csernansky et al. NEJM 2002
0 Final: Neg Sx
BL: Neg Sx
Final: Pos Sx
BL: Pos Sx
Final: total
BL: total
PANSS
Which drug is better for symptoms of schizophrenia? 80
70
60
50
40
30
20
10
Media: Television “A study just released today reports that antidepressants more than doubles the risk of suicide attempts.”
Which Antidepressant is Most Dangerous? New suicidality Antidepressant
0.26%
No antidepressant
0.11% 0.26 / 0.11 > 2
A. B. C. D.
More than doubles the risk Increases the risk by 136% Increases the risk by 0.15% Leads to a new suicidality in 1 person for every 667 treated?
If 0.11% is 100% then 0.26% is 236%, which is 136% higher > 2 0.26% - 0.11% = 0.15% 15 in 10,000, or 1 in X X = 667
Based on the way the results are presented from a single finding, an unsuspecting clinician’s response can range from being gobsmacked to sedated Risk for worsening of suicidality is MORE THAN DOUBLED A “relative” estimate of the true effect
Risk for worsening of suicidality is INCREASED 0.15% An “absolute” estimate of the true effect
Media:Â Newspaper
Dichotomous Outcomes in Psychiatry Response, Remission Relapse, Recurrence Hospitalization Treatment discontinuation rate Treatment adverse effect rates Symptom change threshold (PANSS > ‐20%) Suicidality, Suicide Death
Methods of Comparing Risk for dichotomous outcomes Expressions
Relative risk (RR) Relative risk reduction (RRR) Absolute risk reduction (ARR) Number needed to treat (harm) (NNT or NNH) Odds ratio Hazard ratio
My antidepressant can reduce your risk of depression by 75% Baseline risk (no treatment
High risk n=64, p=0.05
Moderate risk
New risk (with treatment)
Relative risk reduction
75% 75%
n=268, p=0.05
Low risk n=848, p=0.05
Negligible risk n=2884, p=0.05
75% 75%
Absolute risk reduction
Number needed to treat
My antidepressant can reduce your risk of depression by 75% Baseline risk (no treatment
New risk (with treatment)
Relative risk reduction
High risk
40%
10%
75%
Moderate risk
12%
3%
75%
Low risk
4%
1%
75%
1.2%
0.3%
75%
Negligible risk
Absolute risk reduction
Number needed to treat
My antidepressant can reduce your risk of depression by 75% Baseline risk (no treatment
New risk (with treatment)
Relative risk reduction
Absolute risk reduction
High risk
40%
10%
75%
30%
Moderate risk
12%
3%
75%
9%
Low risk
4%
1%
75%
3%
1.2%
0.3%
75%
0.9%
Negligible risk
Number needed to treat
A RRR of 75% has no clinical meaning Baseline risk (no treatment
New risk (with treatment)
Relative risk reduction
Absolute risk reduction
Number needed to treat
High risk
40%
10%
75%
30%
4
Moderate risk
12%
3%
75%
9%
12
Low risk
4%
1%
75%
3%
34
1.2%
0.3%
75%
0.9%
112
Negligible risk
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85.
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85. Ped. Anx. Rating Scale at 8 weeks (ITT) Mean scores
SD
Fluvoxamine
9.0
7.0
Placebo
15.9
5.3
Effect size =
Step 1 (X1 – X2) : 15.9 – 9.0 = Step 2 (SDP) : (7.0+5.3)/2 =
6.9 6.15
= 1.1
Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001; 344:1279–85.
Absolute risk difference (rate1 – rate2)
Number needed to treat:
= 76% - 29%
If you get 47 more responders for every 100 treated, then you get 1 more responder for every X treated.
= 47%
X = 100/47 = 2.1 (round up to 3)
The p‐value is an over valued idea
The Relationship between statistical significance, sample size, power, and effect size
sample size (power) Statistical significance effect size
Statistical significance
10,000
Sample size
1000
p<0.05
Clinical significance is based on effect size.
100 50 P>0.05
10 0 0
5
10
15 20 Effect size
25
Clinical significance
30
Thinking about p‐values A p‐value indicates the probability of finding a difference between groups of a specific size when the truth is there is no difference between groups. It quantifies the risk of a type 1 error. P<0.05 and P>0.05 is a false dichotomy (p=0.049 ~~ p=0.051) P‐values do not tell you: If a treatment works If a treatment does not work How effective a treatment is If there is no difference in treatments If the study was well or poorly designed
In Summary • Understanding quantitative results is a necessary ability for rational use of psychotropics • Effect size (means) clinical interpretation: understand the numbers, illustrate, consider baseline scores and final scores to infer clinical meaning • Relative, absolute, and NNT (rates): beware of relativeness and be able to compute the others • P‐values: not as telling as you might hope
Over to you Stan
Brain Teaser Q: If 100 psychiatrists tried a new medication in 3 patients each, what proportion of them would have opposite opinions about the medication if the truth is that it works in 50% of patients. A: 25% ! % with 3/3 responders: 12.5% % with 0/3 responders: 12.5% Beware: experiential learning has risks
Assessment and monitoring
R.I.P. Stan
Pharmacotherapy of children, adolescents, and young adults, circa 1985‐1995
Stimulants
Antipsychotics
Antidepressants
Mood stabilizers
Others
Methylphenidate d‐amphetamine Pemoline Clonidine
Haloperidol Pimozide Chlorpromazine Loxapine
Imipramine Desipramine Clomipramine Doxepin Other TCAs MAOIs?
Lithium Carbamazepine Valproic acid
Propranolol Benzodiazepines Anticholinergics
Judicious baseline assessments and vigilant monitoring was not an option
FDA recommended monitoring of antidepressant therapy (all ages)
Month 1: Weekly Month 2: Biweekly Month 3: a “3 month” visit
US Food and Drug Administration: Medication guide: about using antidepressants in children and teenagers, 2005. http://www.fda.gov/cder/drug/antidepressants/MG_template.pdf
Compliance with FDA recommended monitoring of antidepressant therapy in the treatment of pediatric depression … post SSRI warnings Month 1 “weekly”
Month 2 “biweekly”
Full adherence
Primary care physicians
1.8%
11%
1.5%
Pediatricians
3.6%
16%
2%
Psychiatrists
6.0%
21%
3%
Morrato et al (2008). Frequency of provider contact after FDA advisory on risk of pediatric suicidality with SSRIs. American Journal of Psychiatry, 165(1), 42-50.
What has driven down the value of assessment and monitoring?
Old drugs:
New drugs:
Toxic
Safe
What is lost when follow up intensity declines? • Psychotherapeutic effect • RCT‐like placebo effect • Early management of nuisance side effects • Early detection of serious behavioural adverse effects Lower satisfaction with care
Less clinical improvement
• Opportunity for psycho‐ education • Ability to address new and unresolved concerns • Ability to assess and promote adherence
More treatment interruptions
More serious adverse events
Rational
Pharmacotherapy Selecting Starting Maintaining Combining Stopping
Harms
• • • • •
sts o C
Benef i ts
Measurement • No therapy can proceed without proper measurement of targets • All measurements must account for: amplitude (severity), duration and frequency of targets
Addressing the Target • Has the target been demonstrated to be modifiable by the treatment? • How strong is the modification expected to be? • Is the target measurable? • Is the target part of the “experienced” disease state?
To Measure Use Simple Tools • Efficient • Objective • Facilitate longitudinal assessment of response • Supports decisions to: – – – –
Continue therapy Change dose Change drug Stop therapy
Monitoring • Team function • Benefits • Harms
CGI-S 1– 2– 3– 4– 5– 6– 7–
Normal Borderline ill Mildly ill Moderately ill Markedly ill Severely ill Extremely ill
CGI-I 1– 2– 3– 4– 5– 6– 7–
Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse
Expected Side Effects • All medications have side effects • Side effects are a treatment target • Never forget to target side effects as part of your treatment plan: “APR” – anticipate, prevent, react
Practical Assessment and Monitoring Methods Assessment of problems subjectively or objectively – e.g., pain, anxiety, depression, functional impairment, gastrointestinal distress, sedation, fatigue, weakness, cognitive impairment…
Ordinal scales (4‐point to 7‐point) Visual analogue scales (100 mm) Binary scales (yes/no)
Ordinal Scales General Formats Not a problem
Mild problem
Moderate problem
Severe problem
0
1
2
3
Over the past week my ____ has been:
Over the past week my ____ has been:
Absent
Minimal
Mild
Moderate
Moder‐ ately severe
0
1
2
3
4
Severe
Extreme
5
6
Side Effects Chart: Example Over the last week, how often have you experienced the following: hardly ever (1), occasionally (2); frequently (3); most of the time (4). • Headaches • Sweating • Sexual Difficulties
1 1 1
2 2 2
3 3 3
4 4 4
Med Ed
Trackers • To support improved self‐ and clinician‐ monitoring of medication effects • Patient and care provider to specify monitoring: what when by whom
When Using Measurement Tools • Conduct first measure at baseline • Educate patient as to the meaning of the different values on the scales • Remember not to influence the outcome of the measurement • Measure at the right time • Discuss the measurement with your patient
Critical Thinking – Remember Again Treatment is an ongoing process and medication effects can be determined by a variety of factors, many of which are not attributable to the pharmacokinetics or the pharmacodynamics of the medicine itself: for example – placebo effect
End of Day 2