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Antidepressants in Kids: Benefits of Treatment vs. Risk of Suicidal Behavior. Gregory W. Dalack, MD April 26, 2007. Objectives. Review EBM Steps Develop a PICO question Brief Review of Literature Search technique Focus on one large meta-analysis Discuss study design
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Antidepressants in Kids: Benefits of Treatment vs. Risk of Suicidal Behavior Gregory W. Dalack, MD April 26, 2007
Objectives • Review EBM Steps • Develop a PICO question • Brief Review of Literature Search technique • Focus on one large meta-analysis • Discuss study design • Quality of studies included • Models to pool results from multiple studies • Brief overview of results • Discuss Risk Differences • Number Needed to Treat • Number Needed to Harm • Implications for decision-making
The Practice of EBM • Step 1: Ask– a structured, patient-focused question. Consider the PICO format (Patient/Population; Intervention; Comparison; Outcome). • Step 2: Acquire– do an efficient and effective literature search. • Step 3: Appraise– critically appraise the quality of the studies. • Step 4: Apply– the evidence to your specific patient. • Step 5: Assess– the result of the application of the evidence
Good clinical questions • “Background” Questions • General knowledge • Two components • Root (who, what, when, where, why) • A disorder or aspect of a disorder • E.g., “What is the typical age of onset of bipolar disorder?” • “How do I decide to use a typical vs. atypical antipsychotic for agitation?”
Good clinical questions • “Foreground” Questions • These ask for specific information about managing a patient with a disorder • They have 3-4 essential components • P • I • C • O
P is a 14 year old boy who has been diagnosed by his pediatrician with depression. There is a family history of depressive illness and a completed suicide by a maternal uncle. P is withdrawn, gloomy and irritable at times, and often very dysphoric. He is not sleeping well and has had a difficult time attending and keeping up in school.
The patient’s father, a nurse, and his mother, a lawyer, are anxious about their son’s condition and want some recommendations about medication treatment for depression. The pediatrician has sent them to you for a consultation. • What do you tell them? What recommendations do you make?
The Well-Built, Patient-Oriented Clinical Question • P- Patient or population—Describe the most important characteristics of the patient • I- Intervention– Describe the main intervention • C- Comparison– Describe the main alternative being considered • O- Outcome– Describe what you are trying to trying to accomplish/improve/measure/etc.
Search Strategy: the best terms come from P & I • P- Patient or population • I- Intervention • C- Comparison • O- Outcome
Search Strategy: the best terms come from P & I • Let’s try PubMed • “Clinical Queries” • Search by Clinical Study Category • “Narrow” • Enter Search Terms
Let’s pursue the first one • Meta-analysis • Clinical Response and Risk of Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment– JAMA 2007: 297:1683-1696 • Objective: To assess efficacy of antidepressants and risk of reported suicidal ideation/suicide attempt during antidepressant treatment of pediatric MDD, OCD, and non-OCD anxiety disorders
Brief overview of methods • 27 Trials • MDD: 15 • OCD: 6 • Non-OCD Anxiety Disorders: 6 • Risk differences for response and for suicidal ideation/suicide attempt were estimated • Were these trials designed to assess response? • Were these trials designed to assess risk of SI/SA? • Quality Assessment
Quality Assessment • Adequacy of Randomization • Study Entry Criteria • Outcome Measures • Therapeutic and Placebo procedures (e.g., flexible dosing, blinding of pills) • Statistical Analysis- to ITT or not to ITT • In this study, individual items “present” were summed and divided by # possible items to produce a score between 0-1
Brief overview of methods • Outcome Measures • MDD: 8 weeks • OCD: 11 weeks • Non-OCD Anxiety Disorders: 11 weeks • Placebo run-in period- 17-47% of studies • Most (23/27) used flexible dosing schedule • Majority of studies (85%) were multi-site • Median quality score= 0.88—good quality • Most common weaknesses: • Failure to use ITT analyses • Ambiguity about Randomization and exclusionary processes
Fixed Effects vs. Random Effects Model • Fixed Effects Model: assumes that for the studies combined in the meta-analysis there is a single true value; or, if all studies were infinitely large, they would yield the same estimate of the effect. Assumes there is only “within-study” variance and ignores “between-study” variance. • Random Effects Model: assumes that the studies included are a random sample of a population of studies addressing the question posed. Each study tends to estimate a different underlying true effect; the distribution of these is assumed to be normal around a mean value. It takes into account both within and between study variances.
Brief overview of methods • Median treatment period • MDD: CGI in 8/15; Children’s Depression Rating Scale in 11/15 • OCD: all used change score in YBOCS; 3/6 also used > 25% decrease in Children’s YBOCS • Non-OCD Anxiety Disorders: CGI in all 6; Pediatric Anxiety Rating Scale in 2/6
Definition of Terms • Absolute Risk Reduction: difference in the absolute risk (percentage of patients with specified [presumably good] outcome) in those exposed to the intervention vs. those unexposed • Absolute Risk Increase: difference in the absolute risk (percentage of patients with specified [presumably bad] outcome) in those exposed to the intervention vs. those unexposed • Number Needed to Treat: number of patients who need to be treated over a specific period to prevent 1 bad outcome • NNT= inverse of Absolute Risk Reduction • Number Needed to Harm: number of patients who need to be treated over a specific period before one adverse event of the treatment occurs • NNT= inverse of Absolute Risk Increase
Results • MDD studies (13 trials, 2910 subjects) • Pooled absolute response rates: 61% (95% CI 58-63%) in AD treated subjects; 50% (95% CI 47%-53%) in Pbo treated subjects • Pooled risk difference of 11% (95% CI 7%-15%) • NNT= 10 (95% CI 7-15) • Pooled absolute rates of SI/SA: 3% (95% CI 2-4%) in AD treated subjects; 2% (95% CI 1%-2%) in Pbo treated subjects • Pooled risk difference of 1% (95% CI -0.1% to 2%) • NNH= 112 (note there were no suicides in any group)
Results • OCD studies (6 trials, 705 subjects) • Pooled absolute response rates: 52% (95% CI 46-57%) in SSRI treated subjects; 32% (95% CI 27%-37%) in Pbo treated subjects • Pooled risk difference of 20% (95% CI 13-27%) • NNT= 6 (95% CI 4-8) • Pooled absolute rates of SI/SA: 1% (95% CI 0-2%) in SSRI treated subjects; 0.3% (95% CI -0.3-1%) in Pbo treated subjects • Pooled risk difference of 0.5% (95% CI -1% to 2%) • NNH= 200 (note there were no suicides in any group)
Results • Non-OCD Anxiety Disorders (6 trials, 1136 subjects) • Pooled absolute response rates: 69% (95% CI 65-73%) in AD treated subjects; 39% (95% CI 35-43%) in Pbo treated subjects • Pooled risk difference of 37% (95% CI 23-52%) (large variance in risk differences across studies) • NNT= 3 (95% CI 2-5) • Pooled absolute rates of SI/SA: 1% (95% CI 0.2-2%) in AD treated subjects; 0.2% (95% CI -0.2-0.5%) in Pbo treated subjects • Pooled risk difference of 0.7% (95% CI -0.4% to 2%) • NNH= 143 (note there were no suicides in any group)
Conclusions • Evidence of efficacy of AD for treatment of pediatric MDD, OCD and non-OCD anxiety • Strongest effect for non-OCD anxiety, intermediate for OCD and modest for MDD • Similar to previous (FDA) analysis, there was an overall increase in risk of SI/SA (but no completed suicides) associated with antidepressant treatment, but random-effects risk differences were all < 1% and lower than analyses using fixed-effect models. Risk differences were not statistically significant (CI’s included zero)
Conclusions • Relative risk analysis not the focus here- relative risk analysis excludes studies in which there were no events in AD or Pbo groups. • Evidence of efficacy of AD vs. Pbo in MDD across several AD types. However, for children < 12 years old, only fluoxetine outperformed Pbo • Efficacy also inversely proportional to duration of disorder
What to tell the parents? • NNTs of 3-10 balanced against NNH of 112-200 offer a favorable risk-to-benefit profile for AD in the treatment of MDD, OCD and non-OCD anxiety disorders. (N.B., the lack of completed suicides in any of this or other studies is an important factor in this risk-to benefit profile being viewed as favorable) • Quoting from the article: “…strength of evidence support the cautious and well-monitored use of antidepressant medications as one of the first-line treatment options…” • Also: “…the information presented in this report should allow for an informed evaluation of the potential benefits and risks of these medications vs. no treatment and provide a framework for their comparison with nondrug treatments as well.”
References • Bridges JA et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. JAMA 2007; 297:1683-1696 • Users’ Guides to the Medical Literature. Eds. Guyatt G, Rennie D. AMA Press, 2002