1. Antidepressants and Suicide Risk in Children and Adolescents: Weighing the Evidence Jill A. Morris, PA-S

2. Objectives/Goals  Review the current controversy regarding antidepressant use as treatment in child and adolescent patients with depression  Review studies concerning: The safety and efficacy of SSRIs in young patients The safety and efficacy of SSRIs in young patients The risk of suicidal ideation associated with SSRIs in children and adolescent patients The risk of suicidal ideation associated with SSRIs in children and adolescent patients Suicide attempts versus suicide deaths Suicide attempts versus suicide deaths  Summary/Conclusions

3. Depression

4. Background: Depression in Children and Adolescents  Depression is one of the most common diagnosable mental disorders in children and adolescents  Suicide is one of the risk factors associated with depression  SSRIs have been the “Gold Standard” for treating depression in children and adolescents  The downfall: SSRIs now have a warning regarding suicidality in children and adolescents There is limited evidence supporting the safety (with concerns of suicidality) and efficacy of these drugs There is limited evidence supporting the safety (with concerns of suicidality) and efficacy of these drugs Based on the extrapolation of data from adult studies Based on the extrapolation of data from adult studies

5. STUDY #1 The Use of Antidepressants to Treat Depression in Children and Adolescents  Investigated the efficacy profiles of different antidepressants  Involved large RCT’s involving subjects 18 years old and younger with depression  Reviewed by the FDA: 6 published reports 6 published reports 3 of fluoxetine and 1 each of paroxetine, sertraline, and citalopram3 of fluoxetine and 1 each of paroxetine, sertraline, and citalopram 10 unpublished reports 10 unpublished reports 2 each of paroxetine, venlafaxine, nefazodone, and mirtazapine and 1 each of citalopram and escitalopram2 each of paroxetine, venlafaxine, nefazodone, and mirtazapine and 1 each of citalopram and escitalopram

6. Efficacy Profiles of Different Antidepressants: Published Trials Drug/year # of subjects AgeDurationOutcome Fluoxetine, 2004 43912-1712 61 v. 35 Fluoxetine, 1997 967-188 56 v. 33 Paroxetine, 2001 27512-188 66 v. 52 Sertraline, 2003 3766-1710 63 v. 53 Citalopram, 2004 1747-178 47 v. 45

7. Efficacy Profiles of Different Antidepressants: Unpublished Trials Drug # of subjects AgeDurationOutcome Paroxetine27513-1812 69.2 v. 57.3 Paroxetine2037-178 49 v. 46 Escitalopram2646-178 63 v. 52

8. STUDY #2 Suicidality in Pediatric Patients Treated with Antidepressant Drugs  Investigated the relationship between antidepressant drugs and suicidality in pediatric patients in randomized placebo-controlled trials  Data was derived from 4582 patients in 24 trials 16 trials studied patients with MDD with the remaining 8 studied OCD (n=4), generalized anxiety disorder (n=2), and ADHD (n=1) 16 trials studied patients with MDD with the remaining 8 studied OCD (n=4), generalized anxiety disorder (n=2), and ADHD (n=1) Only 20 trials were included in the risk ration analysis of suicidality because 4 trials had no events in the drug or placebo groups Only 20 trials were included in the risk ration analysis of suicidality because 4 trials had no events in the drug or placebo groups

9. Summary of the Overall Risk Ratio of the Primary Outcome by Drug Across all Indications and in MDD Trials Drug MDD Trials All Trials/Indications Citalopram 1.37 (0.53-3.50) Fluvoxamine No MDD trials 5.52 (0.27-112.55) Paroxetine 2.15 (0.71-6.52) 5.52 (0.27-112.55) Fluoxetine 1.53 (0.74-3.16) 2.65 (1.00-7.02) Sertraline 2.16 (0.48-9.62) 1.52 (0.75-3.09) Venlafaxine 8.84 (1.12-69.51) 1.48 (0.42-5.24) Mirtazapine 1.58 (0.06-38.37) 4.97 (1.09-22.72) Nefazodone No events Bupropion No MDD trials No events

10. STUDY #3 Antidepressant drug therapy and suicide in severely depressed children and adults  Design: Case control study  Methods: Researchers used records to compare prescription histories between 263 children and teenagers (6-18 years) who had attempted suicide and 1241 controls who had never attempted suicide (all subjects suffered from depression)  Objective: To evaluate the risk of suicide death and serious suicide attempt in relation to antidepressant use

11. Summary of Associations of Suicide Attempts and Completion with Antidepressant Treatment Children 6-18 y CasesControls Odds Ratio Suicide Attempts (n=263)(n=1241) - No antidepressant drug 54.463.91.00 - Any antidepressant drug 45.636.11.52 - SSRI 29.725.51.24 Suicide Completion (n=8)(n=39) - No antidepressant drug 50.087.21.00 - Any antidepressant drug 50.012.815.62 - SSRI 37.57.711.26

12. Summary  Warnings include all antidepressant medications  Increase in suicidal ideation and behavior are relatively common in depression whereas completed suicides are far less common It is common that a slight increase in ideation does not in fact increase actual completed suicides It is common that a slight increase in ideation does not in fact increase actual completed suicides  Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality The average risk of suicide ideation/behavioral tendencies in patients receiving antidepressants was 4%, twice the placebo risk of 2%; No suicides occurred in these trials The average risk of suicide ideation/behavioral tendencies in patients receiving antidepressants was 4%, twice the placebo risk of 2%; No suicides occurred in these trials  Fluoxetine is the only SSRI approved by FDA for use in children and adolescents and is the most efficacious and safest  Real world data does not suggest completed suicide rate has increased with greater antidepressant use  Causal association between antidepressants and suicide has not been confirmed; further studies are still needed to confirm of safety and efficacy in children and adolescents

13. References Cheung, Amy. The use of antidepressants to treat depression in children and adolescents. CMAJ. 2006; 174(2). Clinical Advisory and Issue Analysis Regarding Antidepressant Use in Children and Adolescents. New Your State Office of Mental Health. 2004. Hammad, Tarek A. Suicidality in Pediatric Patients Treated with Antidepressant Drugs. Archives of General Psychiatry. 2006; 63(3): 332- 339. Olfson, Mark. Antidepressant Drug Therapy and Suicide in Severely Depressed Children and Adults. Archives of General Psychiatry. 2006; 63(8): 865-872. Rosack, Jim. Clinical Trials Controversy Spotlights Flawed System. American Psychiatric Association. 2004; 39(14): 1. Son, Sung E. Depression in Children and Adolescents. American Academy of Family Physicians. 2000; 62(10): 2297-2308, 2311-2. www.mhawinchester.org www.nmha.org www.wikipedia.org