suicidality in children

Results of the Analysis of Suicidality in

Pediatric Trials of Newer Antidepressants

Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory

CommitteeSeptember 13-14, 2004

Tarek A. Hammad, MD, PhD, MSc, MS

Senior Medical ReviewerDivision of Neuropharmacological Drug Products

Center for Drug Evaluation and Research, FDA

Outline•Objective• Data Domain • Findings• Limitations• Summary

Objective • To investigate the relationship

between antidepressants and pediatric suicidality based on:

1.Adverse events reported

1.Suicidality item(s) scores in pertinent depression questionnaires 3

Data Domain• 25 trials conducted in pediatric

patients in nine drug development programs + TADS trial

• Drugs - number of trials: – SSRIs

• Citalopram (Celexa) - 2 • Fluoxetine (Prozac) – 4 + TADS• Fluvoxamine (Luvox) - 1 • Paroxetine (Paxil) - 6 • Sertraline (Zoloft) - 3

– Atypical antidepressants• Bupropion (Wellbutrin) - 2• Mirtazapine (Remeron) – 1• Nefazodone (Serzone) - 2• Venlafaxine (Effexor XR) - 4 4

Data Domain, continued ...• Indications - number of trials

– Major Depressive Disorder (MDD) – 15 (+ TADS)

– Anxiety Disorders• Obsessive Compulsive Disorder - 5• Generalized Anxiety Disorder - 2 • Social anxiety Disorder/Social Phobia - 1

– Attention Deficit Hyperactivity Disorder – 2

• Two trials excluded (Paxil 453-relapse prevention, Wellbutrin 41-uncontrolled)

• Trial year: 1983 to 2004

• Duration: 4 to 16 weeks 5

Outline• Objective• Data Domain • Findings

– Outcomes based on adverse events– Outcomes based on suicidality scores

• Limitations • Summary

Outcomes Based on Adverse Events

Main Outcomes Used in the Analysis

Outcomes Description Number

Outcome 1 Suicidal behavior, codes 1 & 2

n=33Outcome 2 Suicidal ideation, code 6 n=45Outcome 3 (primary outcome)

Suicidal behavior or ideation (codes 1, 2, & 6)

n=78

Outcome 4 Possible suicidal behavior or ideation (codes 1, 2, 6 + 3, 10 )

n=109

8

21 “not eligible”(outside d-b)

Disposition of Events as Classified by Columbia

427 AEs narratives evaluated

260 others, not pertinent to the analysis

(Codes 7, 8, 9, 12)

167 potential events(Codes 1, 2, 3, 4, 5, 6, 10, 11)

141 unique patients(47 events in 21 patients, most severe chosen as [1 or 2] > 6 > 3 > [4 or 5] > 10)

120 “eligible” --> 109 “pertinent” (double-blind) Codes 1, 2, 3, 6, 10)

Adjudication of Sponsors’ Original Events

113 possibly suicide-related events

-11 “not pertinent”

29 new events from broader search & classification

+ 22 pertinent events (5 “not eligible”, 2 “not pertinent”)

-15 “not eligible”

109 pertinent events(codes 1, 2, 3, 6, 10)

87 pertinent events

10

Caveats!• Possibility for chance finding

– Post- hoc analyses– Multiple outcomes– Many sub-analyses

• Difficult to compare across drugs– Low power for individual trials– Differences in size of drugs’ databases– Potential role of differences in level of

ascertainment of events and completeness of narratives between trials/development programs 11

Examining Effect Modification and Confounding

Examining Effect Modification

Analysis was done by trial

Examining effect modification (interaction) was difficult due to small number of events

Variables examined were:•Age group (6-11, 12-18)•Gender•History of suicide attempt at baseline

None was found to meaningfully impact the risk estimates 13

Examining ConfoundingAnalysis was done by trial

Examining confounding effect of many variables•Demographics variables •Trial-related variables•Disease-related variables•Drug-related variables•Psychiatric history

None was found to meaningfully impact the risk estimates

14

Suicidal behavior or ideation (codes 1, 2, & 6)

by Drug

Celexa

Celexa, MDD(Fixed effect model)

Suicidal Behavior or Ideation [codes 1, 2, & 6]Risk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.46 (0.04,4.95) CELE(MDD,18) 29.1

1.74 (0.60,5.05) CELE(MDD,94404) 70.9

1.37 (0.53,3.50) Overall (95% CI)

17

Placebo is worse

Drug is worse

Paxil, all indications(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

3.78 (0.43,33.21) PAXIL(MDD,329) 18.2

1.58 (0.33,7.69) PAXIL(MDD,377) 46.3

1.96 (0.18,21.30) PAXIL(MDD,701) 17.9

3.24 (0.13,78.62) PAXIL(OCD, 704) 8.5

6.62 (0.34,127.14) PAXIL(SAD, 676) 9.1

2.65 (1.00,7.02) Overall (95% CI)

19

Prozac

Prozac, all indications(Fixed effect model)

Suicide Behavior or Ideation [codes 1, 2, & 6]Risk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.30 (0.01,7.02) PROZ(MDD,HCCJ) 15.4

1.01 (0.34,3.03) PROZ(MDD,HCJE) 58.4

1.00 (0.15,6.81) PROZ(MDD,X065) 19.6

1.38 (0.06,32.87) PROZ(OCD,HCJW) 6.7

0.92 (0.39,2.19) Overall (95% CI)

21

TADS trial

Group Event code * Number of events

PROZ (109)

1 (suicidal behavior)6 (suicidal ideation)

27

PBO (112) 6 (suicidal ideation)

2* Events were classified by the

Columbia expert group

22

Prozac, all indications(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

4.62 (1.02,20.92) PROZ(MDD, TADS) 16.2

0.30 (0.01,7.02) PROZ(MDD,HCCJ) 12.9

1.01 (0.34,3.03) PROZ(MDD,HCJE) 48.9

1.00 (0.15,6.81) PROZ(MDD,X065) 16.4

1.38 (0.06,32.87) PROZ(OCD,HCJW) 5.6

1.52 (0.75,3.09) Overall (95% CI)

23

Zoloft

Zoloft, all indications(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

6.57 (0.34,125.49) ZOLO(MDD,501001) 12.9

1.01 (0.15,7.02) ZOLO(MDD,501017) 49.8

0.34 (0.01,8.16) ZOLO(OCD, 0498) 37.3

1.48 (0.42,5.24) Overall (95% CI)

25

Effexor XR

Effexor, All indications(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

1.03 (0.07,16.11) EFFEX(GAD, 397) 49.5

7.43 (0.39,141.66) EFFEX(MDD,382) 24.3

10.15 (0.57,181.03) EFFEX(MDD,394) 26.1

4.97 (1.09,22.72) Overall (95% CI)

27

EFFEX (GAD, 396)

Overall relative risks (RR) of suicidal behavior or ideation (codes 1, 2, & 6)

by drugDrug Relative Risk

(95% CI), MDD trials

Relative Risk (95% CI), all trials, all indications

Celexa 1.37 (0.53, 3.50) 1.37 (0.53, 3.50)Luvox No MDD trials 5.52 (0.27, 112.55)Paxil 2.15 (0.71, 6.52) 2.65 (1.00, 7.02)Prozac * 1.53 (0.74, 3.16) 1.52 (0.75, 3.09)Zoloft 2.16 (0.48, 9.62) 1.48 (0.42, 5.24)Effexor XR

8.84 (1.12, 69.51)

4.97 (1.09, 22.72)

Remeron 1.58 (0.06, 38.37)

1.58 (0.06, 38.37)

Serzone No events No eventsWellbutrin

No MDD trials No events

28 * Note that TADS data are added to Prozac

Trial Design Attributes• The following trial design attributes were

examined:– Location (North Am/non-NA)– Setting (inpatient/outpatient)– Presence of an active control arm– Sample size– Rate of discontinuation – Number of centers – Extensive screening– Exclusion of placebo respondents– Exclusion of treatment-resistant patients– Exclusion of baseline suicide risk– Exclusion of history of suicide attempt – Exclusion of homicide risk

• None was found to consistently explain the observed differences in the risk estimates between trials within/between development programs

29

Components of suicidal behavior or ideation (codes

1, 2, & 6)1. Suicidal Behavior (codes 1

& 2)2. Suicidal Ideation (code 6)

Overall relative risks of suicidal behavior or ideation (codes 1, 2, & 6)

by drug in MDD trialsDrug Relative Risk (95%

CI), suicidal behavior (codes 1 & 2)

Relative Risk (95% CI), suicidal ideation (code 6)

Relative Risk (95% CI), suicidal behavior or ideation (codes 1, 2, & 6)

Celexa 2.23 (0.59, 8.46) 0.75 (0.19, 2.95) 1.37 (0.53, 3.50)

Paxil 2.30 (0.67, 7.93) 1.09 (0.24, 5.01) 2.15 (0.71, 6.52)

Prozac * 2.15 (0.50, 9.26) 1.30 (0.59, 2.87) 1.53 (0.74, 3.16)

Zoloft 0.98 (0.17, 5.68) 3.88 (0.44, 34.54) 2.16 (0.48, 9.62)

Effexor XR

2.77 (0.11, 67.10) 7.89 (0.99, 62.59) 8.84 (1.12, 69.51)

Remeron No events 1.58 (0.07, 38.37) 1.58 (0.06, 38.37)

31 * Note that TADS data are added to Prozac

Sensitivity Analysis

Robustness of the risk estimates of suicidal behavior or ideation (codes 1,2, &

6) to event ascertainment: results of outcome 4 “possible suicidal behavior or

ideation”Outcomes Overall RR (95% CI),

all trials, all indicationsOverall RR (95% CI), SSRI MDD trials

Suicidal behavior or ideation (codes 1,2, & 6)

1.95 (1.28, 2.98) 1.66 (1.02, 2.68)

Possible suicidal behavior or ideation (codes 1, 2, 6 + 3, 10)

2.19 (1.50, 3.19) 1.91 (1.27, 2.89)

33

• The signal was slightly altered• Note that TADS data are added to all analyses

Analysis of Risk Difference (RD)

Analysis of Risk Difference (RD)• This analysis estimates the absolute

increase in the risk of the event of interest due to treatment

• Risk in the drug grp - risk in the placebo grp

• Overall RD for SSRIs in MDD trials = 2 to 3%

• Out of 100 patients treated, we might expect 2 to 3 patients to have some increase in suicidality due to short-term treatment, i.e., beyond the risk that occurs with the disease being treated 35

Outcomes Based on Suicidality Scores

Worsening of Suicidality Score (Outcome 6, n=434)

• Increase in the suicidality item(s) score of pertinent depression questionnaires relative to baseline, regardless of subsequent change

• Questionnaires used: HAM-D, CDRS-R, MADRS, and K-SADS

37

Emergence of Suicidality (Outcome 7, n=349)

• Same concept as above, but with normal baseline score

Worsening of Suicidality (Outcome6)

• Effect modification and confounding were examined none was found

All trials, all indications(Fixed effect model)

Worsening/Emergence of SuicidalityRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.38 (0.14,1.04) CELE(MDD,18) 6.3 0.54 (0.26,1.12) CELE(MDD,94404) 9.2 1.97 (0.83,4.69) EFFEX(MDD,382) 3.4 0.77 (0.35,1.69) EFFEX(MDD,394) 6.3 1.14 (0.68,1.90) PAXIL(MDD,329) 10.4 0.66 (0.32,1.35) PAXIL(MDD,377) 7.9 1.84 (0.82,4.15) PAXIL(MDD,701) 4.1 1.42 (0.24,8.37) PAXIL(SAD, 676) 1.0 0.90 (0.26,3.12) PROZ(MDD,HCCJ) 2.1 0.80 (0.47,1.37) PROZ(MDD,HCJE) 12.1 0.80 (0.42,1.52) PROZ(MDD,X065) 7.6 1.35 (0.15,12.50) PROZ(OCD,HCJW) 0.7 0.86 (0.42,1.73) REMER(MDD,045) 7.3 0.80 (0.33,1.94) SERZ(MDD,141) 5.0 1.34 (0.62,2.91) SERZ(MDD,187) 5.3 1.04 (0.44,2.45) ZOLO(MDD,501001) 4.7 0.93 (0.45,1.94) ZOLO(MDD,501017) 6.5

0.92 (0.76,1.11) Overall (95% CI)

39 Results By discontin.

Emergence of Suicidality (Outcome 7)

• Effect modification and confounding were examined none was found


Emergence of SuicidalityRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)


0.93 (0.75,1.15) Overall (95% CI)

41

42

Other Analyses • Additional sensitivity analysis

• Fixed-effect vs. random-effects

• Completers analysis

• Time-to-event analysis•Kaplan-Meier survival estimates•Hazard functions for pooled SSRIs in MDD

trials

• Potential “activation” syndrome

• Post-hoc power analysis

Limitations• Post-hoc analyses with multiple outcomes

involved, in addition to many sub-analyses. Therefore, caution is warranted in the interpretation of the findings

• Observed differences between drugs– Chance finding– True differences between drugs (i.e. no class

effect)– Differences in size of drugs’ databases– Differences in level of ascertainment of events

and completeness of narratives– Differences in trial design attributes

• Short-term exposure (4-16 weeks) 43

Limitations, continued…

• Medication noncompliance may have influenced the occurrence of the events of interest. However, the determination of noncompliance was suboptimal

• Observed rates of suicidality associated with the use of antidepressants might not reflect actual rates among patients in the general population

• Most trials were conducted with a flexible dosing scheme eliminating our ability to examine the dose effect

44

Summary of Findings– The broader search for adverse events in

various drug development programs and the blinded classification process identified many new events and also eliminated several events that were not appropriately classified

– There were NO completed suicides

– Many individual trials had a RR of 2 or more for suicidality and some CIs of overall estimates did not include 1

– The sensitivity analyses did not yield a meaningful difference in the evaluation of the estimated risks 45

Summary of Findings, continued…

– None of the examined covariates was found to be an effect modifier or to meaningfully impact the risk estimates as a confounder

– Among the examined trial design attributes, none was found to consistently explain the observed differences in the risk estimates between trials

– No signal was observed in outcomes based on the suicidality scores 46

Backup Slides

49

Meta-analysis• Meta-analysis estimates of overall

effectsDealing with zero cellsTrial was used as the unit of analysis

– “fixed” effects models using the Mantel-Haenszel (M-H) method

Sensitivity analysis– “Possible” events added– Fixed-effect vs. random-effects

Completers analysis

Fixed Effect vs. Random Effects• In the fixed effect approach, the premise is that the

real effect that we are trying to estimate is fixed, and the observed variation between trials is by chance

• In the random effects approach, the premise is that the real effect vary around an average within a distribution reflected in the variation observed between trials

• The idea is that the results of various trials are given a different weight based on the underlying premise

• The random effects approach usually results in a wider CI

• Results are reported both ways for comparison50

Power Curves

51

Assuming 100 patient per arm

Incidence in placebo group

1%

5%

Sample Size Calculation

0

240

480

720

960

1200

1 2 3 4 5 6 7

Relative risk

0.010.05

p0

52

Incidence in placebo group

Assuming 80% power

1%

5%

Phase 1

Phase 2

Phase 3

Phase 4

Phase 5

Phase 6

Phases of the 141 relevant events

Trial end 8 31

120

2

8

1

4

3

2

53

Definition of “phases” based on the timing of AEs Phases Description

Phase 1 Event occurred in double-blind acute treatment phase or within one day of the end of this phase[1]. The end of trials with a tapering period was set to be at the beginning of the tapering period.

Phase 2 Event occurred during a taper phase following the end of the double-blind period

Phase 3 Event occurred during the discontinuation phase--this phase was defined as 2 to 8 days after the cessation of medication for all drugs except Prozac where it was 2 to 31 days after the cessation of medication because it has a long half life and active metabolites. For an event to be classified in this phase, the patient must not have been taking drug at the time of the event

Phase 4 Event occurred between 2 and 8 days (2 and 31 days for Prozac) after the cessation of double-blind acute phase study medication and the patient had continued in an extension phase or started on a prescription anti-depressant

Phase 5 Event occurred between 9 and 31 days after the cessation of double-blind acute phase study medication and the patient had continued in an extension phase or started on a prescription anti-depressant (this category would not apply to Prozac patients)

Phase 6 Event occurred more than 30 days after the cessation of double-blind medication in the acute phase 54

Pooling of data from different trials treating them as one large trial fails to preserve the randomization effect and might introduce bias and confounding

Maintaining the randomization guards against the foreseen (e.g. age and gender) and unforeseen (e.g. differences in medical practices or case ascertainment) imbalances between treatment groups

The issue of trial similarity is not only pertinent to having the same protocols, but is also pertinent to the implementation of those protocols (implementation of criteria of inclusion and exclusion, patients care in reality…etc) 55

Trial vs. Patient as the Unit of Analysis

Disposition of Sponsors’ Events113 possibly suicide-related events

(108+3+2)

-11 taken out( 2 events code 8 1 event code 4 5 events code 5 3 events code 11)

29 new events+ 22 events added( 1 event code 110 events code 6 4 events code 3 7 events code 10)

+ 5 outside d-b (2, 5, 3x6)

+ 2 not pertinent (4, 11)

-15 outside double-blind( 6 events code 1 1 event code 3 1 event code 5 7 events code 6)

109 pertinent events

87 pertinent events(26 events code 1 6 events code 2 20 events code 3 35 events code 6)

Relationship Between Sponsors’ and Columbia’s Classifications

Columbia Sponsor Total

No Yes

No event 4418 17 4435

Suicidal behavior (codes 1 & 2) 1 32 33

Suicidal ideation (code 6) 10 35 45

Suicidal behavior /ideation (codes 1, 2, & 6)

11 67 78

Possible suicidal behavior/ideation (codes 1, 2, 3, 6, & 10)

22 87 109

Self-injurious behavior, non-suicidal (codes 4, 5, & 11)

2 9 11

22 new events 26 events out

Relationship Between Sponsors’ and Columbia’s Classification

SponsorClassification

Change after Columbia

Final count

No event 4420 +26 4446

Suicidal behavior (codes 1 & 2)

32 +1 33

Suicidal ideation (code 6)

35 +10 45

Possible events (code 3, 10)

20 +11 31

58

– Codes 1, 2, & 6 pooled as “suicidal behavior or ideation” and is the primary outcome

Dealing with Zero Cells in Meta-analysis

– Trials with no outcomes in both arms were excluded

• For the primary outcome (outcome 3), four trials did not have any events (trials # 75 [Wellbutrin, ADHD], 141 & 187 [Serzone, MDD], and 396 [Effexor XR, GAD])

– Continuity correction: “0.5” was added to each of the 4 cells before proceeding with the analysis

59

Dealing with Zero Cells: Trial 676Data before correction: Event No event Drug 3 165 Placebo 0 156 Data after correction: Event No event Drug 3.5 165.5 Placebo 0.5 156.5 RR = (3.5/169)/(0.5/157) = 6.50

60

Calculation of the weight used in the M-H method

Event No event Group size

Drug a b n1Placebo c d n2

The weight (W) assigned to the RR will be equal to:

W= (c * n1)/N

Where N = n1 + n2 61

What is “Confounding”?• From the Latin confundere, to mix together

• “The distortion of the apparent effect of an exposure (e.g. an SSRI) on risk (e.g. suicidal behavior) brought about by the association with other factor[s] (e.g. history of suicide attempt) that can influence the outcome” A Dictionary of Epidemiology by John Last, 1995.

History of Suicide Attempt

Suicidal behaviorTreatment

62

What is “Confounding”?, continued...

• Confounding Principles:– Indirect (spurious or weaker than we think)

association (A1) between exposure (E) and disease (D) that depends on A2 [and is weaker than direct association (A3) between confounder and disease]

– Confounder (C) must associate with both E & D– More likely to explain small effects

A1

A2 A3

63

Treatment(E)

Suicidal behavior(D)

History of Suicide Attempt(C)

• Demographics variables • Age, gender, race, & BMI

• Trial-related variables• Trial location (North America vs. not)• Trial setting (inpatient vs. outpatient vs. both)

• Disease-related variables• Baseline severity score• Suicidality score at baseline• Duration of illness prior to treatment

• Drug-related variables• Discontinuation • Erratic compliance (defined as: not taking drug as prescribed during RCT)

• Prior history of:• Suicide attempt or ideation• Psychiatric hospitalization• Substance abuse• Hostility or aggressive behavior• Irritability or agitation• Insomnia 64

List of Covariates

Completeness of Explanatory Variables

• Explanatory variables that were completely reported in all trials are age, gender, race, setting of trial, location of trial, baseline severity score, and all outcomes

• Variables that were notably missing in many trials were duration of illness prior to randomization (10), and history of psychiatric hospitalization (21), substance abuse (9), and hostility or aggressive behavior (8) 65

Suicidal Behavior or Ideation (Codes 1,2, & 6), Overall



.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.46 (0.04,4.95) CELE(MDD,18) 6.5 1.74 (0.60,5.05) CELE(MDD,94404) 15.8 1.03 (0.07,16.11) EFFEX(GAD, 397) 3.1 7.43 (0.39,141.66) EFFEX(MDD,382) 1.5 10.15 (0.57,181.03) EFFEX(MDD,394) 1.6 5.52 (0.27,112.55) FLUV(OCD, 01) 1.5 3.78 (0.43,33.21) PAXIL(MDD,329) 3.2 1.58 (0.33,7.69) PAXIL(MDD,377) 8.1 1.96 (0.18,21.30) PAXIL(MDD,701) 3.1 3.24 (0.13,78.62) PAXIL(OCD, 704) 1.5 6.62 (0.34,127.14) PAXIL(SAD, 676) 1.6 4.62 (1.02,20.92) PROZ(MDD, TADS) 6.1 0.30 (0.01,7.02) PROZ(MDD,HCCJ) 4.9 1.01 (0.34,3.03) PROZ(MDD,HCJE) 18.6 1.00 (0.15,6.81) PROZ(MDD,X065) 6.2 1.38 (0.06,32.87) PROZ(OCD,HCJW) 2.1 1.58 (0.06,38.37) REMER(MDD,045) 2.0 6.57 (0.34,125.49) ZOLO(MDD,501001) 1.6 1.01 (0.15,7.02) ZOLO(MDD,501017) 6.2 0.34 (0.01,8.16) ZOLO(OCD, 0498) 4.6

1.95 (1.28,2.98) Overall (95% CI) Random-effects 1.75 (1.11, 2.76)

67

Suicidal Behavior or Ideation (Codes 1,2, & 6) by Indication

and Drug Class

SSRIs as a Class in MDD trials:Celexa, Prozac*, Paxil, & Zoloft

68 events, 2033 patients, 11 MDD trials

* Note that TADS data are added

SSRI, MDD(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.46 (0.04,4.95) CELE(MDD,18) 8.1 1.74 (0.60,5.05) CELE(MDD,94404) 19.7 3.78 (0.43,33.21) PAXIL(MDD,329) 4.0 1.58 (0.33,7.69) PAXIL(MDD,377) 10.1 1.96 (0.18,21.30) PAXIL(MDD,701) 3.9 4.62 (1.02,20.92) PROZ(MDD, TADS) 7.6 0.30 (0.01,7.02) PROZ(MDD,HCCJ) 6.1 1.01 (0.34,3.03) PROZ(MDD,HCJE) 23.1 1.00 (0.15,6.81) PROZ(MDD,X065) 7.7 6.57 (0.34,125.49) ZOLO(MDD,501001) 2.0 1.01 (0.15,7.02) ZOLO(MDD,501017) 7.7

1.66 (1.02,2.68) Overall (95% CI)

70

Random-effects 1.56 (0.94, 2.59)

All drugs, OCD, GAD, & SAD(Fixed effect model)


.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

1.03 (0.07,16.11) EFFEX(GAD, 397) 21.3

5.52 (0.27,112.55) FLUV(OCD, 01) 10.3

3.24 (0.13,78.62) PAXIL(OCD, 704) 10.4

6.62 (0.34,127.14) PAXIL(SAD, 676) 11.1

1.38 (0.06,32.87) PROZ(OCD,HCJW) 14.8

0.34 (0.01,8.16) ZOLO(OCD, 0498) 32.2

2.17 (0.72,6.48) Overall (95% CI)

71

Random-effects 1.99 (0.58, 6.85)

Outcome 4 and Sponsor’s Events, Overall


Sponsor's suicide-related eventsRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.46 (0.04,4.95) CELE(MDD,18) 5.2 1.72 (0.79,3.74) CELE(MDD,94404) 22.7 1.03 (0.07,16.11) EFFEX(GAD, 397) 2.5 1.77 (0.44,7.17) EFFEX(MDD,382) 7.2 13.83 (0.80,238.96) EFFEX(MDD,394) 1.3 3.31 (0.14,79.67) FLUV(OCD, 01) 1.2 7.57 (0.97,59.29) PAXIL(MDD,329) 2.6 1.19 (0.38,3.76) PAXIL(MDD,377) 13.0 1.47 (0.25,8.62) PAXIL(MDD,701) 5.0 3.24 (0.13,78.62) PAXIL(OCD, 704) 1.2 8.51 (0.46,156.81) PAXIL(SAD, 676) 1.3 0.90 (0.06,13.48) PROZ(MDD,HCCJ) 2.6 1.01 (0.26,3.93) PROZ(MDD,HCJE) 9.9 1.00 (0.15,6.81) PROZ(MDD,X065) 5.0 0.90 (0.08,9.58) PROZ(OCD,HCJW) 3.4 0.52 (0.03,8.27) REMER(MDD,045) 3.3 3.00 (0.12,72.73) SERZ(MDD,141) 1.2 1.54 (0.06,37.46) SERZ(MDD,187) 1.6 8.45 (0.46,154.76) ZOLO(MDD,501001) 1.3 1.01 (0.15,7.02) ZOLO(MDD,501017) 4.9 0.34 (0.01,8.16) ZOLO(OCD, 0498) 3.7

1.81 (1.24,2.64) Overall (95% CI)

73


Possible suicidal behavior/Ideation [codes 1, 2, 3, 6, & 10]Risk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.17 (0.01,4.16) BUPR(ADHD, 75) 5.2 0.46 (0.04,4.95) CELE(MDD,18) 5.5 2.26 (0.90,5.68) CELE(MDD,94404) 15.9 1.03 (0.07,16.11) EFFEX(GAD, 397) 2.6 5.31 (0.63,44.49) EFFEX(MDD,382) 2.5 13.83 (0.80,238.96) EFFEX(MDD,394) 1.4 5.52 (0.27,112.55) FLUV(OCD, 01) 1.2 6.62 (0.83,52.75) PAXIL(MDD,329) 2.7 1.23 (0.33,4.65) PAXIL(MDD,377) 10.3 2.94 (0.31,27.82) PAXIL(MDD,701) 2.6 5.40 (0.26,111.11) PAXIL(OCD, 704) 1.3 10.40 (0.58,186.60) PAXIL(SAD, 676) 1.3 4.62 (1.02,20.92) PROZ(MDD, TADS) 5.2 0.90 (0.06,13.48) PROZ(MDD,HCCJ) 2.7 1.35 (0.48,3.75) PROZ(MDD,HCJE) 15.6 0.50 (0.05,5.33) PROZ(MDD,X065) 5.2 0.90 (0.08,9.58) PROZ(OCD,HCJW) 3.6 1.05 (0.10,11.39) REMER(MDD,045) 3.4 3.00 (0.12,72.73) SERZ(MDD,141) 1.3 8.45 (0.46,154.76) ZOLO(MDD,501001) 1.3 1.01 (0.15,7.02) ZOLO(MDD,501017) 5.2 0.34 (0.01,8.16) ZOLO(OCD, 0498) 3.9

2.19 (1.50,3.19) Overall (95% CI)

74

Components of suicidal behavior or ideation (codes 1, 2, & 6)

• Suicidal Behavior (codes 1 & 2)• Suicidal Ideation (code 6)


Suicidal Behavior [codes 1 & 2]Risk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.91 (0.06,14.39) CELE(MDD,18) 7.5 2.90 (0.60,14.10) CELE(MDD,94404) 14.5 1.03 (0.07,16.11) EFFEX(GAD, 397) 7.1 2.77 (0.11,67.10) EFFEX(MDD,394) 3.7 4.73 (0.23,97.25) PAXIL(MDD,329) 3.7 1.32 (0.26,6.67) PAXIL(MDD,377) 18.7 4.90 (0.24,100.93) PAXIL(MDD,701) 3.6 5.14 (0.25,105.78) PROZ(MDD, TADS) 3.5 0.30 (0.01,7.02) PROZ(MDD,HCCJ) 11.2 5.00 (0.25,101.48) PROZ(MDD,X065) 3.6 1.38 (0.06,32.87) PROZ(OCD,HCJW) 4.9 2.82 (0.12,68.26) ZOLO(MDD,501001) 3.7 0.51 (0.05,5.48) ZOLO(MDD,501017) 14.2

1.90 (1.00,3.63) Overall (95% CI)

76


Suicidal Ideation [code 6]Risk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.30 (0.01,7.39) CELE(MDD,18) 6.6 0.97 (0.20,4.70) CELE(MDD,94404) 12.8 7.43 (0.39,141.66) EFFEX(MDD,382) 2.0 8.30 (0.45,152.14) EFFEX(MDD,394) 2.2 5.52 (0.27,112.55) FLUV(OCD, 01) 2.0 1.89 (0.17,20.50) PAXIL(MDD,329) 4.3 1.59 (0.07,38.69) PAXIL(MDD,377) 2.7 0.33 (0.01,7.93) PAXIL(MDD,701) 6.3 3.24 (0.13,78.62) PAXIL(OCD, 704) 2.0 6.62 (0.34,127.14) PAXIL(SAD, 676) 2.2 3.60 (0.76,16.93) PROZ(MDD, TADS) 8.3 1.01 (0.34,3.03) PROZ(MDD,HCJE) 25.0 0.20 (0.01,4.06) PROZ(MDD,X065) 10.5 1.58 (0.06,38.37) REMER(MDD,045) 2.7 4.69 (0.23,96.47) ZOLO(MDD,501001) 2.2 3.03 (0.13,73.48) ZOLO(MDD,501017) 2.1 0.34 (0.01,8.16) ZOLO(OCD, 0498) 6.2

1.74 (1.06,2.86) Overall (95% CI)

77

Trials Design Attributes

Trials Design Attributes: Celexa

Trial design attributes Trial CIT_18 Trial 94404Location North America Non-North AmericaSetting Outpatient Inpatient/outpatientExcluded placebo responders

Yes No

Extensive screening No NoExcluded Tx. resistant Yes NoExcluded baseline suicide risk

Yes No

Excluded history of suicide attempt

Yes No

79

Trials Design Attributes: PaxilTrial design attributes Trial 329 Trial 377 Trial 701Excluded placebo responders

No Yes No

Extensive screening Yes No NoExcluded tx-resistant No No Yes Excluded baseline suicide risk

Yes Yes Yes


No No No

Other attributes Active control Largest

80

Trials Design Attributes: Prozac

Trial design attributes Trial HCCJ Trial X065 Trial HCJE

TADS

Excluded placebo responders

Yes Yes Yes No

Extensive screening No Yes Yes Yes Excluded tx-resistant No No Yes Yes Excluded baseline suicide risk

Yes No Yes Yes


No No No No

Other attributes Early termination

81

Trials Design Attributes: Zoloft

Trial design attributes Trial 1001 Trial 1017Excluded placebo responders (placebo lead-in)

No No

Extensive screening No NoExcluded tx-resistant No YesExcluded baseline suicide risk

Yes Yes


Yes Yes

82

Trials Design Attributes: Effexor XR

Trial design attributes Trial 382 Trial 394Excluded placebo responders

Yes Yes

Extensive screening No NoExcluded tx-resistant No NoExcluded baseline suicide risk

Yes Yes


No No

83

Worsening of Suicidality (Outcome 6) Stratified by Premature

Discontinuation: Completers Analysis


Worsening/Emergence of Suicidality/No discontRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)


0.82 (0.65,1.04) Overall (95% CI)

85


Worsening/Emergence of Suicidality/discontRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)


1.11 (0.81,1.50) Overall (95% CI)

86

Suicidal behavior or ideation (codes 1,2, & 6) Stratified by Premature

Discontinuation: Completers Analysis

7594

404

CIT-1

8HC

CJHC

JE

X065

HCJW 11

414

118

767

632

937

770

170

4

3-04

510

0110

17 498

396

397

382

394

Trials

Frequency of Discontinuation by Trial

Drug Placebo 88

Overall RRs of suicidal behavior or ideation (codes 1,2, & 6) in

completers and non-completersDrug RR and 95% CI in

completersRR and 95% CI in non-completers

Prozac * 1.17 (0.30, 4.61) 0.84 (0.29, 2.44)Paxil 2.79 (0.47, 16.53) 1.86 (0.70, 4.95)Zoloft 0.34 (0.01, 8.16) 1.35 (0.34, 5.40)Celexa 0.94 (0.20, 4.50) 1.67 (0.52, 5.33)Luvox 2.85 (0.12, 67.68) 4.20 (0.18, 97.89) Effexor XR 3.12 (0.13, 75.39) 6.22 (0.81, 47.94)Remeron No events 1.73 (0.07, 40.32) All SSRIs in MDD trials

1.08 (0.45, 2.60) 1.40 (0.76, 2.56)

89 * Note that TADS data are NOT added to Prozac

Overall RRs of suicidal behavior or ideation (codes 1,2, & 6) by drug,

stratified by history of suicide attempt at baseline

9440

4

CIT

-18

HC

CJ

HC

JE

X06

5

141

187

329

377

701

3-04

5

1001

1017 382

394

Trials

Frequency of Patients with a History of Suicide Attempt or I deation at Baseline in MDD Trials

DrugPlacebo

91

12 events

14 events

5 events

8 events

39/66=59%

Exclusion

Overall RRs of suicidal behavior or ideation (codes 1,2, & 6) stratified by

history of suicide attempt at baseline by drug

Drug RR and 95% CI in patients with no history

RR and 95% CI in patients with history

Prozac * 0.91 (0.30, 2.72) 0.92 (0.21, 4.14)Paxil 1.36 (0.18, 10.35) 2.13 (0.66, 6.88)Zoloft 2.42 (0.36, 16.06) 1.37 (0.18, 10.40)Celexa 1.39 (0.30, 6.49) 1.16 (0.39, 3.44)Effexor XR 5.67 (0.69, 46.68) 4.56 (0.52, 39.72)Remeron 1.63 (0.07, 39.57) No eventsAll SSRIs 1.26 (0.60, 2.64) 1.40 (0.73, 2.72)All drugs 1.61 (0.83, 3.13) 1.60 (0.86, 2.98)

92 * Note that TADS data are NOT added to Prozac

All MDD trials(Fixed effect model)

Suicide Behavior or Ideation [1, 2, 6]/HistoryRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

1.15 (0.38,3.44) CELE(MDD,94404) 36.0 4.29 (0.19,97.73) EFFEX(MDD,382) 2.7 4.78 (0.24,94.12) EFFEX(MDD,394) 3.4 3.08 (0.33,28.96) PAXIL(MDD,329) 6.5 1.55 (0.32,7.45) PAXIL(MDD,377) 17.3 3.39 (0.15,79.22) PAXIL(MDD,701) 3.1 0.68 (0.05,10.14) PROZ(MDD,HCJE) 7.8 1.07 (0.17,6.61) PROZ(MDD,X065) 12.7 1.97 (0.08,45.77) ZOLO(MDD,501001) 4.0 1.00 (0.07,15.12) ZOLO(MDD,501017) 6.6

1.60 (0.86,2.97) Overall (95% CI)

93


Suicide Behavior or Ideation [1, 2, 6]/No HistoryRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

0.43 (0.04,4.63) CELE(MDD,18) 15.7 5.87 (0.29,119.44) CELE(MDD,94404) 3.4 4.93 (0.24,100.70) EFFEX(MDD,382) 3.7 6.40 (0.34,121.74) EFFEX(MDD,394) 3.8 2.09 (0.09,48.04) PAXIL(MDD,329) 4.3 0.94 (0.06,14.75) PAXIL(MDD,701) 7.5 0.31 (0.01,6.85) PROZ(MDD,HCCJ) 11.4 1.11 (0.33,3.69) PROZ(MDD,HCJE) 34.7 1.63 (0.07,39.57) REMER(MDD,045) 4.7 5.29 (0.26,108.17) ZOLO(MDD,501001) 3.6 1.01 (0.06,15.90) ZOLO(MDD,501017) 7.2

1.61 (0.83,3.12) Overall (95% CI)

94

Potential “Activation” Syndrome

Defined as Treatment-Emergent Hostility or

Agitation

Overall relative risks of treatment-emergent agitation or hostility by

drug in MDD trials

Drug Relative Risk (95% CI), MDD trials

Celexa 1.87 (0.34, 10.13)Paxil 7.69 (1.80, 32.99)Prozac * 1.01 (0.40, 2.55)Zoloft 2.92 (0.31, 27.83)Effexor XR 2.86 (0.78, 10.44)Remeron 0.52 (0.03, 8.27) Serzone 1.09 (0.53, 2.25)All drugs 1.79 (1.16, 2.76) 96

* Note that TADS data are NOT added to Prozac


Treatment emergent agitation or hostilityRisk ratio

.01 .1 1 10 100

Study % Weight

Risk ratio (95% CI)

2.74 (0.29,25.86) CELE(MDD,18) 3.4 0.97 (0.06,15.30) CELE(MDD,94404) 3.3 1.06 (0.07,16.70) EFFEX(MDD,382) 3.1 3.69 (0.80,16.92) EFFEX(MDD,394) 6.7 16.10 (0.94,274.77) PAXIL(MDD,329) 1.7 6.90 (0.39,121.10) PAXIL(MDD,377) 2.1 3.92 (0.45,34.50) PAXIL(MDD,701) 3.3 1.61 (0.55,4.78) PROZ(MDD,HCJE) 16.0 0.14 (0.01,2.69) PROZ(MDD,X065) 11.3 0.52 (0.03,8.27) REMER(MDD,045) 4.2 1.60 (0.54,4.71) SERZ(MDD,141) 16.1 0.77 (0.28,2.09) SERZ(MDD,187) 25.6 2.82 (0.12,68.26) ZOLO(MDD,501001) 1.7 3.03 (0.13,73.48) ZOLO(MDD,501017) 1.6

1.79 (1.16,2.76) Overall (95% CI)

97

Analysis of Risk Difference (RD):

Suicidal behavior or ideation (codes 1, 2, & 6) and possible suicidal behavior or ideation

(codes 1, 2, 3, 6, & 10)

Risk difference, All trials, all indications(Fixed effect model)

Suicidal Behavior or Ideation [codes 1, 2, & 6]Risk difference

-.2 -.1 0 .1 .2

Study % Weight

Risk difference (95% CI)

-0.01 (-0.05,0.03) CELE(MDD,18) 4.8 0.03 (-0.03,0.09) CELE(MDD,94404) 6.6 0.00 (-0.03,0.04) EFFEX(GAD, 397) 4.2 0.04 (-0.01,0.08) EFFEX(MDD,382) 4.5 0.05 (0.00,0.09) EFFEX(MDD,394) 5.3 0.04 (-0.02,0.09) FLUV(OCD, 01) 3.3 0.03 (-0.02,0.08) PAXIL(MDD,329) 4.9 0.01 (-0.03,0.05) PAXIL(MDD,377) 6.8 0.01 (-0.02,0.04) PAXIL(MDD,701) 5.6 0.01 (-0.02,0.04) PAXIL(OCD, 704) 5.6 0.02 (-0.01,0.04) PAXIL(SAD, 676) 8.7 0.06 (0.01,0.12) PROZ(MDD, TADS) 6.0 -0.05 (-0.18,0.08) PROZ(MDD,HCCJ) 1.1 0.00 (-0.06,0.06) PROZ(MDD,HCJE) 6.0 0.00 (-0.08,0.08) PROZ(MDD,X065) 2.6 0.01 (-0.04,0.07) PROZ(OCD,HCJW) 2.4 0.01 (-0.01,0.03) REMER(MDD,045) 6.4 0.03 (-0.01,0.07) ZOLO(MDD,501001) 5.1 0.00 (-0.04,0.04) ZOLO(MDD,501017) 5.0 -0.01 (-0.04,0.02) ZOLO(OCD, 0498) 5.0

0.02 (0.01,0.03) Overall (95% CI)

100

Risk difference, SSRI, MDD(Fixed effect model)

Suicidal Behavior or Ideation [codes 1, 2, & 6]Risk difference

-.2 -.1 0 .1 .2

Study % Weight


-0.01 (-0.05,0.03) CELE(MDD,18) 8.9 0.03 (-0.03,0.09) CELE(MDD,94404) 12.2 0.03 (-0.02,0.08) PAXIL(MDD,329) 9.0 0.01 (-0.03,0.05) PAXIL(MDD,377) 12.4 0.01 (-0.02,0.04) PAXIL(MDD,701) 10.3 0.06 (0.01,0.12) PROZ(MDD, TADS) 11.0 -0.05 (-0.18,0.08) PROZ(MDD,HCCJ) 2.0 0.00 (-0.06,0.06) PROZ(MDD,HCJE) 10.9 0.00 (-0.08,0.08) PROZ(MDD,X065) 4.8 0.03 (-0.01,0.07) ZOLO(MDD,501001) 9.4 0.00 (-0.04,0.04) ZOLO(MDD,501017) 9.2

0.02 (0.00,0.03) Overall (95% CI)

101

Risk difference, All trials, all indications(Fixed effect model)

Possible suicidal behavior/Ideation [codes 1, 2, 3, 6, & 10]Risk difference

-.2 -.1 0 .1 .2

Study % Weight


-0.03 (-0.09,0.04) BUPR(ADHD, 75) 2.5 -0.01 (-0.05,0.03) CELE(MDD,18) 4.5 0.06 (-0.01,0.13) CELE(MDD,94404) 6.2 0.00 (-0.03,0.04) EFFEX(GAD, 397) 3.9 0.05 (-0.01,0.11) EFFEX(MDD,382) 4.2 0.07 (0.02,0.12) EFFEX(MDD,394) 4.9 0.04 (-0.02,0.09) FLUV(OCD, 01) 3.0 0.06 (0.01,0.12) PAXIL(MDD,329) 4.6 0.01 (-0.04,0.05) PAXIL(MDD,377) 6.3 0.02 (-0.02,0.06) PAXIL(MDD,701) 5.2 0.02 (-0.01,0.05) PAXIL(OCD, 704) 5.2 0.03 (0.00,0.06) PAXIL(SAD, 676) 8.1 0.06 (0.01,0.12) PROZ(MDD, TADS) 5.6 -0.01 (-0.14,0.13) PROZ(MDD,HCCJ) 1.0 0.02 (-0.05,0.08) PROZ(MDD,HCJE) 5.5 -0.02 (-0.09,0.05) PROZ(MDD,X065) 2.4 -0.00 (-0.07,0.07) PROZ(OCD,HCJW) 2.2 0.00 (-0.03,0.03) REMER(MDD,045) 5.9 0.01 (-0.02,0.04) SERZ(MDD,141) 4.8 0.04 (-0.00,0.09) ZOLO(MDD,501001) 4.7 0.00 (-0.04,0.04) ZOLO(MDD,501017) 4.7 -0.01 (-0.04,0.02) ZOLO(OCD, 0498) 4.7

0.02 (0.01,0.03) Overall (95% CI)

102

Risk difference, SSRI, MDD(Fixed effect model)

Possible suicidal behavior/Ideation [codes 1, 2, 3, 6, & 10]Risk difference

-.2 -.1 0 .1 .2

Study % Weight


-0.01 (-0.05,0.03) CELE(MDD,18) 8.9 0.06 (-0.01,0.13) CELE(MDD,94404) 12.2 0.06 (0.01,0.12) PAXIL(MDD,329) 9.0 0.01 (-0.04,0.05) PAXIL(MDD,377) 12.4 0.02 (-0.02,0.06) PAXIL(MDD,701) 10.3 0.06 (0.01,0.12) PROZ(MDD, TADS) 11.0 -0.01 (-0.14,0.13) PROZ(MDD,HCCJ) 2.0 0.02 (-0.05,0.08) PROZ(MDD,HCJE) 10.9 -0.02 (-0.09,0.05) PROZ(MDD,X065) 4.8 0.04 (-0.00,0.09) ZOLO(MDD,501001) 9.4 0.00 (-0.04,0.04) ZOLO(MDD,501017) 9.2

0.03 (0.01,0.04) Overall (95% CI)

103

Sensitivity Analysis

Robustness of the risk estimates of suicidal behavior or ideation (codes 1,2, & 6) to meta-

analysis method (results of random effects models)

Suicidal behavior or ideation (codes 1,2, & 6),

Overall RR (95% CI), fixed effect

Overall RR (95% CI), random effects

Overall 1.95 (1.28, 2.98)

1.75 (1.11, 2.76)

SSRI MDD 1.66 (1.02, 2.68)

1.56 (0.94, 2.59)

Other indications

2.17 (0.72, 648) 1.99 (0.58, 6.85)

105

• The signal was slightly altered• Note that TADS data are added to all analyses

Time to Event Analysis:Hazard Functions for All

SSRIs in MDD Trials57 events, 1812

patients, ten trials

• Note that TADS data are NOT added

.000

2.0

003

.000

4.0

005

.000

6.0

007

0 20 40 60 80Days

Placebo SSRI

Haz

ard

Func

tion

Smoothed Hazard Estimates, SSRIs, MDD Trials

107 10 trials, 57 events,

1812 patients

4 events (1 drug and 3 placebo)

0.0

005

.001

.001

5.0

02

0 20 40 60 80 0 20 40 60 80

0 1

95% CI Smoothed hazard function

Days

Graphs by Treat

Smoothed hazard estimates, by Treat

HR=1.45 (0.85, 2.48) vs. RR=1.41 (0.84, 2.37)

Placebo Drug

108

.000

2.0

003

.000

4.0

005

.000

6.0

007

0 20 40 60 80Days

Placebo SSRI

Haz

ard

Func

tion

Smoothed Hazard Estimates, SSRIs, MDD Trials

109

HR 2.20 (1.04, 4.61)

HR 0.20 (0.02, 1.80)HR 1.33 (0.50, 3.50)

10 trials, 57 events, 1812 patients

Time-to-Event Analysis by Trial

Time-to-Event Analysis: Trial 94404

111 111

Time-to-Event Analysis: Trial HCJE

112 112


113 113


114 114

Codes for Columbia University Classification

• 1: suicide attempt (n=27)• 2: preparatory actions (n=6)• 3: self-injurious behavior, intent unknown (n=24)• 4: self-injurious behavior, no intent, primarily to affect

circumstance (n=2)• 5: self-injurious behavior, no intent, primarily to affect

internal state (n=5)• 6: suicidal ideation (n=45)• 7: other: accident• 8: other: psychiatric• 9: other: medical• 10: not enough information (n=7)• 11: self-injurious behavior, no suicidal intent (n=4)• 12: “other” 115

suicidality in children

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