1. Greg Cowan Ph. D. UW Wausau Family Medicine April 30, 2009
Adult and Pediatric Antidepressant Black Box Warnings: Rationale, Clinical Implications, and Effects on Patient Care
Greg Cowan Ph. D.
UW Wausau Family Medicine
April 30, 2009

2. Overview
Rationale-what events led up to BBW- ch & adol. 10/04, young adult /07
Methodology and results of FDA review
Content of BBWs- what recommendations do they make
What evidence is there regarding consequences on patterns of clinical care since BBWs

3. Suicide third-leading cause of death in adolescents 15-19 y.o.
Approximately 1800 suicides/year ages 15-19
Accidents and homicide leading causes
Three-quarters male
Annual prevalence MDD
-children (8-12) 2-3%
-adolescents (12-18) 4-8%

4. Suicidality in depressed children and adolescents
Suicide attempts: 9%
Suicidal ideation: 66% (Kovacs at al. J Amer Acad Child Adolesc Psycyhiatry. 1993)

5. Antidepressants and Suicide
-Significant percentage of suicide deaths in total population are due to AD overdose
Forensic analysis of 15,000 suicides (cited in FDA analysis)
-No SSRI’s detected in the 52 suicides of those younger than 15
Poisoning of any kind not one of primary methods-of poisoning suicides, close to half are AD related (2004-colo. 45 poisoning suicides-20 were antidep.)
-Most common methods firearms, hanging/suffocation
Even in AD suicides, we do not know if person was taking as prescribed prior to death
32000 suicides/year in U.S.-CDC

6. Leon et al, 2006
, 41 suicides under 18 in NYC
36 had serum toxicology analysis
1 had buproprion and sertaline
No others had antidepressant detected

7. Clinical Psychiatry, by Mayer-Gross, Slater, and Roth, London, 1960, p
“With beginning convalescence (following initiation of treatment with tricyclic antidepressants), the risk of suicide once more becomes serious as retardation fades.”

8. Pediatric Warnings-Background
FDA concern re unpublished negative results
June FDA alert -GlaxoSmithKline analysis of Paroxetine pediatric clinical trials
June UK bans Paxil for pediatric use
Neg results-unpublished-and different results re suicide risk provided to FDA and UK MHPR (Med and Health care products reg agency)
1980’s- German gov’t would not license prozac without suicide warning
There is some evidence in uncovered Lilly internal memos from 1980’s that Prozac suicide data hidden or manipulated (orders to describe suicide attempt as “overdose” and suicidal ideation as “depression”)
May 22, 2003-GSK submitted analysis of suicide-related adverse events in pediatric trials of paroxetine
-This analysis showed stat. sig. increase in these events with paroxetine compared to placebo
-Division of Neuropharmalogical Drug Products (DNDP) requested makers of 8 other antidepressants to conduct similar searches of their clinical trial databases.
-after receiving this info, in Feb 2004 DNDP proposed plan for outsourcing a review of patient-level data sets from these trials
June NY state sues GSK over undisclosed safety and efficacy info on Paxil
Unpublished results re efficacy, suicide risk

9. October 2003-FDA PHA, FDA requests trial data sets from 8 manufacturers
December 2003-UK bans all SSRIs except Prozac for ped use
Feb FDA plans own review of data

10. Sept. 2004-publicized advisory committee mtg-open public hearing
October Black Box warning issued
15 to 8 in favor of BBW-at meeting of the Center for drug evaluation and research psychopharmacologic drugs advisory committee and the FDA pediatric advisory committee Sept 13-14, 2004

11. Review of Data Blinded review of suicide-related AE’s
Reviewers assembled by Columbia U.
Investigate relationship between psychotropic drugs and suicidality
-AE’s (adverse events) assessed by10 suicidology experts
-reviewers blinded to med, manufacturer, whether active or placebo

12. Data Base 9 antidepressant medications
23 short-term trials, from 1983 to 2001
4487 Subjects
Ages 6-18
Multiple indications(MDD,OCD,GAD,SAD,ADD)
-prozac, zoloft, paxil, luvox, celexa, wellbutrin, effexor, serzone, remeron
-Trial duration from 4 to 16 weeks- short-term trials
-indications included major depressive disorder (15 trials), anxiety disorder (5 trials of OCD), generalized anxiety disorder (2), Social anxiety disorder (1), ADHD (2)

13. 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” 13

14. Main Outcomes Used in the Analysis (note- no completed suicides)
Description
Number
Outcome 1
Suicidal behavior, codes 1 & 2
n=33
Outcome 2
Suicidal ideation, code 6
n=45
Outcome 3 (primary outcome)
Suicidal behavior or ideation (codes 1, 2, & 6)
n=78
Outcome 4
Possible suicidal behavior or ideation (codes 1, 2, , 10 )
n=109
No completed suicides 14

15. This is the form that data was provided to committee during Sept 2004 open meeting of Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee 15

16. 16

17. 17

18. EFFEX (GAD, 396)
95% confidence interval does not include the value 1 18

19. * Note that TADS data are added to Prozac
Overall relative risks (RR) of suicidal behavior or ideation (codes 1, 2, & 6) by drug
Drug
Relative Risk (95% CI), MDD trials
Relative Risk (95% CI), all trials, all indications
Celexa
1.37 (0.53, 3.50)
Luvox
No MDD trials
5.52 (0.27, )
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)
Serzone
No events
Wellbutrin
* Note that TADS data are added to Prozac 19

20. * Note that TADS data are added to Prozac
Overall relative risks of suicidal behavior or ideation (codes 1, 2, & 6) by drug in MDD trials
Drug
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
0.75
1.37
Paxil
2.30
1.09
2.15
Prozac *
1.30
1.53
Zoloft
0.98
3.88
2.16
Effexor XR
2.77
7.89
8.84
Remeron
No events
1.58 20
* Note that TADS data are added to Prozac

21. SSRIs as a Class in MDD trials: Celexa, Prozac*, Paxil, & Zoloft
68 events, 2033 patients, 11 MDD trials
* Note that TADS data are added

22. Boxes vary in size acc to saple size and effect size
Line is 95% confidence interval
Random-effects 1.56 (0.94, 2.59) 22

23. 23

24. * Note that TADS data are NOT added to Prozac
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)
(0.21, 4.14)
Paxil
1.36 (0.18, )
2.13 (0.66, 6.88)
Zoloft
2.42 (0.36, )
1.37 (0.18, )
Celexa
1.39 (0.30, 6.49)
1.16 (0.39, 3.44)
Effexor XR
5.67 (0.69, )
(0.52, 39.72)
Remeron
1.63 (0.07, )
No events
All 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)
* Note that TADS data are NOT added to Prozac 24

25. Potential “Activation” Syndrome
Defined as Treatment-Emergent Hostility or Agitation
This possibility mentioned in BBW and patient guide, includes anxiety, agitation, insomnia, irritability, panic attacks, aggressiveness, anger

26. * Note that TADS data are NOT added to Prozac
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)
Included in labeling-”The following symptoms-anxiety, agitation, panic attacks,insomnia, irritability, hostility (aggressiveness), impusivity, restlessness, hypomania, and mania have been reported in adult and pediatric patients being treated for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Increases in suicide-related events occurred in first weeks of Tx
Hazard peaks at days
FDA Announcement October 15, 2004
•"Based on these data, FDA is asking that the following points be included in the boxed warning:
–Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
–Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.
* Note that TADS data are NOT added to Prozac 26

27. FDA review- “likelihood of event of primary outcome among patients with hostility or agitation was not evaluable because…determining the time sequence was not possible”

28. Independent contribution of insomnia?
April1, 2009-Wojnar et all paper at World Psychiatric Assoc. Int’l Congress- looked at rel between sleep and suicidal beh in 5,692 U.S. men and women.
Adjusted for substance abuse, depression, age, gender, marital status- most consistent find was in waking up early- twice as likely to have had s. thoughts, three times as likely to have attempted suicide

29. Ascertainment bias
-Those treated with antidep may be more open, articulate about thoughts-
-Those in active arm, treated with antidep, may have increased opportunity to talk if they were having more clinical contact due to side effects, may be asked at these times about s.i.
But-this may account for some reports of suicidal ideation, but would not account for instances of suicidal behavior

30. Limitations Short-term trials
Heterogeneity of trial characteristics-Some trials excluded active suicide risk, H/O attempt, H/O treatment resistance, patient or family H/O bipolar at baseline
Observed rates of suicide may not reflect actual rates in population- “volunteer’s bias”, or due to exclusion of some s’s, as well as selection crirteria

31. Some trials excluded placebo responders (placebo “run-in”)
Trials designed to assess efficacy, not risk
Individual trials insufficiently powered
Excluding placebo responders may have eliminated some less-depressed S’s
Power-assuming an incidence of 1% of s.i./beh in the placebo group, trals with 100 pts in each arm (which most had) had an 80% power to detect a 12-fold increase in risk of suicidality
-assuming 5% incidence on placebo group…80% power to detect 4-fold increase

32. FDA Announcement October 15, 2004
"Based on these data, FDA is asking that the following points be included in the boxed warning:
Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.
-voted on by the FDA combined Psychopharmacologic Drugs committee and the Pediatric Advisory committee (18 to 5)

33. Families and caregivers should also be advised to closely observe the patient and communicate with the prescriber.
Among the antidepressants, only Prozac is approved for use in treating MDD in pediatric patients. Prozac, Zoloft, Luvox, and Anafranil are approved for OCD in pediatric patients. None of the drugs is approved for other psychiatric indications in children."

34. How Should the Risk Be Described in the Warning?
Drug treatment doubled risk of suicidal events versus placebo (Relative risk = 2)
Incidence of suicidal events: Drug 4%; Placebo 2%

35. Black Box Warning
“Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders…Patients who are started on therapy should be observed for clinical worsening, suicidality, or unusual changes in behavior.”

36. “Ideally, such observation would include at least weekly face-to-face contact with pts or their family members or caregivers during the first 4 weeks of tx, then visits every other week for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks”

37. Which Drugs to Include in the Warning?
“These labeling changes are applicable to the entire category of antidepressant medications because the currently available data are not adequate to exclude any single medication from the increased risk of suicidality.”
FDA Public Health Advisory
Straterra added to warnings September 2005.
Prozac included in spite of being only antidepressant with FDA indication for pediatric depression TADS study only one to indicate increased risk of suicidality). Zoloft, prozac, anafranil, luvox FDA app for pediatric OCD.

38. Antidepressants and Suicidality in Adults-PHA 7/1/05; BBW 7/2/07
“The FDA today proposed that makers of all antidepressant medications update the existing black box warning …to include warnings about increased risks of suicidal thinking and behavior…in young adults ages 18 to 24 during initial treatment (generally the first one to two months).”
Background Teicher et al article pts became suicidal after tx with prozac (all given high doses-80 mg)
FDA meeting- FDA concluded increased reports of s.i. in adults were inspired by Teicher article; review of Lilly Clinical trials indicated no evidence of s.i.
Since 2000 there have been mixed results, with several studies showing some increased risk (OR 1.6 to 2) with SSRIs

39. 372 placebo-controlled antidepressant trials Nearly 100,000 patients
Adjudication of PSRAEs as per the Columbia Classification Algorithm of Suicide Assessment (C-CASA)
Due to large number of subjects, adjudications were performed by the sponsors and were not overseen by the FDA

40. Antidepressants Studied
SSRIs
1. Citalopram (Celexa®)
2. Escitalopram (Lexapro®)
3. Fluoxetine (Prozac®)
4. Fluvoxamine (Luvox®)
5. Paroxetine (Paxil®)
6. Sertraline (Zoloft®)
Non-SSRIs
7. Bupropion (Wellbutrin®)
8. Duloxetine (Cymbalta®)
9. Mirtazapine (Remeron®)
10. Nefazodone (Serzone®)
11. Venlafaxine (Effexor®)

41. Selecting Trials for the Dataset
FDA letter provided the following guidance to sponsors on the studies to include in the dataset:
Randomized, placebo-controlled trials only
Trials for any indication
Trials of any length

42. Study Indication Groups
Major depressive disorder (MDD)
Other depressive disorders
Other psychiatric disorders
Behavioral disorders
Other disorders
Non-MDD Indications

43. Other Depressive Disorders
MDD or Bipolar Disorder
Premenstrual Dysphoric Disorder
Post Natal Depression
Seasonal Affective Disorder
Atypical Depression
Bipolar Disorder
Depression (Unspecified)
Depression (Non-MDD)
Dysthymia
Dysthymia or Major Depression

44. Other Psychiatric Disorders
Neurasthenia
Non-Depressed OCD
Obsessive Compulsive Disorder
Pain Disorder
Panic Disorder
Post-traumatic Stress Disorder
Social Anxiety Disorder
ADHD
Adjustment Disorder
Anxiety Disorders
Alzheimer’s Disease
Bulimia
Generalized Anxiety Disorder
Generalized Social Phobia
Negative Symptoms Of Schizophrenia

45. Other Behavioral Disorders
Alcoholism
Insomnia
Insomnia and Anxiety Preceding Surgery
Obesity
Obesity and Hypertension
Obesity, Hypertension and Diabetes
Obesity / Diabetes or Glucose Intolerance
Smoking Cessation
Weight Loss
Weight Maintenance

46. Other Disorders Diabetic Neuropathy Fibromyalgia
Mixed Urinary Incontinence
Migraine Prophylaxis
Neuropathic Pain
Non-Ulcer Dyspepsia
Premature Ejaculation
Stress Urinary Incontinence
Sexual Dysfunction
Sleep in Healthy Volunteers
Urge Urinary Incontinence

47. Events Psychiatric Indications
Treatment Group
Event
Placeb
N27164
Test Drug
N=39729
Active
Control
N=10489
Total
N=77382
Completed suicide 2 5 1 8
Suicide attempt 44 71 18
133
Preparatory acts 3 4 10
Suicidal ideation
147
169 42
358
Total Events
196
248 65
509

49. Suicidal Behavior or Ideation by Age Psychiatric Indications
Odds Ratio Drug/Placebo
95% Confidence Interval
p value
Age<25
1.62
0.97 – 2.71
0.07
Age
0.79
0.64 – 0.98
0.03
Age 65+
0.37
0.18 – 0.76
0.007
FDA noted decreasing risk with age, even a “protective” effect on those over 65

50. Comparison with Pediatric Studies

51. *
* Reanalysis of FDA/Hammad 2004 data

52. Suicidal Behavior or Ideation All Drugs
Odds Ratio
95% CI
Pediatric studies Age <12
2.88
0.90 – 9.18
Pediatric studies Age 12+
2.11
1.27 – 3.52
Adult studies Age <25
1.62
0.97 – 2.71
Adult studies Age 25 – 64
0.79
0.64 – 0.98
Adult studies Age 65+
0.37
0.18 – 0.76

54. Findings
When suicidal behavior and ideation are considered together, the risk associated with drug treatment relative to placebo is
Elevated in subjects under age 25
Reduced in subjects ages 25 – 64
Further reduced in subjects age 65 and older

55. The case of Zoloft
Overview document submitted to FDA 12/16/06- p.39 “Additional analyses involving sertraline”
“There were 57 trials, adult and pediatric, for psych disorders involving sertraline.
In 19 trials with 6002 Ss, sertraline was directly compared with other antidepressants, incl TCA, SSRI, buproprion, and venlafaxine.
In these trials the OR for suicidality relative to placebo was 0.52 for sertraline and 1.35 for other antidepressants.
The diff was statistically sig.
There were no suicidal events in the 2126 Ss assigned to sertraline, 3 events among 1733 placebo Ss, 6 events among Ss assigned to other antidepressant drugs.
OR “suicidality” decreases with age- <25=0.99, 25+=0.62 (not incl. behavior): S. behavior-<25=0.80, 25+=0.29
“Given large number of comparisons made in this review, chance is a very plausible explanation for this diff. but the consistency of the finding indicates a need to entertain other possibilities” (p. 39)

56. What are the effects of the Black Box Warning?

57. FDA Advisory Committee 1991
“Modifying antidepressant drug labeling could lead to reduction in antidepressant use, and this could damage public health.”
Paul Leber, Director, FDA Neuropharmacologic Drug Products

58. FDA’s intent
“The FDA intended the Black Box Warnings to improve physician-patient communication and encourage closer physician monitoring”
(Mayo Clinic Proc. 2007)

59. An Evaluation of the FDA Warnings on Antidepressants and Suicidality on Patterns of Care for MDD (Libby et al 2007)
Study Design: Interrupted time series analysis of subjects with MDD
Population: MDD according to HEDIS criteria (Depression cases N=541,000; N=65,000 unique cases pediatric depression)
Data Source: PharMetrics Longitudinal Database ( )
Interruption: First FDA PHA in October 2003
- 5 years “pre” data ( ), 2 years “post” data ( )
Analysis: Segmented regression analysis
- Run for both pediatric, adult populations
Libby et al, Am J Psychiatry 2007

60. Main Findings: Pediatric Population
Rate of MDD Diagnosing in Population decreased
Rate of diagnosed MDD per 1,000 enrollees dropped significantly
Pediatricians, PCP’s diagnosing MDD less, Psychiatrists more

61. Decrease in antidepressant prescribing
Pediatricians, PCP’s prescribing less, Psychiatrists and other specialists prescribing more (emergency medicine=highest)
Percentage of depressive episodes in which pt received SSRI- down 59% to 28% after 2003 PHA

62. No Major Substitution Patterns are Apparent
No significant shifts towards increased use of psychotherapy or alternative medications

63. Regarding the Decrease in Pediatric Antidepressant Prescribing
Medco pharmacy benefit manager data showed an 18% decrease in number of pediatric patients on antidepressants for the first quarter of 2004
Medco Health Solutions news release, <
From fda meeting 6/28/05-a. mosholdermd-medical officer, fda office of drug safety
This news followed PHA in 10/2003- preceded BBW in 10/04

64. U.S. Data IMS Health Prescription Dataset Robert D. Gibbons
AD prescription rates drawn from random sample of 20,000 pharmacies in U.S. in IMS Health database (represents half of all retail pharmacies in U.S.)
Robert D. Gibbons
Member of 2004 FDA Psychopharmacological Drugs Advisory Committee

68. Prescribing Patterns Mayo Clinic survey 2006
-76% of 233 physicians responding prescribed at same rate
-24% had decreased or stopped prescribing antidepressants
97% of providers knew of BBW’s, and presumably knew intent of warnings- to balance risk with clinical need- but a number of providers backed away from prior med patterns
-sample included wide range of providers

69. 22% had encountered parents or caregivers who refused AD medication for their children because of BBW

70. 40% saw patients more frequently after starting medication
7.5% saw patients weekly for first month -on average, saw them two times first month
Compare to FDA rec-weekly for first mo., every 2 weeks following month

71. (J Child and Adolesc Psychopharmacology 2008)
1,521 clinicians in Nebraska surveyed
15.5 % reduced prescriptions to children
37% reduced prescriptions to adolescents
44% made more referrals to mental health

72. Prescription rates and suicide

73. CDC-”Suicide trends among youths and young adults 10-24, U. S
suicide rate declined 28.5%, from 9.5 to 6.8/100,000
rate increased 8.0%, from 6.8 to 7.3/100,000
Largest single-year increase during
Gibbons 2007, Am J Psychiatry reports total suicides ages 5-19: in suicides; in suicides
Acad Highlights update on c and A depression- rates per 100,000: ages 10-14=1.2; 15-19=7.3; 20-24=12.1 (CDC)
Rel bet suicide rate and Rx rate unclear-suicide rate for went down in 2005, even though that was year prescription rates went down the most

74. 2005- 5% decrease in adolescent and young adult suicide rate

76.
Significant inverse association between SSRI prescriptions and youth suicide rates overall (p<.04)
Strongest effect for boys under 15, r=-.67, p<.05.

77. 2003-2005 22% decrease in youth SSRI prescriptions
49% increase in youth suicide
34 to 51 out of approximately 4 million
446% increase in youth suicide for boys < 15
2 to 11 out of approximately 1.5 million

78. Risk-benefit
Suicide rates in U.S. began dropping in 1987, after 3-decade rise
There were suicides in young adult data

79. Risk-benefit Bridge et al, JAMA 2007- Pediatric data
“NNT (benefit) ranges from 3 to 10”
“NNH (harm) ranges from ”

80. What is the take-home message?
There is evidence of increased suicidality with treatment, especially initially
What the Black Box Warnings actually say
They don’t say avoid these medications-they say monitor for adverse events
There may be two processes at work- one that facilitates suicidality, one that inhibits it- agitation/anxiety that may occur prior to mood-enhancing effects (so you have a depressed, agitated person- worse situation than the old depressed-energized person)

81. -Antidepressant medications not contraindicated
-Depression is a risk factor for suicidal thoughts/actions – weigh risks and benefits
-Monitor patient responses
So it is important to weigh risks and benefits- implies there is risk of failure to treat

82. Am J Psychiatry 2006
The Food and Drug Administration requires a warning that antidepressant medications can sometimes cause or increase thoughts of suicide. Studies in children and adolescents have shown that antidepressants can increase suicidal thoughts. However, other studies have shown that the overall risk of attempting suicide goes down after starting antidepressant medication. Even if antidepressants help most people who take them, some people may have very negative reactions. Thus, it is important that we have regular contact over the next few weeks. If you have thoughts about suicide or about harming yourself, please contact me right away.

83. FDA Web Info
9/13/04 Psychopharmacologic Drugs and Advisory Committee and the Pediatric Advisory Committee:
ac/cder04.html#PsychopharmacologicDrugs

84. FDA Website: AD use in children adolescents, and adults: