# Presentation: 667255

## Antidepressant Drugs and Suicidality

- Marc B. Stone, MD
- Senior Medical Reviewer
- Division of Neurology Products / Division of Psychiatry Products

## Analytical Approach

- Include antidepressant active control arms
- Increases power
- Allows consideration of tricyclics and other older antidepressants
- Estimate odds ratios using conditional (fixed effects) logistic regression

## Studies of Adults

## All Indications All Subjects (including active controls) 

|  | Odds Ratio Drug/Placebo | 95% Confidence Interval  | p value  |
| --- | --- | --- | --- |
| Suicidal Behavior or Ideation | 0.85 | 0.71 – 1.02 | 0.08 |
| Suicidal Behavior | 1.12 | 0.79 – 1.58 | 0.54 |
| Completed Suicide | 2.13 | 0.41 – 11.0 | 0.37 |

## Studies of Adults

- Grouping by Indication

## Indication Groupings

- Major Depressive Disorder (MDD)
- Other Depressive Disorders
- Other Psychiatric Disorders
- Behavioral Indications
- Other Indications

## Number of  Suicidality Events

| Completed          | Attempt  | Preparation | Ideation | Indication |
| --- | --- | --- | --- | --- |
| 8 | 134 | 10 | 378 | All |
| 6 | 90 | 7 | 238 | Major Depression |
| 0 | 7 | 1 | 14 | Other Depression |
| 2 | 36 | 2 | 108 | Other Psychiatric |
| 0 | 1 | 0 | 8 | Other Behavioral |
| 0 | 0 | 0 | 10 | Other |

## Incidence of  Suicidality Events

| Events per 10,000 subject years |  |  |  | Indication |
| --- | --- | --- | --- | --- |
| Completed          | Attempt  | Preparation | Ideation |  |
| 5.1 | 86 | 6.4 | 244 | All |
| 10 | 157 | 12 | 416 | Major Depression |
| 0 | 81 | 12 | 163 | Other Depression |
| 4.1 | 73 | 4.1 | 220 | Other Psychiatric |
| 0 | 4.2 | 0 | 34 | Other Behavioral |
| 0 | 0 | 0 | 60 | Other |

## Slide 9

## Psychiatric Indications Only

|  | Odds Ratio Drug/Placebo | 95% Confidence Interval  | p value  |
| --- | --- | --- | --- |
| Suicidal Behavior or Ideation | 0.83 | 0.69 – 1.00 | 0.05 |
| Suicidal Behavior Only | 1.10 | 0.77 – 1.56 | 0.60 |

## Studies of Adults

- Grouping by Drug Class

## Drug Class

| SSRI | SNRI | Other Modern | Tricyclics | Other |
| --- | --- | --- | --- | --- |
| Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline | Duloxetine
Venlafaxine | Bupropion
MirtazapineNefazodone | Amitriptyline
Clomipramine
DesipramineDothiepin
Imipramine | Mianserin
Trazodone |

## Slide 13

## Slide 14

## Studies of Adults

- Grouping by Age

## Suicidal Behavior or Ideation by Age Psychiatric Indications

|  | Drug |  | Placebo |  |
| --- | --- | --- | --- | --- |
| Age | Subjects with Events | Number of
Subjects | Subjects with Events | Number of
Subjects |
| <25 | 64 | 4780 | 21 | 2621 |
| 25 – 64 | 238 | 41,330 | 152 | 22,126 |
| 65+ | 12 | 3907 | 24 | 2397 |

## 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 25 - 64 | 0.79 | 0.64 – 0.98 | 0.03 |
| Age 65+ | 0.37 | 0.18 – 0.76 | 0.007 |

## Slide 18

## Suicidal Behavior by Age Psychiatric Indications

|  | Drug |  | Placebo |  |
| --- | --- | --- | --- | --- |
| Age | Subjects with Events | Number of
Subjects | Subjects with Events | Number of
Subjects |
| <25 | 32 | 4780 | 8 | 2621 |
| 25 – 64 | 69 | 41,330 | 34 | 22,126 |
| 65+ | 1 | 3907 | 7 | 2397 |

## Suicidal Behavior by Age Psychiatric Indications

|  | Odds Ratio Drug/Placebo | 95% Confidence Interval  | p value  |
| --- | --- | --- | --- |
| Age<25 | 2.30 | 1.04 – 5.09 | 0.04 |
| Age 25 - 64 | 1.03 | 0.68 – 1.58 | 0.88 |
| Age 65+ | 0.06 | 0.01 – 0.58 | 0.01 |

## Slide 21

## Comparison with Pediatric Studies

## Slide 23

## Pediatric Studies

- 24 Trials
- 4487 subjects
- Age range 6 – 18 years

## Pediatric Studies

|  | Risk Ratio | RR
95% CI | Odds Ratio | OR 
95% CI |
| --- | --- | --- | --- | --- |
| Suicidal Behavior or Ideation – 
All Drugs | 2.17 | 1.38 – 3.42 | 2.22 | 1.39 – 3.55 |
| Suicidal Behavior – All Drugs | 2.35 | 1.11 – 4.98 | 2.38 | 1.10 – 5.13 |
| Suicidal Behavior or Ideation – SSRI in MDD | 1.69 | 1.03 – 2.75 | 1.72 | 1.04 – 2.86 |

## Suicidal Behavior or IdeationAll Drugs – Psychiatric Indications

|  | 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 |

## Suicidal BehaviorAll Drugs – Psychiatric Indications

|  | Odds Ratio | 95% CI |
| --- | --- | --- |
| Pediatric studies Age <12 | 3.68 | 0.41 – 33.1 |
| Pediatric studies Age 12+ | 2.22 | 0.97 – 5.06 |
| Adult studies Age <25 | 2.30 | 1.04 – 5.09 |
| Adult studies Age 25 – 64 | 1.03 | 0.68 – 1.58 |
| Adult studies Age 65+ | 0.06 | 0.01 – 0.58 |

## Suicidal Behavior or IdeationSSRI in MDD

|  | Odds Ratio | 95% CI |
| --- | --- | --- |
| Pediatric studies Age <12 | 2.10 | 0.62 – 7.11 |
| Pediatric studies Age 12+ | 1.65 | 0.94 – 2.88 |
| Adult studies Age <25 | 1.25 | 0.48 – 3.27 |
| Adult studies Age 25 – 64 | 1.02 | 0.73 – 1.42 |
| Adult studies Age 65+ | 0.49 | 0.23 – 1.06 |

## Slide 29

## Suicidal Behavior or Ideation

- Age <25

- Age 25-64

- Age 65+

- 0

- 1

- 2

- 3

- Odds Ratio

- 0

- 20

- 40

- 60

- 80

- 100

- age

- Pediatric and Adult Studies

## Slide 31

## Adult and Pediatric StudiesSubjects <Age 25Suicidal Behavior or Ideation

|  | Odds Ratio
Drug/Placebo | 95% Confidence Interval | p value |
| --- | --- | --- | --- |
| Major Depression | 1.88 | 1.25 – 2.84 | 0.003 |
| Other Depression | 1.10 | 0.18 – 6.56 | 0.92 |
| Other Psychiatric | 2.26 | 1.13 – 4.54 | 0.02 |
| All Psychiatric | 1.94 | 1.37 – 2.74 | 0.0002 |

## Adult and Pediatric StudiesSubjects <Age 25Suicidal Behavior 

|  | Odds Ratio
Drug/Placebo | 95% Confidence Interval | p value |
| --- | --- | --- | --- |
| Major Depression | 2.04 | 1.06 – 3.90 | 0.03 |
| Other Depression | 2.07 | 0.22 – 19.5 | 0.52 |
| Other Psychiatric | 3.77 | 1.09 – 13.1 | 0.04 |
| All Psychiatric | 2.35 | 1.35 – 4.09 | 0.002 |

## Slide 34

## Slide 35

## Comparison with Other Meta-Analyses

## Slide 37

## Gunnell et al.

- Summary data by drug, not trial, provided by sponsors to the MHRA
- 6 SSRI drugs
- 477 trials
- 52,503 subjects
- Suicidality events not reviewed or subjected to standard criteria

## Completed Suicides SSRI vs. Placebo Control in Adults

|  |  | SSRI* |  | Placebo |  |
| --- | --- | --- | --- | --- | --- |
|  | Trials | Subjects | Events | Subjects | Events |
| Gunnell | 342 | 23,804 | 9 | 17,022 | 7 |
| FDA | 183 | 23,946 | 1 | 18,509 | 1 |

*** Excludes Fluoxetine and non-depression indications for Citalopram**

## Completed Suicides SSRI vs. Placebo Control in Adults

|  | Odds Ratio | 95% Confidence Interval  | Method  |
| --- | --- | --- | --- |
| Gunnell | 0.85 | 0.20 – 3.40 | Bayesian 
random effects meta-analysis  |
| FDA | 0.86 | 0.12 – 6.30 | Fixed effects logistic regression  |

## Non-Fatal Self Harm SSRI vs. Placebo Control in Adults

|  |  | SSRI* |  | Placebo |  |
| --- | --- | --- | --- | --- | --- |
|  | Trials | Subjects | Events | Subjects | Events |
| Gunnell | 477 | 30,814 | 111 | 21,689 | 61 |
| FDA | 264 | 35,434 | 67 | 26,154 | 38 |

*** Excludes non-depression indications for Citalopram**

## Non-Fatal Self Harm  SSRI vs. Placebo Control in Adults

|  | Odds Ratio | 95% Confidence Interval  | Method  |
| --- | --- | --- | --- |
| Gunnell | 1.29 | 0.90 – 1.91 | Bayesian 
random effects meta-analysis  |
| FDA | 1.25 | 0.84 – 1.89 | Fixed effects logistic regression  |

## Suicidal Thoughts SSRI vs. Placebo Control in Adults

|  |  | SSRI* |  | Placebo |  |
| --- | --- | --- | --- | --- | --- |
|  | Trials | Subjects | Events | Subjects | Events |
| Gunnell | 477 | 26,882 | 96 | 18,822 | 81 |
| FDA | 264 | 35,434 | 141 | 26,154 | 115 |

*** Excludes non-depression indications for Citalopram**

## Suicidal Thoughts in Placebo Controlled Trials in Adults

|  | Odds Ratio | 95% Confidence Interval  | Method  |
| --- | --- | --- | --- |
| Gunnell | 0.79 | 0.48 – 1.28 | Bayesian 
random effects meta-analysis  |
| FDA | 0.76 | 0.59 – 1.00 | Fixed effects logistic regression  |

## Slide 45

## Fergusson  et al.

- Trials reported in the public domain
- Published papers
- Cochrane registry
- Cochrane methodology
- Suicidality events not reviewed or subjected to standard criteria

## Slide 47

| Suicide Attempts
Controlled Trials of  SSRIs in Adults |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  | SSRI |  |  | Control |  |  |
|  | Review | Trials | Subjects | Fatal | Non-
Fatal | Subjects | Fatal | Non-
Fatal |
| SSRI vs.
 Placebo | Fergusson | 189 | 10,557 | 4 | 23 | 7856 | 3 | 6 |
|  | FDA | 272 | 38,017 | 2 | 60 | 26,056 | 2 | 31 |
| SSRI vs.
Tricyclics | Fergusson | 115 | 6126 | 5 | 29 | 5401 | 4 | 31 |
|  | FDA | 37 | 3135 | 0 | 7 | 2791 | 0 | 5 |

## Suicide Attempts Controlled Trials of SSRIs in Adults

|  | Review | Odds
Ratio | 95% CI |
| --- | --- | --- | --- |
| SSRI vs.
 Placebo | Fergusson | 2.28 | 1.14 – 4.55 |
|  | FDA | 1.31 | 0.85 – 2.03 |
| SSRI vs.
Tricyclics | Fergusson | 0.88 | 0.54 – 1.42 |
|  | FDA | 1.11 | 0.62 – 1.99 |

- Suicide Attempts Controlled Trials of SSRIs in Adults

## Discussion

## Findings

- The observed relationship between antidepressant drug treatment and  the incidence of reported suicidality events in clinical trials is strongly related to age

## 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

## Findings

- When suicidal behavior alone is considered, the risk associated with drug treatment relative to placebo is
- Elevated in subjects under age 25
- Neutral in subjects ages 25 – 64
- Reduced in subjects age 65 and older

## Findings

- The observed relationship between suicidality, age and antidepressant treatment appears not only in major depressive disorder but in all subjects with psychiatric diagnoses.

## Interpretation

- The observations are most consistent with two general effects:
- One  promoting suicidality
- One  preventing it
- In older subjects the preventative effect tends to predominate while in younger subjects the opposite is true
- A simpler explanation that denies a preventative effect and assumes only a promoting effect does not explain the protective effect seen in older subjects

## Reporting Effects

- Could antidepressant treatment simply cause more events to be reported?
- Could treatment allow subjects, particularly younger subjects, to simply become more articulate and open about their thoughts and actions?

## Reporting Effects

- However
- Drug effect appears to be at least as great on suicidal behavior as on suicidal thoughts
- Suicidal behavior is potentially directly observable

## Reporting Effects

- For a reporting effect to credibly explain the results
- Drug treatment must have a substantially greater effect on the reporting of  suicidal behavior than the reporting of suicidal thoughts or
- Almost all suicidal behavior was self-reported rather than observed by others
- Reporting effects must be strongly age related

## For Future Investigation

- Differences between drugs and drug classes need confirmation and, if confirmed, explanation.