# Presentation: 370841

## Psychiatric ConditionsAttempts to Confirm SignalJohn McLane, Ph.D.Roche Medical Science and Safety  

- 9/5/00

## Clinical Overview
Pharmaco-epidemiological Assessment
Clinical Analysis of Spontaneous Reports
Additional Assessments
Biological plausibility
Risk Management

- Pharmaco-epidemiological Assessment
- Clinical Analysis of Spontaneous Reports
**Additional Assessments**
- Biological plausibility
- Risk Management

## Assessment Strategy to Confirm Signal 

**Assessment Strategy to Confirm Signal **

- Post-approval analysis
- Retrospective analysis
- Prospective analysis

## Retrospective Epidemiological Analysis Relative Risk - Accutane versus Antibiotic

**Retrospective Epidemiological Analysis Relative Risk - Accutane versus Antibiotic**

- Objective
- Relative risk for psychiatric disorders
- Methods
- Population-based epidemiological study
- Retrospective matched-control cohort
- Analysis of prevalence rates for a variety of psychiatric disorders and suicide/suicide attempts

**Notes:**
SASK database
	Accutane users (n=7,195)
	Antibiotic drug therapy (n=13,700)
GPRD database
	Accutane users (n=340)
	Antibiotic drug therapy (n=676)

	total database sizes 

## Retrospective AnalysisEpidemiological Data Source

**Retrospective Analysis****Epidemiological Data Source**

- Two Validated Healthcare Databases
- Canadian Saskatchewan Health Database (SASK)
- Accutane users (n = 7,195)
- antibiotic drug therapy (n = 13,700)
- UK General Practice Research Database (GPRD)
- Accutane users (n = 340)
- antibiotic drug therapy (n = 676)

## Relative Risk for Disorders SASK Database

**Relative Risk for Disorders ****SASK Database**

- Current Accutane use:	RR= 1.0 (95% CI 0.9-1.3)
- Recent Accutane use:	RR= 0.9 (95% CI 0.6-1.4)
- Current antibiotics use:	RR= 1.3 (95% CI 1.0-1.5)
- Recent antibiotics use:	RR= 0.9 (95% CI 0.7-1.1)
- Prior psychiatric history emerged as the only predictor for the above outcome

**Notes:**
Method: logistic regression model (SAS, ver. 6.12)

## Accutane and Antidepressant Prescriptions:Symmetry Analysis of Prescription Sequence 

**Accutane and Antidepressant Prescriptions:****Symmetry Analysis of Prescription Sequence **

- Accutane did not show effect on prescriptions for antidepressants in symmetry analysis
- Prescription Sequence ratio = A/B, where A = # pts. prescribed Accutane **before** antidepressants B = # pts. prescribed Accutane **after **antidepressants.
- Ratio near unity indicates no effect

## Accutane and Antidepressant Prescribing*Prescription Sequence Symmetry Analysis 

**Accutane Prescribed**_**Before/After (**__***A/B***__**)**_

- 1,382 / 1,439
- 174 / 200
- 874 / 861
- 334 / 378

**Adjusted Rate Ratio*******_**(95% CI)**_

- 0.97 (0.92-1.02)
- 0.90 (0.78-1.04)
- 0.99 (0.93-1.02)
- 0.95 (0.85-1.05)

- All
- Amine
- SSRI
- “Other”

**Antidepressant **_**Drugs**_

***Synergy Pharmacy Claims Database, June 1999 - March 2000**
** ****adjusted for changes in prescribing trends during analysis period**

- Adjusted rate ratio was less than one within each class and for all antidepressants

## Minocycline and Antidepressant Prescribing* Prescription Sequence Symmetry Analysis

- All
- Amine
- SSRI
- “Other”

**Minocycline Prescribed**_** Before/After (**__***A/B***__**)**_

- 3,609 / 3,751
- 494 / 569
- 2,277 / 2,170
- 838 / 1,012

**Adjusted Rate Ratio**_**(95% CI)**_

- 0.98 (0.95-1.02)
- 1.01 (0.93-1.10)
- 1.00 (0.96-1.04)
- 0.94 (0.88-1.00)

**Antidepressant**_** Drugs**_

***Synergy Pharmacy Claims Database, June 1999 - March 2000**
** ****adjusted for changes in trends during analysis period**

## Prospective Analysis of Signal

- Evaluate in clinical trial using 2 tools
- Mood assessment questionnaire
- Beck Depression Inventory (BDI-II)
- Evaluate 600 patients treated with one of 2 formulations of isotretinoin
- Obtain baseline values and end of treatment values
- At monthly visits: Mood assessment questionnaire

## Distribution of Change in Grade on BDI-II

**Treatment Group**

**Distribution of Change in Grade on BDI-II**

**	****Accutane NF ****	**** Accutane ****Change in Grade ****	****N ****	****N**

**	****-2****	****4****	****1**
**	****-1****	****7****	****10**
**	****0****	****283****	****283**
**	****+1****	****3****	****5**
**	****+2****	****2****	****1**

**BDI-II Grades****	****Minimal ****	****	****0-13 ****	**** (– indicates decrease grade / + increase)**
**	****	****Mild****	****	****14-19**
**	****	****Moderate****	****	****20-29**
**	****	****Severe****	****	****30-63**

## Change in BDI-II ScoresBaseline to Week 20

**Mean ******** SD ****	****3.5 ******** 4.6 ****	****1.7 ******** 3.1 ****	****3.6 ******** 4.5****	****1.9 ******** 3.7**
**Range ****	****0 - 24****	**** 0 - 21 ****	****0 - 29 ****	****0 - 28**

**PSY 207, (1492), 9/5/00**

**	****Accutane NF****	****Accutane ****	****N = 263****	****N =255**

**Change in BDI-II Scores****Baseline to Week 20**

## Clinical Overview
Pharmaco-epidemiological Assessment
Clinical Analysis of Spontaneous Reports
Additional Assessments
Biological Plausibility
Risk Management

- Pharmaco-epidemiological Assessment
- Clinical Analysis of Spontaneous Reports
- Additional Assessments
**Biological Plausibility**
- Risk Management

## CNS Relationships With RetinoidsRats and Mice

**CNS Relationships With Retinoids****Rats and Mice**

- Specific dopamine enriched brain regions have retinoid receptors (cortex, hippocampus, caudate/putamen, nucleus accumbens, olfactory tubercle)
- Localization of proteins differs from localization by mRNA
- Dopamine 2 receptor genes have retinoid response elements
- Isotretinoin can be found in the brain after injections

## Biological Summary

- Although some of the component factors are in place, retinoids have not been shown to activate genes to induce behavioral/psychiatric changes
- In mice lacking retinoid receptor genes no behavioral effects other than long term memory (Long Term Potentiation/Depression)
- Lack of evidence demonstrating functionality of retinoid signaling pathways in the mature CNS

## Conclusion

- All available evidence does not confirm signal
- Biological plausibility is not established
- Background disease rate in population warrants attention to signs and symptoms of psychosocial disturbance by Dermatologists

## Clinical Overview
Pharmaco-epidemiological Assessment
Clinical Analysis of Spontaneous Reports
Additional Analysis
Biological Feasibility
Risk Management

- Pharmaco-epidemiological Assessment
- Clinical Analysis of Spontaneous Reports
- Additional Analysis
- Biological Feasibility
**Risk Management**

## End