This document summarizes a presentation about pharmacogenetics in neurology and psychiatry. It discusses how genetic information can be used to permit safer and more effective drug use. It provides examples of genetic factors like CYP enzymes and BDNF that influence drug metabolism and efficacy of drugs like SSRIs. It also describes a study that found patients were 42% less likely to not stabilize if they followed recommendations from the Neurofarmagen pharmacogenetic test over 3 months. The presentation promotes combining pharmacogenetics with environmental and drug interaction data to further improve therapeutic outcomes.

1. MARCO MARCHETTI
FB HEALTH
USO ED ABUSO DEI FARMACI
Venerdì 17 aprile 2015
Sala conferenze Digital for Business - Sesto San Giovanni (MI)
www.digitalforacademy.com

2. PHARMACOGENETICS IN
NEUROLOGY & PSYCHIATRY
NEUROFARMAGEN®

3. PHARMACOGENETICS
“It is not the analysis of disease
genetic risk factors that shows the
most immediate promise for human
health,
but the application of genetic
information to permit safer and
more efficacious use of drugs”*
*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011
Genome- Sequencing
10th Anniversary

4. PHARMACOGENETICS
“It is not the analysis of disease
genetic risk factors that shows the
most immediate promise for human
health,
but the application of genetic
information to permit safer and
more efficacious use of drugs”*
*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011
Genome- Sequencing
10th Anniversary PHARMACOGENETICS
=

5. PHARMACOGENETICS
“It is not the analysis of disease
genetic risk factors that shows the
most immediate promise for human
health,
but the application of genetic
information to permit safer and
more efficacious use of drugs”*
*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011
Genome- Sequencing
10th Anniversary
PERSONALIZED MEDICINE

6. PHARMACOGENETICS
 Pharmacogenetics is not only about drug metabolism!
 Genes can affect both pharmacokinetics and pharmacodynamics
 Response profile to a given drug likely to depend on more
than just one gene
 Imagine checking only creatinine and glucose in a blood analysis
 More specific guidelines than “use with caution” are
desirable
 Provide specific recommendations whenever possible
 Adapt the wording to the available evidence

7. IMPLEMENT genotype-specific recommendations based
on the available evidence
REVIEW of all genetic association studies in international
scientific journals, FDA labels and CPIC and DPWG guidelines
Continuousupdate
List of drugs used in psychiatry & neurology
NEUROFARMAGEN

8. CLOBAZAM DOSE AND CYTOCHROME CYP2C19
 Plasma levels of Clobazam are significantly affected by genetic
variations (polymorphisms) in CYP2C19
 FDA has issued genotype-adjusted dosing guidelines:
EXAMPLES OF SCIENTIFIC BASIS

9. • CYP2D6 UMs: Avoid or increase dose (strong)
• CYP2D6 PMs: Avoid or consider 50% reduction of starting dose (strong)
• CYP2C19 UMs: Consider alternative drug (optional)
• CYP2C19 PMs: Consider 50% reduction of starting dose (moderate)
TRICYCLIC ANTIDEPRESSANTS AND CYTOCHROMES CYP2C19 & 2D6
 Up to 30% of Caucasians carry genetic variants resulting in significantly
altered CYP2C19 or 2D6 metabolism
 CPIC has issued specific recommendations for TCAs affected by
CYP2D6 only (Nortriptyline, Desipramine) or both CYPs (Amitriptyline,
Clomipramine, Doxepin, Imipramine and Trimipramine)1
1) Hicks et al, Clin Pharmacol Therap 2013
EXAMPLES OF SCIENTIFIC BASIS

10. EFFICACY OF SSRIs AND BDNF
 BDNF (Brain-Derived Neurotrophic Factor): Growth factor that
stimulates neuronal survival and synapse formation.
 A recent meta-analysis indicates that a BDNF polymorphism affects
SSRIs efficacy: Val/Met heterozygotes more likely to respond1
1) Niitsu et al., Prog Neur-Psychopharmacol Biol Psychiatr 2013
EXAMPLES OF SCIENTIFIC BASIS

11. TOLERABILITY OF SSRIs AND 5-HTTLPr
 5-HTTLPR is a degenerate repeat polymorphic region in the promoter
of the 5HT transporter (SLC6A4 gene)
 Meta-analyses have linked the short allele to lower risk of good
response1 and to higher risk of adverse effects2 for Caucasian subjects
1) Porcelli et al., Eur Neuropsychopharmacol 2012; 2) Kato et al., Molecular Psychiatr 2010
EXAMPLES OF SCIENTIFIC BASIS

12. TEST IMPLEMENTATION
Saliva Sample
DNA Analysis & InterpretationPharmacogenetic Report

13. TEST IMPLEMENTATION
 Reports can be accessed
online via username &
password
 Color coding indicates most
relevant information for
each drug:
1. Adverse effects
2. Metabolism
3. Good Response
4. Standard
-Priority+

14. TEST IMPLEMENTATION
Double-click opens detailed
information
• Detailed results for each
relevant genetic variant
• Specific recommendations

15. USE OF PHARMACOGENETIC
INFORMATION AND PATIENT
STABILIZATION IN PSYCHIATRIC
PATIENTS

16. • Study conducted at 3 clinical settings in Madrid (Spain), coordinated by IRB
from “Hospital Clínico San Carlos” (Madrid)
• Cross-sectional, naturalistic, retrospective, multi-centric study
• Entry criteria:
• ≥18 years old, with a psychiatric disorder
• CGI-S ≥ 3 at baseline (92% of subjects ≥4)
• Neurofarmagen CORE had been used
• Primary endpoint: rate of stabilization at 3
months, defined as CGI-S ≤ 3
STUDY DESIGN

17. PATIENT FLOWCHART

18.  No significant differences between groups regarding demographic
and clinical characteristics1
 Significant difference at study endpoint (3 months) : number of non-
stabilized patients reduced by 42% in group following NFG
RESULTS
1) years since diagnosis, psychiatric condition, baseline CGI-S , non psychiatric medication, smoking, substance abuse

19. Follows t0 Follows not t0 Follows t3 Follows not t3
CGI-S
 Baseline characteristics were included in a multiple regression model
 Only baseline severity (CGI-S0) and Followed/Did not follow NFG had
a statistically significant effect
 Final model1: r=0.55, p=6x10-15
1) Homoscedasticity and normality of errors verified
RESULTS

20. WHAT NEXT?
Combine Pharmacogenetics,
Environment and Drug Interactions

21. REPORT UPGRADE
Checks interactions with:
 Health condition
 Environmental variables
 Concomitant medication
(psychiatric and non-psychiatric)

22. REPORT UPGRADE
 Patient’s name and surname
are optional
 They are encrypted in the
database, only the doctor
can see them, not FB-Health
or AB-Biotics

23. NEUROFARMAGEN REPORT
GENETICS ONLY GENETICS + PATIENT INFO.
Environmental interactions and
drug interactions are added on
top of the pharmacogenetic
information

24. Designed to help physicians to better understand the drug response of
difficult-to-treat patients, and to achieve better therapeutic outcomes
Neurofarmagen is more than a cytochrome genotyping test:
 Analyzes other genes related to drug metabolism (EPHX1, CES1) or
transport (ABCB1)
 Also many pharmacodynamic genes (5HT signaling, DRD2 cascade)
 Provides genotype and drug-specific drug recommendations
 Clinically tested, more trials ongoing
 Environment and drug interactions implemented soon

25. … Thank You!!!

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