Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

202 Applying Pharmacogenomics in Therapeutics
KEY CONCEPTS
• Genetic variations contribute to individual differences in pharmacokinetics
and pharmacodynamics of neurologic and psychiatric drugs.
• The translation of pharmacodynamic testing into clinical practice has
multiple limitations.
• Challenges exist in determining specific genetic components of SSRI
response to test pharmacogenomically.
• Larger population-based studies are needed to determine the relationship
between polymorphisms and response to drug treatment in neurology and
psychiatry.
INTRODUCTION
The human brain is one of the most complex organs in the body. This complexity
makes the treatment of central nervous system (CNS) disorders very challenging.
CNS medications are the second largest class of drugs (n ≥ 25) whose labels contain
pharmacogenomic information approved by the US Food and Drug Administration
(FDA) (Table 8.1). 1 Genetic variables influencing the pharmacokinetics and pharmacodynamics
of these medications have been extensively described in the literature,
but large-scale randomized controlled clinical studies specifically designed to
assess whether clinical testing is better than standard of care are still limited or
even lacking. 2 These studies are difficult to design and perform because of the multidimensional
biological causes of neurologic and psychiatric diseases and limited
knowledge of the mechanism of action of their treatments. 3 Currently, drug labeling
and consensus guidelines offer some guidance on the potential clinical utility of
pharmacogenetic testing with the use of these medications.
PHARMACOGENETIC STUDIES OF THE RESPONSE
TO NEUROLOGIC/PSYCHOTROPIC MEDICATIONS
Pharmacogenomic studies have been completed with multiple classes of neuropsychiatric
medications, with the major focus on interindividual variation in drug
efficacy. The vast majority of these studies have used a candidate gene approach,
which is usually based on the receptor pharmacology of the neuropsychiatric
medications. Although some studies have shown statistically significant effect
sizes for several of these candidate genes (dopamine 2 receptor and serotonin
transporter), the studies do not yield adequate sensitivity and specificity to reasonably
guide clinical practice. 2,4,5 Additionally, alternative treatment strategies
for the genetic carriers who may not respond well to medications have not been
empirically tested, because most prescribed neurologic or psychotropic drugs
have similar primary targets in each major class. 2
Another area of research where functional significance is important, but one
in which fewer studies have focused, is the cytochrome P450 (CYP450) system
in neurologic or psychiatric pharmacogenomics. 6 This may be due to the lack of
compelling empirical support for a relationship between plasma drug levels and