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

Essential Pharmacogenomic Biomarkers in Clinical Practice
61
Psychiatric Disorders
Amitriptyline
Amitriptyline is a tricyclic antidepressant that has been considered one of the
reference compounds for depression therapy. 70 Amitriptyline is also used systemically
for the management of neuropathic pain. 71 Though amitriptyline is an
efficacious antidepressant drug, it is associated with a number of side effects, such as
clumsiness, drowsiness, muscle aches, and sleepiness. 72 Polymorphisms in CYP2C19
and CYP2D6 have been associated with its efficacy and the risk for side effects
in amitriptyline therapy. 73–75 For example, it has been confirmed that the increased
activity of the CYP2C19*17 allele is associated with the increased metabolism of
amitriptyline. 76 In contrast, the CYP2D6*4 allele, the main polymorphism resulting
in reduced enzyme activity in Caucasians, has been associated with the increased
toxicity (risk of developing symptoms of hyponatremia or low blood sodium concentrations)
77 of antidepressants including amitriptyline. 78
Nortriptyline
Nortriptyline, a second-generation tricyclic antidepressant, is an active metabolite
of amitriptyline. It is used in the treatment of major depression and childhood nocturnal
enuresis. Major side effects of nortriptyline include sedation, hypotension,
and anticholinergic effects. Nortriptyline is metabolized by the hepatic enzyme
CYP2D6. Approximately 7–10% of Caucasian individuals are poor metabolizers
with lower CYP2D6 enzyme activity, and might experience more adverse effects:
therefore, a lower dosage may be required in these individuals. Similar to amitriptyline,
CYP2D6 polymorphisms, such as the CYP2D6*4 allele, has been associated
with the increased toxicity of nortriptyline.
Citalopram
Citalopram, a drug of the selective serotonin reuptake inhibitor (SSRI) class that affects
neurotransmitters, 79 has been approved to treat major depression, given that an imbalance
of neurotransmitters is known to be the cause of depression. Although SSRIs have
better overall safety and tolerability than older antidepressants, adverse effects, such as
sexual dysfunction, weight gain, sleep disturbance, and suicidal thinking, may be associated
with long-term SSRI therapy. 80 Genetic variation in a GRIK4 (kainic acid–type
glutamate receptor) has been demonstrated to be reproducibly associated with response
to the antidepressant citalopram, suggesting that the glutamate system plays an important
role in modulating response to SSRIs. 81 In addition, since citalopram is metabolized
in the liver mostly by CYP2C19, as well as by CYP3A4 and CYP2D6, genetic variants
in these P450 genes are likely to influence the response to this drug.
Other Disorders
Abacavir for Viral Infection
Abacavir, a nucleoside analog reverse transcriptase inhibitor, is an antiretroviral
agent used together with other medicines to treat human immunodeficiency virus
(HIV) infection. 82 Abacavir has been well tolerated with main side effects of