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CONTINUING PROFESSIONAL DEVELOPMENT
that past pharmacogenetic studies have
typically examined a very small number
of gene variants (usually only one or two).
tests, now being used increasingly
often overseas, can simultaneously
measure multiple gene variants relevant
to a number of different drugs, at very
low cost per variant (see Australian
Pharmacist July 2014 and May 2015).
A combinatorial pharmacogenomic
approach to antidepressant therapy is
taken by the proprietorial GeneSight
CPGx test, which assesses select variants
of four CYP enzymes (1A2, 2C9, 2C19,
2D6), the serotonin transporter gene
SLC6A4 and the serotonin 2A receptor
HTR2A gene.36 This multivariate approach
outperformed traditional single gene tests
in selecting more appropriate medicines
and predicting clinical outcomes for
patients with depression, and in predicting
healthcare utilisations and disability claims
by patients with high-risk genotypes.
The study also illustrates the use of a ‘traffic
lights’ system to flag drugs according to
the patient’s genotype as green (‘use as
directed’), yellow (‘use with caution’) or red
(‘use with increased caution and more
frequent monitoring’). This is a user-friendly
approach to simplifying the interpretation
and use of multivariate pharmacogenomic
test results in clinical practice.
Multifactorial pharmacogenomic testing
with the GeneSight CPGx test also
reduced patient costs substantially in
a group of 1662 patients with various
psychiatric conditions including
depression, anxiety and bipolar disorders
and schizophrenia, who had failed initial
treatments, in addition to improving
medicine adherence and reducing
medicines for comorbid conditions over
a one-year period.37
Another polygene test, CNSdose, tests a
suite of transporter and metabolic genes
similar but not identical to those tested
by GeneSight. One notable difference
being that the former test includes
genes from the ABC family, including
the P-glycoprotein gene.
In a 12-week
prospective double-blind randomised
study of 148 Caucasian adults with
major depressive disorder, using
various antidepressants including SSRIs,
SNRIs and TCAs, remission occurred in
72% of patients when antidepressant
prescribing was genetically guided
based on CNSdose test results,
compared to 28% for unguided dosing,
equating to over 2.5-fold greater
chance of remission (95% confidence
interval [CI]=1.71-3.73, p<0.0001).
Remission of symptoms (e.g. return of
depression rating scales to normative
levels) is a better gauge of long-term
clinical efficacy and eventual recovery38
as patients who initially respond to
treatment but don’t remit tend to
There were also significant
reductions of intolerability and in the
proportion of patients taking sick leave
and the number of sick days taken.
The favourable patient health and cost
outcomes described in these studies
make a compelling case for considering
pharmacogenomic factors when
prescribing antidepressants, particularly
for patients with treatment-resistant
depression and anxiety. While there
is currently no legal requirement for
genomic testing in conjunction with
antidepressant treatment, increasing
numbers of people are having
pharmacogenetic tests performed in a
variety of contexts in Australia as well
as overseas. If a patient who has been
prescribed antidepressants has already
had DNA testing performed for relevant
genes, they may wish to consider
showing and discussing their results
with their healthcare professional to
achieve optimal use of medicines.
Pharmacists who have an understanding
of the different issues involved will be in
a better position to provide appropriate
information and advice to these patients
and other health professionals.
Although current evidence does not
support targeted testing of individual
gene variants, where relevant
multivariant genomic information
is available, it should be taken into
consideration in guiding antidepressant
therapies for patients with suboptimal
responses. With pharmacogenomic
testing increasing, pharmacists
need to keep apace of this area to
provide appropriate information
and guidance to patients and other
healthcare professionals, as highlighted
by the recent addition of a chapter
on pharmacogenomics in the
Australian pharmaceutical formulary and
Useful information sources
beyondblue support service 1300 22
4636 and at: www.beyondblue.org.au
1. Beyond Blue. Anxiety and depression: an information
booklet. 2015. At: resources.beyondblue.org.au/prism/
2. Binder EB, Holsboer F. Pharmacogenomics and
antidepressant drugs. Ann Med 2006;38(2): 82–94.
3. Horstmann S, Binder EB. Pharmacogenomics of
antidepressant drugs. Pharmacol Ther 2009;124(1):57–73.
4. Singh AB. Improved antidepressant remission in major
depression via a pharmacokinetic pathway polygene
pharmacogenetic report. Clin Psychopharmacol Neurosci
5. Rossi S, ed. Australian medicines handbook. Adelaide:
Australian Medicines Handbook; 2015.
6. Perlis RH. Pharmacogenomic testing and personalized
treatment of depression. Clin Chem 2014;60(1):53–9 .
7. Licinio J, Wong ML. Pharmacogenomics of antidepressant
treatment effects. Dialogues Clin Neurosci 2011;13(1):63–71.
8. Fabbri C, Serretti A. Pharmacogenetics of major depressive
disorder: top genes and pathways toward clinical
applications. Curr Psychiatry Rep 2015;17(7):50.
9. U.S. Department of Health and Human Services Food
and Drug Administration. Guidance for industry:
Clinical pharmacogenomics: premarket evaluation in
early-phase clinical studies and recommendations for
labeling. 2013. At: www.fda.gov/downloads/drugs/
10. Couroussé T, Gautron S. Role of organic cation transporters
(OCTs) in the brain. Pharmacol Ther 2015;146:94–103.
11. Thuerauf N, Fromm MF. The role of the transporter
P-glycoprotein for disposition and effects of centrally acting
drugs and for the pathogenesis of CNS diseases. Eur Arch
Psychiatry Clin Neurosci 2006;256(5):281–6 .
12. Ohtsuki S, Terasaki T. Contribution of carrier-mediated
transport systems to the blood-brain barrier as a
supporting and protecting interface for the brain;
importance for CNS drug discovery and development.
Pharm Res 2007;24:1745–58.
13. Breitenstein B, Brückl TM, Ising M, et al. ABCB1 gene
variants and antidepressant treatment outcome: a
meta-analysis. Am J Med Genet B Neuropsychiatr Genet
14. O’Brien FE, Clarke G, Fitzgerald P, et al. Inhibition of
P-glycoprotein enhances transport of imipramine across
the blood-brain barrier: microdialysis studies in conscious
freely moving rats. Br J Pharmacol 2012;166(4):1333–43.
15. O’Brien FE, Clarke G, Dinan TG, et al. Human P-glycoprotein
differentially affects antidepressant drug transport:
relevance to blood-brain barrier permeability. Int J
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