Pharmacogenetics in psychiatry — promising but not yet proven
Published in Health News and Evidence
Date published: About this date
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Practice points | Variable response to psychotropic treatment | Applying pharmacogenetics in clinical psychiatry | Pharmacogenetics – an emerging field | Regulatory processes not based on clinical utility | CYP450 genetic variants and drug metabolism | References
Responses to treatment with antidepressants and antipsychotics are highly variable. Genetic testing offers the promise to predict treatment response and individualise prescribing through advances in pharmacogenetics but clinical application is currently limited. Although variability in drug metabolism can be explained by variation in genes encoding drug metabolising enzymes, there is currently insufficient evidence to support genetic testing to inform treatment decisions.
- Patient responses to psychotropic treatment vary — there is currently insufficient evidence to support the use of genetic testing to select or modify treatment.1-3
- Dose adjustments are commonly needed in people taking psychotropic drugs, especially where a person develops tolerance or due to the changing nature of their condition.1
- Monitor and reduce the impact of adverse effects by starting at low doses and slowly stepping up doses.1
Major depressive disorder, schizophrenia and related disorders are a significant cause of death and disability. In 2011–12 three million Australians reported having a mental and behavioural condition and this number has increased steadily over the last decade.4 Mental illnesses (e.g. anxiety and depression) are also among the most common problems managed in general practice,5 and GPs play an important role in early intervention and monitoring treatment and clinical progress as well as referral to specialist services.1
Psychotropics (antidepressants and antipsychotics) are the standard treatments where most drugs have equivalent efficacy but differ in side effects.1 There are many drug treatments available but the response to treatment is highly variable and many people do not achieve a sufficient therapeutic response. As a consequence, maximising clinical outcomes in mental health disorders is an important research focus.
Managing psychotropic dose
Inter-individual variability in response to treatment dose is a major clinical problem affecting the use of most psychotropic drugs. For example, the FDA is investigating two deaths in patients in the US who received an intramuscular injection of an antipsychotic (olanzapine pamoate) and who were found to have very high serum levels of the drug after death.6
Despite substantial variation in plasma levels, drug level monitoring is currently not thought to be useful for most psychotropics.7 This may be because of a lack of empirical support for a relationship between plasma drug levels and psychotropic drug efficacy.2
The future of pharmacogenetics
Pharmacogenetics has the potential to advance treatment by offering meaningful predictors of efficacy and/or adverse effect burden to inform treatment decisions.2 In the absence of prognostic biomarkers, currently these aspects are mostly informed by clinical experience through a process of trial and error.7
There are two important applications for pharmacogenetics in clinical psychiatry:8
- to identify genetic variants in pathways involved in the mechanism of action for psychotropic drugs to identify patients likely to benefit
- to identify heritable aspects that influence pharmacokinetics of psychotropic drugs.
This article focuses on the second application, in particular the clinical utility of tests for genetic variants in the cytochrome P450 (CYP450) family of enzymes.
Pharmacogenetics is an emerging field that promises to deliver on a cornerstone of personalised medicine — the ability to predict response and thus individualise treatment. By identifying genetic variants that underlie differential drug responses, pharmacogenetics theoretically offers a means to predict not only efficacy of treatment response but also the potential for adverse outcomes.
To date the translation of pharmacogenetic research findings into clinical practice has been limited although there have been some successes, particularly in cancer treatment.9-12
In clinical psychiatry, advances such as biological markers and laboratory tests were a high hope for the fifth update of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). However, the translation of scientific advancements into clinical practice has not yet delivered.13
Are we there yet?
In short, no — the potential for pharmacogenetics to inform treatment with psychotropics has not yet been realised clinically.2,3 A recent review highlighted there are no randomised clinical trials that support the use of genetic testing to guide prescribing in psychiatry.3
While there has been intensive research and evidence is mounting that genetic variants contribute to drug responses, a number of issues need to be resolved before findings can be applied to clinical practice.8 A major challenge to implementation is the lack of sufficient levels of sensitivity and specificity to meet regulatory requirements on the basis of clinical utility.2
In Australia, in vitro diagnostic devices intended for DNA sample collection are regulated by the TGA and tests are conducted in accordance with national standards in accredited laboratories to ensure appropriate quality control for medical genetic testing.14 Many genetics tests that are currently available in commercial laboratories have not been approved based on an assessment of their clinical utility and are not routinely subject to post-marketing surveillance by regulatory authorities. Indeed, there is some debate about the threshold of evidence required for use in practice.15
Few tests are approved and clinical uptake is modest
Only one pharmacogenetic test for use in psychiatry was approved by the FDA as of 2012. It involves the CYP450 gene family and was approved based on data demonstrating a relationship between CYP450 genotypes and response to psychotropic drugs. No clinical claims were granted involving a specific drug or drug class. The clinical uptake of these tests in the US has been modest with concerns about interpretation, a lack of prospective data in support of an influence on clinical outcomes and a lack of reimbursement for what is an expensive test.2
Commercial tests available in Australia but not TGA-approved
In Australia, there are currently no TGA-approved CYP450 genetic tests. In spite of limited evidence to support clinical utility and to inform interpretation, there are already commercial laboratories marketing CYP450 genetic testing as a means to predict adverse drug reactions or non-response prior to prescription of a range of common drugs. In Australia these tests are not subsidised on the MBS leaving the cost of testing to be borne by the consumer.
So what is the current evidence for the influence of variation in CYP450 genes in determining psychotropic drug response?
Genetic variation in CYP450 genes
CYP450 enzymes are responsible for metabolising most psychotropic drugs—the most relevant are CYP2C19, CYP2D6 and CYP2C9.16 Pharmacokinetic studies have evaluated genetic variants in relation to psychotropic drug response identifying substantial and functional genetic variation in these enzymes.2 For example, CYP2D6 — which is responsible for metabolising up to 25% of commonly prescribed drugs, including psychotropics17 — is encoded by a gene that contains substantial sequence variation with over 100 genetic variants described.2,17 Many of these variants yield non-functional or lower functioning enzymes.2
Impact of CYP2D6 variants on drug metabolism
On the basis of particular combinations of variants in CYP2D6, specifically the number of positive variants (i.e. those that yield higher functioning enzymes), individuals can be assigned to four groups: poor, intermediate, extensive or ultrarapid metabolisers.17 Poor metabolisers represent about 5% to 10% of the population in Caucasians, but this phenotype is rare in Asians.18 Poor metabolisers tend to accumulate higher drug levels in blood, theoretically require lower doses to achieve therapeutic effects and may be at increased risk of drug toxicity.2,17 On the other hand, the less than 1% of the population who are ultrarapid metabolisers may require higher doses because of faster elimination.2 Extensive metabolisers have normal enzymatic activity and represent 60 to 85% of the Caucasian population.17
Pharmacogenetic data from clinical studies have been systematically evaluated to determine the impact of genetic variation on antidepressant and antipsychotic drug response including the application of dose adjustments.16 By evaluating mostly retrospective data, the authors concluded that for many drugs variability in drug response (defined by assessing variants in CYP450 genes) can be readily accounted for by dose adjustments. However, the clinical outcomes of therapeutic strategies informed by pharmacogenetic data need to be tested in prospective studies to validate any resulting dose adjustments and to make specific clinical recommendations.8,16
- Therapeutic Guidelines Limited. eTG Complete. Psychotropic 2013. http://etg.hcn.com.au/ (accessed 17 June 2013).
- Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry 2012;17:760–9. [PubMed]
- Zhang JP, Malhotra AK. Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol 2013;9:183–91. [PubMed]
- Australian Bureau of Statistics. Australian health survey: first results, 2011–12. 2012. http://www.ausstats.abs.gov.au/ausstats/subscriber.nsf/0/1680ECA402368CCFCA257AC90015AA4E/$File/4364.0.55.001.pdf(accessed 26 March 2013).
- Britt H MG, Henderson J, Charles J, Valenti L, Harrison C, Bayram C, Zhang C, Pollack AJ, O'Halloran J, Pan Y. General practice activity in Australia 2011–12. Family Medicine Research Centre, 2012. http://hdl.handle.net/2123/8675 (accessed 26 March 2013).
- Federal Drug Administration. Zyprexa Relprevv (olanzapine pamoate): Drug safety communication - FDA investigating two deaths following injection. 2013. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProductsucm357601.htm (accessed 27 June 2013).
- Lombard J, Doraiswamy PM. What is the role of pharmacogenetics in clinical psychiatry? Expert Opin Drug Metab Toxicol 2013;9:1–4. [PubMed]
- Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol 2011;7:9–37. [PubMed]
- Bilous M, Morey AL, Armes JE, et al. Assessing HER2 amplification in breast cancer: findings from the Australian in situ hybridization program. Breast Cancer Res Treat 2012;134:617–24.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16. [Online]
- Ibrahim EM, Zekri JM, Bin Sadiq BM. Cetuximab-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of K-ras mutations. Int J Colorectal Dis 2010;25:713–21. [PubMed]
- Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707–14. [Online]
- Roehr B. American Psychiatric Association explains DSM-5. BMJ 2013;346:f3591. [PubMed]
- National Health and Medical Research Council. DNA genetic testing in the Australian context: a statement from the National Health and Medical Research Council. 2012. http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ps0002_dna_genetic_testing_consumers.pdf (accessed 22 November 2012).
- Mrazek DA, Lerman C. Facilitating clinical implementation of pharmacogenomics. JAMA 2011;306:304–5. [PubMed]
- Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004;9:442–73. [PubMed]
- Samer CF, Lorenzini KI, Rollason V, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther 2013;17:165–84. [PubMed]
- McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol 2012;8:371–82. [PubMed]