Psychiatric Pharmacogenomics: An Overview

CATEGORY 1 CME

Premiere Date: June 20, 2026 

Expiration Date: December 20, 2027

This activity offers CE credits for: 

1. Physicians (CME) 

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To appreciate the rapid evolution of the field of psychiatric pharmacogenomics (PPGx) following the completion of the 2001 first draft sequencing of the human genome, and how this knowledge has been integrated into clinical practice.

LEARNING OBJECTIVES

1. Describe the nomenclature of the various genes relevant to PPGx and understand the difference between a gene’s genotype and the gene product’s functional phenotype.

2. Differentiate the 5 classical phenotypes of metabolic activity of the cytochrome P450 isoenzymes that are hypothesized based on the DNA sequence of a person’s alleles (genes) for that isoenzyme.

3. Become familiar with the subset of cytochrome P450 isoenzymes applicable to the clinical practice of psychopharmacology.

4. Understand the role of the enzymes involved in biotransformation of molecules through phase 2 metabolism to facilitate their excretion from the human body through urine and bile.

5. Appreciate the numerous variables, of which PPGx is but one, that can impact the serum level of psychiatric medications.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Psychiatric pharmacogenomics (PPGx) is a rapidly evolving science that has added a third pillar to psychopharmacologists’ foundational knowledge base, alongside pharmacokinetics and pharmacodynamics. A great deal has been learned since the completion of the first draft of the human genome in 2001. However, current clinically actionable PPGx testing is quite limited, although the future is ripe with possibilities. This article will provide a comprehensive overview of the current state of PPGx, reviewing the foundational principles, the established nomenclature, the types of DNA gene product proteins involved, and a detailed review of the human cytochrome P450 (CYP450) isoenzymes, which have been pivotal to the understanding of PPGx. A brief overview of phase 2 metabolism will be provided, including the important metabolic process of glucuronidation. A future article will explore the nongenetic variables that can result in a phenomena called phenoconversion—when a patient’s actual clinical phenotype is at odds with the predicted genotype/gene-based phenotype—and will provide a review of the PPGx monitoring of 2 human leukocyte antigen (HLA) alleles for specific subpopulations/medications, review the history of the nonprofit organizations that developed to monitor PPGx testing, and conclude by summarizing the PPGx testing that is currently evidence-based for clinical applications in psychiatry.

Defining PPGx

PPGx utilizes a patient’s genomic sequence variations as 1 of many important factors when choosing a psychiatric medication and hypothesizing the appropriate dose, potential drug-drug interactions, and risk of adverse effects. The genotype for a particular protein can help the clinician predict a specific drug’s pharmacokinetics (what the body does to a drug; for example, drug metabolism) and pharmacodynamics (what a drug does to the body; for example, binding to a specific receptor). Table 1 lists the categories of proteins with examples of common gene products derived from the genome.

PPGx is a young field that fully emerged following the initial sequencing of the human genome in 2001 and subsequent refinement and publication of the 3 billion base pair sequence containing the nucleotides adenine, thymine, cytosine, and guanine. Remarkably, only approximately 2% of the human genome contains protein-coding sequences, which contain the amino acid sequences transcribed and translated into a range of protein families from 20,000 genes.¹

Although beyond the scope of this review, at least 80% of the remaining human genome has essential biological functions. Over the course of evolution, mutations in the human genome that increased the likelihood of survival became enriched, and as humans migrated through time and geography, a single gene for a single protein became polymorphic. Hence, today, a protein that was originally encoded by a single gene in DNA is often the product of genetic polymorphism, in which many genes, called alleles, code for variations of the same protein, which can affect its structure and function. In psychiatry, the best example of this is the gene CYP450 2D6 (CYP2D6), which has more than 133 alleles.

Usually, a person’s genome has 2 copies of each gene: one that came from the sperm and the other from the egg. However, genes occasionally undergo duplication through evolution, and once again, CYP2D6 is a stellar example of this, with a single person’s genome containing anywhere from 2 to 13 genes, adding another variable to determine a person’s gene-based phenotype. A phenotype is the amount of a gene product’s activity at a single point in time, which remains fluid throughout a person’s life. Briefly, if a person had one gene for CYP2D6 with poor functionality and one with normal functionality, the CYP2D6 functional phenotype would be intermediate. On the other hand, if a person had 5 copies of a normal CYP2D6 gene, the phenotype would be ultrarapid. It is crucial to note that numerous factors determine a person's functional phenotype at any given time, including drug-drug interactions and epigenetic modifications. Finally, many medications can be metabolized by several different enzymatic pathways. Hence, if the drug’s primary pathway has poor activity or is inhibited by another medication, alternative pathways can be utilized. The astute clinician needs to be mindful of the numerous variables that ultimately determine a medication’s serum levels and its target protein’s impact.

CYP450 Isoenzymes: Phase 1 Metabolism

CYP450 isoenzymes are a ubiquitous class of isoenzymes that serve important roles in metabolizing endogenous substrates, detoxifying xenobiotics, and metabolizing many medications.¹ Referred to as phase 1 metabolism, these isoenzymes initiate the oxidative process that transforms molecules into metabolites that will ultimately be excreted through the urine and/or bile. CYP450 is an acronym with the letters “CY” representing cytochrome, “P” for protein, and “450” representing these enzymes’ shared property of absorbing light at a wavelength of 450 nm. This acronym is followed by a number representing the gene family, a capital letter indicating the subfamily, and a number denoting the isoenzyme (Figure 1).^2,3

CYP450 isoenzyme expression is the highest in the liver, though they are also present in the small intestine, lungs, kidneys, and brain.⁴ The high expression of CYP450 isoenzymes in the liver provides the opportunity for what is often termed “first-pass metabolism,” an accurate term for all isoenzymes except CYP3A4, which is ubiquitous in the enterocytes of the small intestine as well. Nutrients absorbed from the gastrointestinal tract are transported to the liver via the mesenteric veins that form the hepatic portal vein, which delivers these nutrients to the liver, where they are metabolized and then enter the systemic circulation. This gives the organism the opportunity to detoxify potentially dangerous molecules that were ingested before they pass through the liver to the rest of the body. Although at least 57 CYP450 isoenzymes exist, approximately 12 isoenzymes belonging to the CYP450 1, 2, and 3 families are the primary metabolic pathways for 75% of medications in use clinically. In the liver, the most abundant are CYP450 3A4, 2C9, 2C8, 2E1, and 1A2 followed by 2A6, 2D6, 2B6, 2C19, and 3A5.⁵

CYP450 isoenzyme activity differs at any given time based on genetic, epigenetic, medical, and environmental factors. Genetic alleles are inherited, whereas epigenetic modifications occur in utero and throughout life and can be reversible. Environmental exposures vary widely and can affect gene expression through epigenetic modifications, as well as the functional activity of CYP450 isoenzymes. For example, isoenzymes can be induced or inhibited by specific drugs or naturally occurring products, leading to significant increases or decreases in the activity of the isoenzymes.⁶ CYP450 isoenzymes of particular relevance to psychiatric medications include 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Based on expert consensus guidelines, developed and maintained by the Clinical Pharmacogenetics Implementation Consortium and the International Society of Psychiatric Genetics, 4 of these CYP450 isoenzymes are “clinically actionable” through PPGx testing (CYP2B6, 2C9, 2C19, and 2D6), as shown in Table 2.^7-9

CYP450 Genetic Polymorphisms Determine Isoenzyme Activity

There is a wide range of in vivo activity for each CYP450 isoenzyme, based on the effects of various nucleic acid mutations on the final gene product. For most isoenzymes, there are 2 genes in a person’s genome, also known as CYP450 gene polymorphisms, whose sequences determine the activity of the gene product. Experts in PPGx determine the expected activity of the CYP450 isoenzyme displayed by each of the alleles of a specific isoenzyme. The result is 1 of 5 distinctive metabolic phenotypes that a person’s genotype predicts: poor metabolizers, intermediate metabolizers, normal (previously called “extensive”) metabolizers, rapid metabolizers, and ultrarapid metabolizers.¹⁰

Poor metabolizers have 2 functionally absent or severely deficient alleles, whereas intermediate metabolizers are heterozygous with 1 functionally absent or severely deficient allele and 1 normally functional allele. Normal metabolizers have 2 copies of alleles that are considered normal-functioning, sometimes called wild-type alleles. Rapid and ultrarapid metabolizers have 1 or more alleles with increased activity that exceeds or greatly exceeds the activity of the normal allele, respectively. Depending on the gene’s function, an individual with a high copy number of that gene may demonstrate an extreme degree of activity for substrates metabolized by that gene.

CYP1A2

CYP1A2 plays an important role in psychiatry as 2 commonly used atypical antipsychotics are primarily metabolized by this isoenzyme: clozapine and olanzapine. Fluvoxamine is a potent inhibitor and has been shown to increase clozapine serum levels by 500% when added to a patient on steady-state clozapine. Additionally, tobacco smoke, and likely smoke in general, is a potent inducer of CYP1A2. This induction is not from the nicotine but from the production of polycyclic aromatic hydrocarbons during tobacco combustion, which activate aryl hydrocarbon receptors, ultimately increasing transcription of the CYP1 family of genes. Finally, caffeine and theophylline are both metabolized by CYP1A2, and their serum levels are likely impacted by tobacco smoke and fluvoxamine.

Case Study on Clozapine and CYP1A2

“Tom” is a 36-year-old man with a 15-year history of schizophrenia who continues to experience daily auditory hallucinations and delusions despite numerous trials of antipsychotics. He also has comorbid obsessive-compulsive disorder, which has been significantly improved by fluvoxamine 200 mg a day. Tom’s only substance use is 1 pack per day of cigarettes, which he is not interested in decreasing or attempting to quit smoking. At today’s visit with Tom and his treatment team, the decision was made to begin a trial of clozapine, which is primarily metabolized by the liver’s CYP1A2 isoenzyme. A psychiatric resident on the team enthusiastically suggests that you order PPGx testing of Tom’s CYP1A2 genotype to inform your planned dosage regimen. To the resident’s astonishment and disappointment, you reply that no clinically useful information would result from getting this test. You then explain how CYP1A2 is currently not an actionable PPGx test due to a lack of evidence-based data. However, you educate the resident that fluvoxamine is a potent CYP1A2 inhibitor, which will increase the clozapine’s serum level by approximately 500%. Additionally, daily smoke from cigarettes induces CYP1A2 activity, which will lower the clozapine’s serum level, and it is established that 10 cigarettes per day will maximally increase the activity of CYP1A2 by a mean of 1.66-fold. Given all these variables, you plan to begin the clozapine at a low dose, slowly titrate upward, and monitor 12-hour post-dose clozapine levels weekly until the initial desirable serum level is achieved.

CYP2B6

CYP2B6 is a minor isoenzyme with few substrates; the most relevant in psychiatry is bupropion, for which there is strong evidence that CYP2B6 is the major CYP450 enzyme involved in its metabolism. This becomes a relevant potential drug-drug interaction if a patient is on carbamazepine, which is a potent inducer of CYP2B6. Interestingly, CYP2B6 is listed as one of the clinically actionable PPGx gene tests, but only for sertraline, which is also metabolized by CYP2C19.^7,11

CYP2C9

CYP2C9 contributes to the metabolism of phenytoin, fosphenytoin, and doxepin. It is considered a clinically actionable PPGx gene test only for fosphenytoin and phenytoin.

CYP2C19

CYP2C19 joins CYP2D6 as 1 of the 2 best studied CYP450 isoenzymes in psychiatry. In 2004, Roche’s AmpliChip CYP450 Test was FDA approved as the first pharmacogenetic test available for clinical use. Using microarray technology developed by Affymetrix GeneChip, the test was able to identify 33 alleles of CYP2D6 and 3 alleles of CYP2C19. However, it fell out of clinical use because it did not keep pace with the ongoing discovery of additional alleles of both the CYP2D6 and CYP2C19 genes. Its legacy was identifying the 2 CYP450 isoenzymes that are best understood in psychiatry and are the 2 most evidence-based PPGx gene tests. The common actionable substrates metabolized by CYP2C19 include 4 tricyclic antidepressants, citalopram, escitalopram, sertraline, clobazam, and diazepam.⁸

CYP2D6

CYP2D6 is an important gene in psychopharmacology and has been credited with establishing the field of pharmacogenomics. In psychiatry, it is an important metabolic enzyme for many antidepressants, antipsychotics, atomoxetine, amphetamine, and the 3 vesicular monoamine transporter type 2 inhibitors. It is the best-studied CYP450 isoenzyme, and its history dates back to the late 1970s, when Mahgoub et al¹² observed unusual variability in the metabolism of the antihypertensive medication debrisoquine. They discovered 2 distinct patterns of metabolism—normal and very poor—which were attributed to a trait of a single gene that was inherited. Biochemical research during the 1980s on human liver microsomes discovered the enzyme responsible for this polymorphic metabolism as a member of the CYP450 isoenzyme family. It was named P450db1 and was shown to also metabolize the structurally unrelated medications codeine, dextromethorphan, metoprolol, and nortriptyline.¹³ As molecular genetics advanced in the early 1990s, the gene encoding P450db1 was isolated, and the enzyme was renamed CYP2D6.

CYP2D6 is the most polymorphic of all the 57 CYP450 enzymes. This results from a wide range of mutations in the CYP2D6 gene, including single-nucleotide polymorphisms, deletions and/or insertions of small nucleotide sequences, gene duplications that increase genomic copy numbers up to 13 genes, and mutations into nonfunctional pseudogenes (CYP2D7). With at least 133 different alleles, the range of activity of CYP2D6-mediated microsomal metabolism varies up to 60-fold, with significant ethnic and individual differences.

Although only 2% to 4% of hepatic CYP450 enzymes are 2D6, this enzyme is involved in the metabolism of approximately 20% of commonly prescribed medications. Despite its ubiquity, there are no medications that induce CYP2D6. Increased enzyme activity is due to genetic polymorphisms and gene duplications, which can result in clinically rapid or ultrarapid metabolizers.¹⁴In addition to its important role in psychiatry, where it metabolizes many commonly prescribed medications, it also metabolizes a wide range of nonpsychiatric medications, including analgesics, antihypertensives, the anticancer drug tamoxifen, and ondansetron. Let us review a few important medications that are vulnerable to CYP2D6 genetic phenotypes and drug-drug interactions.

Tamoxifen

Tamoxifen is used as chemotherapy for some forms of breast cancer. Approximately 20 years ago, it was discovered that tamoxifen is a prodrug with little inherent activity and is metabolized by CYP2D6 to the active metabolite endoxifen.^15,16 It is well established that 3 antidepressant medications—fluoxetine, paroxetine, and bupropion—are potent CYP2D6 inhibitors and may influence the drug serum levels of CYP2D6 substrates. This has been demonstrated with tamoxifen, and the current standard of care is to avoid these 3 antidepressants in women being treated with tamoxifen to mitigate the likelihood of subtherapeutic endoxifen levels due to CYP2D6’s decreased activity (Figure 2). This exemplifies a foundational concept: The synergistic consequences of both the individual patient’s CYP450 isoenzyme phenotype based on the specific alleles, and the presence of medications or other molecules that may inhibit or induce that isoenzyme. A patient who is a phenotypic intermediate or poor CYP2D6 metabolizer and is also taking fluoxetine, paroxetine, or bupropion would likely have minimal CYP2D6 activity and therefore would not metabolize the inactive prodrug tamoxifen to the active molecule endoxifen.

Codeine and Tramadol

The analgesics codeine and tramadol are prodrugs with significantly less mu-opioid agonism than their active metabolites, morphine and O-desmethyltramadol, respectively. Both drugs are primarily metabolized by CYP2D6 and, consequently, are vulnerable to the influence of an individual patient’s CYP2D6 genetic phenotype.¹⁷ A patient who is a poor or intermediate metabolizer will likely achieve little or no analgesia from codeine or tramadol, as they will be minimally converted to their active metabolites, which produce significantly more analgesia.

In contrast, patients who are ultrarapid CYP2D6 metabolizers are at risk of severe sedation, respiratory depression, and death from codeine and tramadol due to their rapid conversion to the much more potent morphine and O-desmethyltramadol, respectively. Ultrarapid metabolizers comprise approximately 1% of the population. As of 2016, the FDA had received confirmed reports of severe respiratory depression and deaths in children younger than 18 years who had been prescribed codeine or tramadol for pain following tonsillectomy and/or adenoidectomy. There were also reports of codeine causing excess sleepiness and respiratory distress, with 1 death, in breastfed infants of mothers taking codeine. These reports have led to increasing warnings by the FDA starting in 2013, and most recently updated in 2018, about the use of codeine, hydrocodone, and tramadol. The general recommendations include the following¹⁸:

• Contraindication of these analgesics in children younger than 12 years
• Contraindication following tonsillectomy/adenoidectomy in patients younger than 18 years
• Warning against the use of these medications in breastfeeding mothers
• Avoiding these medications in patients who are known CYP2D6 ultrarapid metabolizers

CYP3A4

CYP3A4 is the most abundant and clinically important CYP450 isoenzyme. It is primarily located in the liver and small intestine. Of the 57 CYP450 isoenzymes, it is the most prolific and is estimated to be involved in the metabolism of more than 50% of all prescription medications. Its location in the small intestine allows for true first-pass metabolism, as it begins to metabolize orally ingested substrates there, even before they reach the liver. CYP3A4 has significantly fewer genetic polymorphisms (fewer alleles), especially compared with CYP2B6, 2C9, 2C19, and 2D6, which may, in part, explain the paucity of psychiatric drug-gene interactions involving CYP3A4. However, it makes up for this by being affected by significant drug-drug interactions, as well as having many xenobiotics that induce and inhibit its activity. Additionally, CYP3A4 metabolizes a wide range of endogenous molecules, including cholesterol derivatives, fatty acids, retinoids, and steroid hormones.

Most prescribers will be familiar with the caution that pharmacists instill in our patients who have been prescribed a medication that is primarily metabolized by CYP3A4: Do not eat grapefruits or drink grapefruit juice! Certain citrus fruits contain compounds of a family of molecules called furanocoumarins. One such compound, dihydroxybergamottin, which exists in varying concentrations in grapefruit, potently inhibits CYP3A4.¹⁹ This drug-xenobiotic interaction could significantly increase the serum level of the CYP3A4 metabolized drug about to be dispensed, with potentially serious consequences. Due to significant heterogeneity among species of grapefruit trees, the only way to know how much dihydroxybergamottin is present in a specific grapefruit or juice container is to test it—a practice rarely, if ever, done. Table 3 lists some of the common medications that are strong inducers or inhibitors of CYP3A4.^20,21

Phase 2 Metabolism Enzymes

Phase 2 metabolism involves biotransformation by adding a hydrophilic molecule to a medication that is not metabolized by phase 1 metabolism (eg, lorazepam), metabolites of medications that were biotransformed by phase 1 metabolism, or other xenobiotics to make them more water-soluble to facilitate their elimination from the body through urine or bile. Most of these enzymes are in the liver but can also occur in other organs. The genes that encode these enzymes have varying degrees of genetic polymorphisms, and like the CYP450 isoenzymes, there can be a range of phenotypes depending on the individual’s genotype. The general principles of CYP450 enzymes apply to phase 2 metabolic enzymes, including PPGx variability and drug-drug interactions that can induce or inhibit their activity. In general, phase 2 metabolic enzymes are less well characterized than the CYP450 isoenzymes, but the literature continues to evolve.

The most common metabolic pathway in phase 2 metabolism is glucuronidation. The enzyme family of uridine 5’-diphosphateglucuronosyltransferases (UGT) adds a molecule of glucuronic acid to the substrate, making it more hydrophilic. Additional phase 2 metabolic pathways include sulfonation, acetylation, methylation (including the enzyme catechol-O-methyltransferase), glutathione conjugation, and amino acid conjugation.

The UGT genes/enzymes share a similar nomenclature to the CYP450 system. UGT2B15 is the enzyme that metabolizes lorazepam and oxazepam, and the genotype has at least 3 phenotypes: extensive, intermediate, and poor metabolism. However, these are not yet clinically actionable in a PPGx test. Valproic acid is metabolized by at least 3 UGT enzymes: UGT1A6, 1A9, and 2B7. Lamotrigine is metabolized by UGT1A4 to lamotrigine-glucuronide, and this enzymatic reaction is inhibited by valproic acid and induced by ethinylestradiol.

The 3 Ps

When choosing a psychiatric medication, determining the starting and likely target doses, and informing the patient about the range of possible adverse effects, a clinician needs to assimilate the factors resulting from the “3 Ps”: pharmacokinetics, pharmacodynamics, and pharmacogenomics. Although limited, the patient’s genetic phenotype, based on their sequenced genotype, can still provide insights into the treatment planning. This is especially true for the CYP2D6 isoenzyme, the PPGx gene that is best understood and is involved in the metabolism of many psychiatric medications. Additionally, a large body of clinically meaningful information about the CYP450 isoenzyme system exists, including specific or multiple pathways involved in a drug’s metabolism. Foremost in the prescriber’s mind should be potential drug-drug interactions, for which numerous excellent resources exist.²²

These should include all prescription medications, over-the-counter medications, vitamins, and herbal supplements a patient is taking, as well as dietary habits, substance use, and smoking status. For any medication FDA approved since 1990, a tremendous amount of information had to be submitted for approval, creating a database of readily accessible pharmacokinetic and pharmacodynamic properties in the medication’s product insert (Table 4).

Concluding Thoughts

This article provided a review of the rapidly evolving field of PPGx, which, during the past 30 years, has exploded with new information and changing paradigms, resulting in the inevitable growing pains of any new field of science and medicine. The idealistic optimism for clinical applications of PPGx testing, including the utilization of combinatorial gene panels, in the first decade of the 21st century had to be revised as additional PPGx research expanded our knowledge base. A lot remains to be learned about many of the protein products that are transcribed and translated from the human genome.

A solid foundation of knowledge exists for phase 1 biotransformation enzymes, primarily the CYP450 isoenzymes, and a great deal has been learned about the enzymes involved in phase 2 metabolism. Evidence-based PPGx testing should be used in conjunction with a comprehensive understanding of the pharmacodynamic and pharmacokinetic properties relevant to the clinical situation at hand. A future article will review the diverse factors that contribute to the functional phenotype of a CYP450 isoenzyme, which is in a constant state of flux over the course of a patient’s life—a phenomenon called phenoconversion. Additionally, clinically relevant alleles of human leukocyte antigens and the history and importance of the nonprofit organizations that vet and curate PPGx will be reviewed. Fortunately, the prescribing clinician has access to a wide range of pharmacological properties, all of which should be actively considered when making medication-related decisions.

Dr Ao is a first-year psychiatry resident in the Kaiser Oakland Psychiatry Residency Program and a graduate of Touro University California College of Osteopathic Medicine.

Dr Bourgeois is vice chair of Hospital Psychiatry Services and a professor at UC Davis Health in Sacramento, California.

Dr Miller is the medical director of Brain Health in Exeter, New Hampshire; editor in chief of Psychiatric Times; a voluntary consulting psychiatrist at Seacoast Mental Health Center in Exeter/Portsmouth, New Hampshire; and a consulting psychiatrist at Insight Meditation Society in Barre, Massachusetts.

Acknowledgments

The authors would like to thank Mackenzie Pierce, PharmD, and Kendall Gardener, MS-4, for their input and contributions in earlier drafts of this article.

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