Recent research has revealed that differing bodies may metabolize the same drug differently. Why and how does this occur? Investigation into the burgeoning field of pharmacogenomics can help answer those important questions. Pharmacogenomics is the study of all genes in the genome that may determine drug response.1 Looking into studies where psychiatric patients have been diagnosed with the same disease, we can see a large sample of patients that react differently to similar or the same medications. In pharmacogenomics of the psychiatric population, drugs are divided into three categories based on safety and effectiveness: red category, yellow category, and green category; red-zone, yellow-zone, and green-zone. The subjects of the studies cited herein are a sampling of those who took either red, yellow, or green categorized FDA-approved drugs. There is also a small sample of subjects who took a combination of yellow and green drugs simultaneously. However, there are no subjects that took a combination of red and yellow or a combination of red and green; and there are also no subjects that took drugs from all three categories. Drugs that treat depression are the focus of this research, as psychiatric medicines, such as antidepressants, have a large sampling of patients who have or have not done well with the various medications. Pharmacogenomic testing will help treat patients more effectively with medication that correspond better to the patient’s genetic makeup. This results in a more personalized approach to medicine.

Keywords: gene, personalized medicine, pharmacogenomics, psychiatric

ADHD, Attention Deficit Hyperactivity Disorder; CPGx, Combination Pharmacogenomics; DNA, Deoxyribonucleic Acid; JRA, Juvenile Rheumatoid Arthritis; MTHFR, Methylenetetrahydrofolate Reductase; OA, Osteoarthritis; OCD, Obsessive-Compulsive Disorder; PMDD, Premenstrual Dysmorphic Disorder; PTSD, Post-Traumatic Stress Disorder; RA, Rheumatoid Arthritis; SNRI, Serotonin And Norepinephrine Reuptake Inhibitors; SSRI, Selective Serotonin Reuptake Inhibitor; URM, Ultra-Rapid Metabolizer

Individual patients can respond differently to the same or similar medication. The differences can be due to a multitude of factors: age, ethnicity, body mass, nutrition, metabolizing enzymes, and/or genetics. Studying the effects of genetic factors on medications might help physicians select the best medication for a particular patient. The study of human genes and how they affect medication and efficacy is termed, pharmacogenomics. One of the most important features of pharmacogenomics is that it can be used to predict, and thus prevent, adverse drug reactions that can seriously affect a patient’s quality of life.² Pharmacogenomics can also be used to look into toxicity levels in patients, thus reducing overdosing on a prescribed medication. Pharmacogenomics is a piece of what is called, “personalized medicine” which could change the paradigm of medical care for individual patients for the better. The more specific patient treatment can become the more likelihood for improved outcomes. The Golden Helix Institute of Biomedical Research has deployed several genomic databases as a web service so that healthcare providers and researchers can access the many studies and results.³ This type of intercommunication and sharing of information is essential to the field of pharmacogenomics as it goes forward. The research reviewed herein is focused on psychiatric patients and the medications that are typically used. But first, a brief review of the “basics” follows.

What is DNA?

Deoxyribonucleic acid (DNA) is a genetic material sequence that contains a unique configuration in every individual; even identical twins develop genetic mutations specific to the individual. Individual DNA consists of 3 million base pairs, which is called a human genome. DNA’s information is stored by codes made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). The purine and the pyrimidine bases are linked together in pairs to form a double helix; as such, purine (A,G) and pyrimidine(C,T). DNA purine base A pairs with pyrimidine T and purine base G pairs with pyrimidine base C. The sequence, of these bases determines the specific information that is packaged in the chromosome.^4,5

What are chromosomes?

A chromosome is the organization of DNA into a package. There are 23 pairs of chromosomes in each cell of an individual. One copy of chromosomes is received from one’s mother and the other from one’s father. There are 22 chromosomes that are arranged from the shortest to the longest chromosome, and the last pair is the sex chromosome, which determines the gender of the individual. A mother always passes on one X chromosome, but a father can pass on one X or one Y. One X chromosome from the father and the other from mother will result in female gender child. If the father gives the Y chromosome, with the X chromosome from the mother, this results in a male gender child. Each chromosome has a centromere. A centromere divides the chromosome into two sections. There is a short arm and a long arm. The short arm of the chromosome is the “p arm.” The long arm of the chromosome is the “q arm.” When DNA is stained and viewed, there is a light and a dark band, which is the pattern that is used to describe a specific gene’s location.^4,5

What are alleles?

An allele is one of two, or more, alternative forms of a gene that arises by mutation; and they can be found in the same place on a chromosome. Alleles make different types of proteins, which may be slightly different for each individual. Some of these determine how fast medication is metabolized in different patients, which affects how a patient is affected by the medication. There may be many different alleles for a single gene present among individuals in the general population, and the combination of alleles in a single individual’s gene also presents various possibilities.^4,5 Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people. Each SNP replaces a single nucleotide with another in a stretch of DNA. SNPs occur normally throughout a person’s DNA. SNPs occur once in every 300 nucleotides on average. They can be used as a biological marker to locate genes associated with diseases. Some of these genetic differences have proven to be very important in the study of human health. SNPs helps predict an individual’s response to certain drugs, susceptibility to toxins, and the risk of developing disease.⁴⁻⁶

Testing process

The gene-testing agent analyzes how the patient’s genes affect the commonly prescribed, FDA-approved medications. The four different types of psychiatric testing are psychotropic, analgesic, ADHD, and methylene tetrahydrofolate reductase (MTHFR). Psychotropic testing analyzes drugs used to treat depression, anxiety, bipolar disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), obsessive-compulsive disorder (OCD), schizophrenia, and other behavioral health conditions. The test provides information regarding 99% of antidepressant prescriptions that are used for depression.⁷ The pharmacokinetic genes analyzed are: cytochrome P450 2D6 (CYP2D6), 2C19 (CYP2C19), 2C9 (CYP2C9), 3A4 (CYP3A4), 2B6 (CYP2B6), 1A2 (CYP1A2) and serotonin transporter and receptor pharmacodynamics genes, SLC6A4 and HTR2A.⁴ FDA-approved opioids, NSAIDs, and muscle relaxants are commonly prescribed to treat acute and/or chronic pain, opioid dependency, osteoarthritis (OA), rheumatoid arthritis (RA), and juvenile rheumatoid arthritis (JRA). The test provides information regarding 98% of prescriptions for low back pain.⁷ The pharmacokinetic genes analyzed for this category are cytochrome P450 2D6 (CYP2D6), 2C19 (CYP2C19), 2C9 (CYP2C9), 3A4 (CYP3A4), 2B6 (CYP2B6), 1A2 (CYP1A2) and opioid pharmacodynamics gene OPRM1⁷. The ADHD test analyzes how genes affect the way one’s body may respond to FDA-approved medicines that are commonly prescribed to treat ADHD or narcolepsy. The test provides information to healthcare providers on 100% of the FDA-approved medications for ADHD.⁷ The genes analyzed in this section are pharmacokinetic gene cytochrome P450 2D6 (CYP2D6) and pharmacodynamics genes COMT and ADRA2A.⁴

The MTHFR test analyzes one important gene, which predicts how a body converts folic acid into its active form. Folic acid must be in its active form for a body to be able to utilize it. This information will help the healthcare provider decide if a patient would benefit from taking an additional folic acid supplement. Folate deficiency can result in abnormal homocysteine levels and may interfere with the creation of dopamine, norepinephrine, and serotonin⁷. Antidepressants are among the most prescribed medications, but only about half of patients respond to these medications; and even fewer remit following an initial antidepressant trial. Currently, many patients go through trial-and-error to find the medication that works for them and has side effects they can live with. Some case studies were done by Union Health Services (UHU) Study Design. The effect on health care utilization when prescribed a red category (genetically discordant) medication was evaluated in a 1-year, blinded, retrospective study of 96 subjects with a DSM-IV-TR diagnosis of depression or anxiety disorder. The study consisted of current psychiatric patients who were screened for inclusion criteria: a diagnosis of depression and/or anxiety disorder. Each patient was treated with one or more of the 26 FDA-approved drugs from the GeneSight Psychotropic CPGx test.⁸⁻¹⁰ The subjects were followed; they took a buccal swab and it was tested. DNA extraction was performed and amplified; 50 alleles were measured for 6 genes: 4 cytochrome P450 genes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter gene (SLC6A4) and the serotonin 2A receptor gene (5HTR2A).⁸⁻¹⁰ Genotype results were converted to a composite phenotype for each psychiatric medication on the panel using the GeneSight interpretive report, in which each of the 26 medications was placed in the category of use as directed (green bin), use with caution (yellow bin) or use with caution and more frequent monitoring (red bin).

Other studies

The La Crosse Antidepressant Efficacy Study had 18 control subjects, 18 Hamm Clinic studies, and 20 subjects in the Pine Rest studies; these studies were all double-blind studies. Subjects were Caucasians between the age of 19-75 years of age. All subjects were patients of a psychiatrist, and were considered to be treatment-resistant because they had failed at least one prior psychiatric medication trial.⁷ The subjects provided DNA contained within a buccal swab. The swab was shipped to Assurex Health, which is CLIA-accredited and CAP-accredited, and the New York Department of Health-approved laboratory in Mason, Ohio, USA. On the basis of extensive literature that associates drug metabolism and response with single nucleotide polymorphisms in genes for CYP enzymes and serotonin effector proteins, polymorphisms in 50 variants were measured: CYP2D6 (17 alleles and duplication), CYP2C19 (8 alleles), CYP1A2 (15 alleles), the long and short 5HTTLPR variants of the SLC6A4 serotonin transporter gene (2 alleles), HTR2A (2 alleles) and, for the UHS study, CYP2C9 (6 alleles).¹¹ Subjects in the three clinical studies had similar results. Those who were treated with a red category drug demonstrated less clinical improvement, and they experienced more adverse effects from the medication being taken. Subjects within the red category showed 61.5% less improvement than the yellow category subjects (t=3.15; P=0.002), green category (t=2.22, P=0.02), or yellow± green category medications (t=2.97, P=0.003). In the three composite phenotypes, all subjects exhibited similar levels of depressive illness at the baseline, so this ruled out the issue being caused by varying degrees of depressive illness. Of the subjects, 31 subjects entered the study on green category medications, and 59 subjects entered on yellow category medications. The remainder was 29 subjects taking red category medications. The pooled subjects showed a nonsignificant trend for an overall difference in the number of panel medications they were prescribed upon starting the study. Those on red category medications were prescribed 2.0±0.14 (mean±s.e.m.) panel medications, which exceeded the 1.5±0.15 medications for the green category subjects (t=2.33; P=0.02) and the slightly higher 1.7±0.11 medications prescribed for the yellow category subjects (t=1.46, P=0.15).⁷

Selective serotonin reuptake inhibitors (SSRIs) are used to treat various psychiatric conditions; such as depression, anxiety, or personality disorder. These drugs block the serotonin (5-HT) receptors in the brain. The drugs that fall into this category are citalopram (celexa), escitalopram (Lexapro), fluoxetine (prozac), fluvoxamine (luvox CR), paroxetine (paxil), sertraline (zoloft), and vilazodone. Genes analyzed for this category are CYP2D6, CYP3A4, SLC6A4, CYP2C19, and HTR2A⁷. Side effects of SSRIs may include nausea, vomiting, diarrhea, sexual dysfunction, headache, weight gain, anxiety, dizziness, dry mouth, and trouble sleeping. In children, teens, and young adults (18 to 24 years old), there is a chance of increased suicide ideation within the first few months of treatment, or when the dose is changed. Serotonin and norepinephrine reuptake inhibitors (SNRIs), in this case, are desvenlafaxine (Pristiq), duloxetine (Cymbalta), venlafaxine (Effexor), venlafaxine XR (Effexor XR), milnacipran (Savella), and levomilnacipran (Fetzima).⁴ SSRIs only block serotonin, whereas SNRIs delay or block the uptake of both serotonin and norepinephrine. Side effects most common to the class of SNRIs include nausea, dizziness, dry mouth, headache, excessive sweating, tiredness, constipation, insomnia, and loss of appetite. The genes for the serotonin and norepinephrine reuptake inhibitors are CYP2D6, CYP3A4, CYP2B6, and SLC6A4. If a patient does not have these genes to metabolize the medication, they may need an increased dosage of this medication, or could have serious side effects from the drugs. Tricyclic antidepressants (TCAs) are prescribed to treat depression. TCAs act by blocking the neuronal uptake of norepinephrine and serotonin. However, TCAs and SNRIs are not the same classification of drug. This is due to the greater ability of TCAs to affect cells of more types. The genes for the TCAs are the CYP2D6 and CYP2C19. TCA medications included here are amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), and Trimipramine (Surmontil).⁴ Side effects includes blurred vision, constipation, dry mouth, drowsiness, urine retention, and decreased blood pressure while moving sitting to standing position. Many psychotropic medications are metabolized by CYP2D6. It is the primary metabolizer for five antidepressants: fluoxetine, paroxetine, venlafaxine, desipramine, and nortriptyline. It substantially metabolizes amitriptyline, imipramine, doxepin, duloxetine, trazodone, and mirtazapine. It is also the primary metabolizer for risperidone, and four of the typical antipsychotic medications: chlorpromazine, thioridazine, perphenazine, and haloperidol. It has substantial involvement in the metabolism of aripiprazole and olanzapine. It is also the primary metabolizer of atomoxetine and dextroamphetamine.¹² CY2C19 is mainly used for antidepressant metabolism. CYP2C19 was the second metabolizing enzyme gene that was used to identify patients with increased or decreased metabolic capacity. This enzyme is located on chromosome 10 and codes enzymes that contains 490 amino acids. Individuals lacking this enzyme are 7% Caucasians for the cYP2D6 and about 25% for the CYP2C19. Twenty-five percent of North Africans and Middle Easterners have two or more alleles of CYP2D6, which makes them ultra-rapid metabolizers.⁸ CYP2C19 metabolizes citalopram, escitalopram, clomipramine, amitriptyline, sertraline, imipramine, nortriptyline, doxepin, clozapine, thioridazine, and diazepam. The enzymes are the main enzymes in some drugs, and less in others. CYP2C9 is also located on chromosome 10, but this gene does not play much of a role yet in the more prescribed drugs in psychiatry; however, it is the only secondary pathway to metabolize fluoxetine. Therefore, if a patient is a poor metabolizer of the drug, they will experience some adverse effect on a standard dose of fluoxetine. Fluoxetine is a SSRI. Fluoxetine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT1A auto-receptors. Fluoxetine is used to treat major depression, but 30-40 % of the patients do not respond to this therapy. These patients do not respond because they do not have the gene necessary to metabolize the drug effectively. The genes that influence the drug’s pharmacodynamics are polymorphisms of SLC6A4, HTR1A and MAO-A; and seem to be involved in the response to fluoxetine, while the genes COMT, CRHR1, PDEA1, PDEA11 GSK3B and serpin-1 also seem to play a role.

Many metabolizing genes influence drug response. Cytochrome P450 2D6 (CYP2D6) was the first gene that identified the increase and decrease of metabolic capacity in a psychiatric patient.² CYP2D6 is located on chromosome 22, and this gene is highly polymorphic. The polymorphism of CYP2D6 can change the way a patient metabolizes a particular drug. Patients are classified as poor metabolizers, intermediate metabolizers, or ultra-rapid metabolizers. Patients with multiple gene copies of CYP2D6 will metabolize a particular drug more rapidly (these are the ultra-rapid metabolizers), and will also need a slightly lower dosage of the medication than individuals without the gene or with less alleles. Poor metabolizers will metabolize a particular drug slowly, and are more susceptible to having more side effect/adverse drug effects. This is extremely important in psychiatry because 50% of the drugs prescribed are drugs that are primarily metabolized by CYP2D6, such as the SSRIs, SNRIs, and TCAs.

Most antidepressant medications are metabolized by two or more CYP enzymes. The phenotypes are used by the GeneSight test to predict how each patient is likely to respond to each panel of medication. The combination approach can compensate for the variability and relatively small effect sizes for associations between single alleles and psychiatric medication response by aggregating the more consistently predictive genes, such as CYP2C19, CYP2D6, and CYP1A2. Just over seven percent (7.3%) of Caucasians are poor metabolizers or ultra-rapid metabolizers for CYP2D6, 3.7% are poor metabolizers for CYP2C19, and 49% are ultra-rapid metabolizers for CYP1A2.¹²

The concept that some patients will react differently than other patients to certain medications is not a novel concept. Hippocrates was one of the first advocates of personalized medicine; the theory of the four humors is a classic historical example of this ideology.^11,13 Technology has advanced to a point where we can prove what Hippocrates could only hypothesize, and can build a more advanced, patient-specific form of care. It is essential to a patient’s overall health and quality of life that the attitude of one size fits all–particularly in the area of psychiatry–must be removed entirely from the healthcare field.¹³ In psychiatry, with personalized medicine and the use of pharmacogenomics, more effective drug treatments can be developed. Safety precautions of the patient pool will be known. Drugs can be more specific.¹⁴ The key will be to develop greater precision in the use of pharmacogenomics for the practitioner.¹⁵ The strength of studies and research directly affect how well a concept, like pharmacogenomics, is received by healthcare professionals. The clinical studies, reported herein, have shown the benefit of finding genes that affect the way a psychiatric patient metabolizes their medication. Performing additional research, as well as assisting in the collation of information into the public repositories, will help patients be better tested for their ability to metabolize medications. Knowing this information will allow for the building of profiles; so that, in addition to the effects of the single alleles, combinations can also be considered, as they too may be indicators for certain conditions and, subsequently, a particular drug prescription. Performing pharmacogenomic testing on psychiatric patients will help the physician determine a management plan that would best help relieve the patients symptoms while reducing or eliminating undesirable side effects. This will ultimately improve the lives of patients, and reduce the cost of medical care which occurs through the trial-and-error method that is commonly used today in the management of psychiatric patients.

None.

The author declares that the research was conducted in the absence of any commercial of financial relationships that could be construed as a potential conflict of interest.

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