Genetic Testing Patient Guide

Transcription

1 Genetic Testing Patient Guide Over the last decade, pharmacogenetics has become increasingly significant to clinical practice. Psychiatric patients, in particular, may benefit from pharmacogenetic testing as many of the psychotropic medications prescribed in practice lead to varied response rates and a wide range of side effects. The use of pharmacogenetic testing can help tailor psychotropic treatment and inform personalized treatment plans with the highest likelihood of success. Recently, many studies have been published demonstrating improved patient outcomes and decreased healthcare costs for psychiatric patients who utilize genetic testing. Psychiatric disorders cover a wide range of clinical phenotypes and are generally classified by symptoms. In addition to counseling and other forms of behavioral treatment, treatment commonly involves one or more psychotropic medications that are aimed at alleviating symptoms of the disorder. Although there are a wide variety of effective medications, treatment of psychiatric disease is characterized by relatively high rates of inadequate response. This often necessitates numerous trials of individual agents and combinations of medications in order to achieve optimal response. Genes Relevant to Mental Health Disorders Mental disorders encompass a wide range of conditions: the DSM-5 includes more than 300 different disorders. However, currently available genetic testing for mental health disorders is primarily related to several clinical situations: Risk stratifying patients for one of several mental health conditions, including schizophrenia and related psychotic disorders, bipolar and related disorders, depressive disorders, obsessive compulsive and related disorders, and substance-related and addictive disorders. Knowledge of the physiologic and genetic underpinnings of psychiatric disorders is advancing rapidly and may substantially alter the way in which these disorders are classified and treated. Genetic testing could potentially be used in several ways including stratifying patients risks of developing a particular disorder, aiding diagnosis, targeting medication therapy, and optimally dosing medication. Better understanding of these factors may lead to an improved ability to target medications to the specific underlying abnormalities, with potential improvement in the efficiency and efficacy of treatment.

2 Predicting patients response to, dose requirement for, or adverse effects from one of several medications (or classes of medications) used to treat mental health conditions, including: typical and atypical antipsychotic agents, serotonin and serotonin/norepinephrine reuptake inhibitors (SSRIs), and medications used to treat addiction, such as disulfiram. Panels of genetic tests have been developed and have been proposed for use in the management of mental health disorders. Genes that have been implicated in mental health disorders or their treatments and that are included in currently available panels include the following:

3 Serotonin Transporter (SLC6A4). This gene is responsible for coding the protein that clears serotonin metabolites (5-HT) from the synaptic spaces in the central nervous system (CNS). This protein is the principal target for many of the serotonin reuptake inhibitors (SSRIs). By inhibiting the activity of the SLC6A4 protein, the concentration of 5-HT in the synaptic spaces is increased. A common polymorphism in this gene consists of insertion or deletion of 44 base pairs in the serotonintransporter-linked polymorphic region (5-HTTLPR), leading to the terminology of the long (L) and short (S) variants of this gene. These polymorphisms have been studied in relation to a variety of psychiatric and nonpsychiatric conditions, including anxiety, obsessive compulsive disorder, and response to SSRIs. Serotonin Receptor (5HT2C). This gene codes for 1 of at least 6 subtypes of the serotonin receptor that is involved in the release of dopamine and norepinephrine. These receptors play a role in controlling mood, motor function, appetite, and endocrine secretion. Alterations in functional status have been associated with affective disorders such as anxiety and depression. Certain antidepressants, e.g., mirtazapine and nefazodone, are direct antagonists of this receptor. There is also interest in developing agonists of the 5HT2C receptor as treatment for obesity and schizophrenia, but no such medications are commercially available at present. Serotonin Receptor (5HT2A). The 5HT2A gene codes for another subtype of the serotonin receptor. Variations in the 5HT2A gene have been associated with susceptibility to schizophrenia and obsessive-compulsive disorder and response to certain antidepressants. Sulfotransferase Family 4A, Member 1 (SULT4A1). SULT4A1 encodes a protein that is involved in the metabolism of monoamines, particularly dopamine and norepinephrine. Dopamine Receptors (DRD1, DRD2, DRD4). The DRD2 gene codes for a subtype of the dopamine receptor, called the D2 subtype. The activity of this receptor is modulated by G-proteins, which inhibit adenyl cyclase. These receptors are involved in a variety of physiologic functions related to motor and endocrine processes. The D2 receptor is the target of certain antipsychotic drugs. Mutations in this gene have been associated with schizophrenia and myoclonic dystonia. Polymorphisms of the DRD2 gene have been associated with addictive behaviors, such as smoking and alcoholism. The DRD1 gene encodes another G-protein coupled receptor that interacts with dopamine to mediate some behavioral responses and modulate D2 receptor-mediated events. Polymorphisms of the DRD1 gene have been associated with nicotine dependence and schizophrenia. The DRD4 gene encodes a dopamine receptor with a similar structure; DRD4 polymorphisms have been associated with risk-taking behavior and attention deficit hyperactivity disorder. Dopamine Transporter (DAT1 or SLC6A3). Similar to the SCL6A4 gene, this gene product encodes a transporter that mediates the active reuptake of dopamine from the synaptic spaces in the CNS. Polymorphisms in this gene are associated with Parkinson disease, Tourette syndrome, and addictive behaviors. Dopamine Beta-Hydroxylase (DBH). The dopamine beta-hydroxylase protein encoded by this gene catalyzes the hydroxylase of dopamine to norepinephrine. It is primarily located in the adrenal medulla and in postganglionic sympathetic neurons. Variation in the DBH gene has been investigated as a modulator of psychotic symptoms in psychiatric disorders and in tobacco addiction. Gated Calcium Channel (CACNA1C). This gene is responsible for coding of a protein that controls activation of voltage-sensitive calcium channels. Receptors for this protein are found widely throughout the body, including skeletal muscle, cardiac muscle, and in neurons in the CNS. In the

4 brain, different modes of calcium entry into neurons determine which signaling pathways are activated, thus modulating excitatory cellular mechanisms. Associations of polymorphisms of this gene have been most frequently studied in relation to cardiac disorders. Specific polymorphisms have been associated with Brugada syndrome and a subtype of long QT syndrome (Timothy syndrome). Ankyrin 3 (ANK3). Ankyrins are proteins that are components of the cell membrane and interconnect with the spectrin-based cell membrane skeleton. The ANK3 gene codes for the protein Ankyrin G, which has a role in regulating sodium channels in neurons. Alterations of this gene have been associated with cardiac arrhythmias such as Brugada syndrome. Polymorphisms of this gene have also been associated with bipolar disorder, cyclothymic depression, and schizophrenia. Catechol-O-Methyltransferase (COMT). This gene codes for the COMT enzyme that is responsible for the metabolism of the catecholamine neurotransmitters, dopamine, epinephrine and norepinephrine. COMT inhibitors, such as entacapone are currently used in the treatment of Parkinson disease. A polymorphism of the COMT gene, the Val158Met polymorphism, has been associated with alterations in emotional processing and executive function and has also been implicated in increasing susceptibility to schizophrenia. Methylenetetrahydrofolate reductase (MTHFR). This is a widely studied gene that codes for the protein that converts folic acid to methylfolate. Methylfolate is a precursor for the synthesis of norepinephrine, dopamine, and serotonin. It is a key step in the metabolism of homocysteine to methionine, and deficiency of MTHFR can cause hyperhomocysteinemia and homocysteinuria. The MTHFR protein also plays a major role in epigenetics, through methylation of somatic genes. A number of polymorphisms have been identified that result in altered activity of the MTHFR enzyme. These polymorphisms have been associated with a wide variety of clinical disorders, including vascular disease, neural tube defects, dementia, colon cancer, and leukemia. Aminobutyric acid A receptor. This gene encodes a ligand-gated chloride channel composed of 5 subunits that responds to GABA, a major inhibitory neurotransmitter. Mutations in the GABA receptor have been associated with several epilepsy syndromes. Opioid Receptors (OPRM1 and OPRK1). OPRM1 encodes the mu opioid receptor, which is a G- protein coupled receptor that is the primary site of action for commonly used opioids, including morphine, heroin, fentanyl, and methadone. Polymorphisms in the OPRM1 gene have been associated with differences in dose requirements for opioids. OPRK1 encodes the kappa opioid receptor, which binds the natural ligand dynorphin and a number of synthetic ligands.

5 Cytochrome P450 genes (CYP2D6, CYP2C19, CYP3A4, CYP1A2). These 4 genes code for hepatic enzymes that are members of the cytochrome p450 family, and are responsible for the metabolism of a wide variety of medications, including many psychotropic agents. For each of these genes, polymorphisms exist that impact the rate of activity, and therefore the rapidity of elimination of drugs and their metabolites. Based on the presence or absence of polymorphisms, patients can be classified as rapid metabolizers (RM), intermediate metabolizers (IM), and poor metabolizers (PM). What Is CYP2D6 and CYP2C19 Testing for Psychiatric Drug Response? Many antidepressant drugs are metabolized, or processed, by two enzymes called CYP2D6 and CYP2C19. Drugs used to treat psychosis (antipsychotics) and Strattera (generic name atomoxetine), an attention deficit with hyperactivity disorder (ADHD) drug, are also metabolized by the CYP2D6 enzyme. Changes in the genes that make these enzymes can cause you to metabolize drugs in an unexpected way. The way people respond to the same antidepressant or antipsychotic drug and dose varies a lot. Changes in certain genes may change the response to a drug. Genetic testing can look for common changes in the CYP2D6 and CYP2C19 genes to find people who metabolize certain drugs faster or slower than usual. If you metabolize faster, you are called an "Ultrarapid Metabolizer." If you metabolize more slowly, you are called a "Poor Metabolizer." People who metabolize a little more slowly than usual are called "Intermediate Metabolizers." Sometimes this information can be used by your doctor to predict if you are more likely to have side effects or less likely to get relief of your symptoms from certain drugs. The goal of this kind of testing is to help your doctor choose the best drug and dose for you with less trial and error.

6 Extensive Metabolizer Intermediate Metabolizer Poor Metabolizer Ultrarapid Metabolizer Drug Response This is the most common result and is considered "normal". extensive metabolizers have two genes that work normally. They make a normal amount of enzyme and usually have a normal drug response. intermediate metabolizers have at least one gene that isn't working normally. They make less enzyme than normal. Usually there is enough enzyme to process most drugs relatively well, but there may be less response or more side effects from certain drugs. poor metabolizers have variants in both of their genes that cause neither gene to work normally. They make much less enzyme than normal or none at all. poor metabolizers have a higher risk for side effects from some drugs and may need to avoid those drugs or take a lower dose. They may also need a higher dose of a drug, in the rare case where a drug has to be broken down before it works. ultrarapid metabolizers have extra copies of these genes. They make more enzyme than normal. Ultrarapid metabolizers may break some drugs down so quickly that the drug doesn't help at usual doses. They may also need a lower dose of a drug, in the rare case where a drug has to be metabolized before it works.

7 What Affects Psychiatric Drug Response? How a person responds to a drug depends partly on how that drug is processed, or metabolized, by enzymes in the body. Enzymes are proteins that help to speed up metabolism. Drug metabolism genes tell the body how to make these enzymes that process drugs. This metabolism happens mostly in the liver, but other organs may also be involved. Enzymes that belong to a group called CYP450 enzymes metabolize many prescribed drugs. Two members of the CYP450 family called CYP2D6 and CYP2C19 seem to be especially important in metabolizing many antidepressants, antipsychotics, and an ADHD drug called atomoxetine. Changes in the genes that make these enzymes can cause people to metabolize certain drugs faster or slower than usual. But, for most drugs, we don't know yet if doctors can prescribe drugs more effectively and safely by just knowing if you are a fast or slow metabolizer. How you respond to a drug is complex it involves more than just metabolism. Other factors affect how a drug works like additional drugs, age, gender, medical conditions, and variations in other genes that interact with a drug. We also usually have more than one way to process a drug, so different enzymes may be able to step in when there is a problem with another enzyme.

8 Who Should Consider CYP2D6 and CYP2C19 Testing for Psychiatric Drug Response? Most of the time, antidepressants, antipsychotics, and atomoxetine (brand name Strattera ) can be safely and effectively prescribed for anyone regardless of how they metabolize the drug. So, genetic testing isn't usually recommended for people before they start treatment. Many drugs are prescribed in a way that maximizes safety and minimizes the risk of side effects already. For instance, your doctor will often start you at a lower dose than you probably need to control your symptoms. Then, the dose may be increased as you show that you can tolerate it and you need more to control symptoms. Knowing a person's metabolizer status is probably most helpful for prescribing drugs that only have a small range of a safe dose for a specific person and the risks of not treating fully and fast enough are high. Doctors may also find that simply monitoring drug levels or using other ways to measure a patient's response helps more than knowing a metabolizer status. Testing may be useful for some people who have had difficulty with certain antidepressant drugs, antipsychotic drugs, or atomoxetine. If you have had intolerable side effects or you haven't gotten relief of your symptoms from one of these drugs, follow the links below. You can learn more about signs that you don't metabolize normally and what the experts say about genetic testing.

9 How Testing Works for CYP2D6 and CYP2C19 Psychiatric Drug Response Testing looks for the most common variants in two genes, called CYP2D6 and CYP2C19. Our genes act as the body's instruction manual for making the enzymes we need to process food, medications, and other chemicals that enter our body. We all have genes that don't work in the usual way. This happens because we inherit small variations in our instruction codes that make us unique. Genetic changes affect how well the CYP2D6 and CYP2C19 enzymes work. Most genetic variations are uncommon. For more information about the variants and how often they appear in different ethnic groups. CYP2D6 The CYP2D6 gene (or simply 2D6) is a member of the cytochrome P450 drug metabolism gene family. This gene makes the 2D6 enzyme that is involved in metabolizing about one quarter of all currently used drugs, including several antidepressants and antipsychotics. There are at least 70 different variants of the 2D6 gene. Most are too rare to need widespread testing. So, genetic tests usually just look for a group of the most common gene variants. CYP2C19 The CYP2C19 gene (or simply 2C19) is a member of the cytochrome P450 drug metabolism gene family. This gene makes the 2C19 enzyme that is involved in metabolizing about 15% of currently used drugs, including several antidepressants. There are at least 20 different variants of the 2C19 gene, but most of these are also too rare to need widespread testing. Testing for the two most common variants, called 2C19*2 and 2C19*3, finds most people who are poor metabolizers from any ethnic background. Your Metabolizer Status Every person has two copies of each drug metabolism gene - one from each parent. Your combination of variants places you in a specific category for each gene that is tested: Metabolizer Type Extensive Metabolizer (EM) Poor Metabolizer (PM) Ultrarapid Metabolizer (UM) Drug Response This is the most common result and is "normal." An EM's genes produce a typical amount of enzyme. EMs usually have normal drug response. PMs have gene variations that result in an inactive enzyme or no enzyme at all. PMs have a reduced response or no response and may have increased side effects UMs usually have more than two functional copies of the gene, and they produce a larger-than-normal amount of enzyme. UMs may have a reduced or no response and may have increased side effects

10 Test Limitations Genetic testing looks only at a group of the most common variants. This testing can't find all variants in the CYP2D6 or CYP2C19 genes that could cause someone to be a poor or ultrarapid metabolizer. A test result is considered normal (extensive metabolizer) when no variants are found. A normal result doesn't guarantee that you don't have a variant and won't have altered metabolism but it does make it much less likely. Also, there are many different factors that influence your response to a drug. There are genes and enzymes other than CYP2D6 and CYP2C19 involved, as well as medical and personal factors. If you have strong reason to believe that you have altered drug metabolism, a different test is also possible. This test involves giving you a specific dose of a drug that is metabolized by the enzyme in question called a "probe" drug. Your doctor can then track your urine levels of the drug and/or its components as it is being broken down to figure out how quickly you metabolize the probe drug. This information helps predict your metabolizer status. Genetics of CYP2D6 and CYP2C19 Drug Response The CYP2D6 and CYP2C19 enzymes are made by instructions coded within our genes. We all have genes that don't work in the usual way. This happens because we inherit small variations in our instruction codes that make us unique. CYP2D6 There are at least 70 different variants of the CYP2D6 gene. The "normal" forms of the 2D6 gene are called CYP2D6*1, or CYP2D6*2. Some of the most common variants are listed in the table below. The variants that aren't in the table are less common. Percent of People Who Have CYP2D6 Variants Based on Race/Ethnicity Variant Caucasian/White African/Black Asian CYP2D6*2 25% to 35% 2% to 45% 9% to 20% CYP2D6*2XN (amplification) 1% to 5% 2% Up to 2% CYP2D6*3 2% Rare Rare CYP2D6*4 12% to 21% 2% 1% CYP2D6*5 2% to 7% 4% 6% CYP2D6*6 About 1% Rare Rare CYP2D6*9 About 2% Rare Up to 3% CYP2D6*10 1% to 2% 6% 51% CYP2D6*17 Rare Up to 34% Rare CYP2D6*29 Rare Up to 20% in some parts of Africa Unknown CYP2D6*41A 20% 3% to 8% 2% to 11%

11 CYP2C19 There are at least 20 different variants of the 2C19 gene. The "normal" form of the 2C19 gene is called CYP2C19*1. The two most common variants are 2C19*2 and 2C19*3. The CYP2C19*1 variant makes enzyme that works normally. The CYP2C19*2 and *3 variants don't make enzyme that works, and the CYP2C19*17 variant is associated with ultrarapid metabolism. Other variants are usually found in less than 2% of people. Percent of People Who Have CYP2C19 Variants Based on Race/Ethnicity Metabolizer Status Variant Caucasian/White African/Black Asian 2C19*2 13% to 15% 16% to 18% About 30% 2C19*3 Less than 1% Less than 1% 5% to 10% 2C19*17 About 20% About 20% Less than 5% Genes come in pairs. How well your CYP2D6 and CYP2C19 enzymes work depends on your particular combination of gene variants. Extensive (normal) metabolizers have two genes that work normally. poor metabolizers have variants in both of their genes that cause neither gene to work normally. ultrarapid metabolizers have extra copies of these genes so they make more enzyme than normal. The table below shows how common poor and ultrarapid metabolizers are in people from different ethnic backgrounds. Inheritance Metabolizer Status Caucasians African-Americans Asians 2D6 Poor Metabolizer 5-10% Up to 1% 1% 2D6 Ultrarapid Metabolizer 1-5% 2% 0-2% 2C19 Poor Metabolizer 3-5% 3% 15-20% 2C19 Ultrarapid Metabolizer About 20% About 20% Less than 5% The gene variants that cause people to be poor or ultrarapid metabolizers are inherited. So, close family members may be more likely to share similar drug response profiles. Poor Metabolizers Poor metabolizers usually inherit variations in both copies of their drug metabolism genes that cause nonfunctional enzyme. This means that a poor metabolizer has no working copy of that particular drug metabolism gene. Usually, both parents of a poor metabolizer have at least one gene that doesn't work. All children of a poor metabolizer will also inherit at least one gene that doesn't work. Having one gene that doesn't work is sometimes called an "intermediate metabolizer".

12 Ultrarapid Metabolizers The ultrarapid metabolizers that genetic testing finds have more than two copies of a drug metabolism gene. Most people just have two copies of each gene. If you have extra gene copies, you will likely make more enzyme than usual. More enzyme leads to faster metabolism of drugs broken down by that enzyme. At least one parent of an ultrarapid metabolizer should also be an ultrarapid metabolizer. Each child of an ultrarapid metabolizer has a 50% chance of also being an ultrarapid metabolizer. CYP2D6, CYP2C19 and Antidepressants There are many different classes of antidepressants. Each class works a little differently on the brain chemicals. Two of the first kinds of antidepressants developed were tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). A newer class, called selective serotonin reuptake inhibitors (SSRIs), has become a common first choice for treating depression because SSRIs tend to cause fewer side effects. There are also other classes of antidepressants that include drugs like Wellbutrin, Effexor, and Cymbalta. All antidepressants don't work equally well for everyone. It is difficult to predict which antidepressant may be best for a specific person. So, doctors usually take a trial and error approach they use what they know about a patient's symptoms and medical history to choose a drug and then adjust the drug and dosage based on how the person responds. Only about 50% to 60% of people who take an SSRI get relief from their symptoms. Up to 15% of people stop taking an SSRI because they can't tolerate the side effects.

13 Drug response is influenced by many different factors including how that drug is metabolized. Genetic variations in the CYP2D6 and CYP2C19 drug metabolism enzymes may a play a role in how people respond to several different antidepressants especially SSRIs or TCAs. These enzymes don't metabolize all antidepressants. For some antidepressants that are metabolized by CYP2D6 or CYP2C19, enzyme variants don't seem to play an important role in how they work in practice. SSRIs and SNRIs Generic Name Brand Name(s) Major Metabolizing Enzyme citalopram Celexa, Ran-Citalo CYP2C19 escitalopram Lexapro, Cipralex CYP2C19 fluoxetine Prozac, Sarafem, FXT CYP2D6 fluvoxamine Luvox, Riva-Fluvox CYP2D6 paroxetine Paxil, Pexeva CYP2D6 sertraline Zoloft CYP2C19 venlafaxine Effexor CYP2D6 duloxetine Cymbalta CYP2D6 TCAs Generic Name Brand Name Major Metabolizing Enzyme amitriptyline Elavil, Endep, Enovil, Etrafon, Levate CYP2C19 and CYP2D6 clomipramine Anafranil, Novo-Clopamine CYP2C19 and CYP2D6 desipramine Norpramin, Pertofrane CYP2D6 doxepin Adapin, Sinequan, Prudoxin, Silenor, Zonalon, Triadapin CYP2D6 imipramine Tofranil, Impril, Novo-pramine CYP2D6 nortriptyline Pamelor, Aventyl, Norventyl CYP2D6 Signs of Abnormal Antidepressant Metabolism A CYP2C19 Poor Metabolizer May have intolerable side effects from average doses of the SSRIs: citalopram, escitalopram, and sertraline. Is more likely to have side effects from certain TCAs (notably amitriptyline and clomipramine).

14 A CYP219 Ultrarapid Metabolizer May need higher doses than usual of some TCAs (amitryptyline and clomipramine) and other antidepressants that are metabolized by CYP2C19 (citalopram, escitalopram and sertraline) to get symptom relief, but this isn't certain. A CYP2D6 Poor Metabolizer Is more likely to have intolerable side effects from usual doses of most TCAs. May be at increased risk for side effects from SSRIs metabolized by 2D6 (fluoxetine, fluvoxamine, and paroxetine). May also be at risk for side effects from certain other antidepressants that are metabolized by CYP2D6 like duloxetine and venlafaxine. A CYP2D6 Ultrarapid Metabolizer May need higher doses than usual of most of the TCAs to get symptom relief. Could, in theory, need higher doses of other antidepressants that are metabolized by CYP2D6 but this isn't certain. Drug CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5 Aripiprazole X X Asenapine X X X Chlorpromazine X X X Clozapine X X X X X Fluphenazine X Haloperidol X X X Iloperidone X X Olanzapine X X Paliperidone X X

15 Drug CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5 Perphenazine X X X X X Quetiapine X X Risperidone X X Thioridazine X X Ziprasidone X X CYP3A4 may be involved in paliperidone metabolism, but in vivo studies indicate that their role in eliminating paliperidone is minimal Testing for Antidepressant Response CYP2D6 and CYP2C19 testing isn't recommended for everyone taking (or planning to take) an antidepressant. A group of experts supported by the Centers for Disease Control and Prevention (CDC) recently looked at all of the available research about how these variants relate to prescribing SSRIs specifically. Although these enzymes are clearly involved in metabolizing many SSRIs, these experts found that there was very little research to show that doctors could prescribe SSRIs more safely or effectively when they know your metabolizer status. They discouraged doctors from ordering genetic testing before they prescribe SSRIs until more information is available. This group of experts specifically looked at whether CYP2D6 and CYP2C19 testing is useful for everyone starting SSRI treatment. They didn't look at whether testing might be valuable for patients who have had problems with SSRIs, TCAs, or other drugs that are metabolized by these enzymes. No other professional organizations have made clear recommendations either. As a result, it is up to your doctor to review your history and decide if testing might. CYP2D6 and Antipsychotics Antipsychotics are used to treat conditions like schizophrenia that cause symptoms of psychosis (being out of touch with reality, as apparent by delusions, hallucinations and disorganized speech). There are two main classes of antipsychotics. The first antipsychotics developed are often called "typical antipsychotics." These first drugs have an increased risk for side effects like stiff muscles, tremors, and, if taken for an extended time, a movement disorder called tardive dyskinesia. Newer drugs, called "atypical antipsychotics," have a lower risk for side effects and are now used more commonly.

16 All antipsychotics can cause side effects in some people and they don't all work equally well for everyone. Currently, only about 50% of people with schizophrenia who take an antipsychotic drug get sufficient relief of their symptoms. It is difficult to predict which antipsychotic may be best for a specific person. So, doctors must take a trial and error approach they use what they know about a patient's symptoms and medical history to choose a drug and then adjust the drug and dosage based on how the person responds. Drug response is influenced by many different factors including how that drug is metabolized. Genetic variations in the CYP2D6 drug metabolism enzyme may a play a role in how people respond to certain antipsychotics. CYP2D6 isn't important for all antipsychotics. Antipsychotics Processed by CYP2D6 Typical Antipsychotics Atypical Antipsychotics Generic Name haloperidol thioridazine perphenazine chlorpromazine risperidone aripiprazole Brand Name Haldol, Helperon, Peridol, Novo-Peridol Mellaril, Novo-Ridazine Trilafon Thorazine Risperdal Abilify Signs of Abnormal Antipsychotic Metabolism A CYP2D6 Poor Metabolizer o May have side effects from usual doses of most typical antipsychotics and the atypical antipsychotics aripiprazole and risperidone. o Wouldn't be expected to have an increased risk for adverse reactions to other atypical antipsychotics, like clozapine, olanzapine, quetiapine, or ziprasidone. A CYP2D6 Ultrarapid Metabolizer o May not respond as expected to usual doses of most typical antipsychotics, aripiprazole, and risperidone. Testing for Antipsychotic Response CYP2D6 testing isn't recommended for everyone taking (or planning to take) an antipsychotic drug. Although CYP2D6 may be important in metabolizing certain drugs, there is very little research to show that doctors can actually prescribe antipsychotics more safely or effectively when they know your metabolizer status. There are several possible reasons for this. Many factors affect drug response, not just metabolism. Simply monitoring drug levels may actually work better for choosing the best dose of a drug or figuring out that a certain drug may cause problems. Testing could be helpful for some people who have had difficulty with either intolerable side effects or simply not responding to certain antipsychotics. If you have a reason to think that you may metabolize these antipsychotics abnormally, talk to your doctor about whether testing may be helpful.

17 CYP2D6 and Atomoxetine Atomoxetine (Strattera ) is a drug used to treat children and adults with attention deficit hyperactivity disorder (ADHD). Many drugs for ADHD are stimulants. Atomoxetine is different because it treats both attention and hyperactivity symptoms without being a stimulant. As with most drugs, the dose of atomoxetine varies from person to person. Atomoxetine is metabolized mostly by the CYP2D6 drug metabolism enzyme. Variations in the CYP2D6 enzyme may partly explain why people respond to the drug differently. Signs of Abnormal Atomoxetine Metabolism A CYP2D6 Poor Metabolizer o May have symptoms that improve more than expected based on the dose. A poor metabolizer is actually being exposed to higher levels of the drug for longer because the drug isn't broken down as quickly as usual. o May have a higher heart rate and blood pressure than extensive metabolizers taking the o same dose. Has a slightly higher risk for certain side effects, especially tremor, but most are relatively mild and don't cause a person to stop taking the drug. A CYP2D6 Ultrarapid Metabolizer o May need higher atomoxetine doses than extensive (normal) metabolizers. Testing for Atomoxetine Response CYP2D6 testing isn't routinely recommended for everyone taking (or planning to take) atomoxetine. Although CYP2D6 is clearly important in metabolizing the drug, there aren't any professional guidelines to help doctors decide when to test patients for CYP2D6 variants to predict atomoxetine response at this time. However, the Food and Drug Administration (FDA) has special prescribing information for poor metabolizers who take atomoxetine. The FDA highlights that laboratory tests are available to identify CYP2D6 poor metabolizers. The FDA has also included CYP2D6 testing for atomoxetine on its list of FDA approved biomarkers for drug response. Doctors must weigh all available information and decide if testing is likely to be useful given a patient's specific medical history. CYP2D6, CYP2C19, and Other Drugs CYP2D6 and CYP2C19 are general metabolism enzymes. They are involved in metabolizing many different drugs, not just psychiatric drugs. Once a metabolizer status for an enzyme is known, that information may be used to predict the response to any drug metabolized by that enzyme. Some examples of commonly prescribed drugs metabolized by CYP2D6 and CYP2C19 are shown in the tables below. There are also drugs that keep an enzyme from working fully. These drugs are called "inhibitors". A person with normal drug metabolism genes can actually respond to a drug like a poor metabolizer if they are also taking an inhibitor drug. Poor metabolizers have an especially high risk for side effects when they take a drug that is metabolized by their nonfunctioning enzyme and they also take an inhibitor drug.

18 The following lists aren't complete. You should always make your doctors and pharmacy aware of all drugs you are taking and, if you know it, your enzyme metabolizer status. CYP2D6 Below are examples of drugs that are metabolized by CYP2D6. A poor or ultrarapid metabolizer may respond to these drugs in an unexpected way. Beta Blockers antidepressants antipsychotics Others metoprolol propafenone timolol amitriptyline clomipramine desipramine duloxetine imipramine paroxetine venlafaxine aripiprazole haloperidol risperidone thioridazine codeine dextromethorphan flecainide ondansetron tamoxifen tramadol Adapted from Flockhart DA. P450 Drug Interaction Table The following are some drugs that keep CYP2D6 from working normally. These are called inhibitors. CYP2D6 Inhibitors amiodarone bupropion chlorpheniramine cimetidine clomipramine duloxetine fluoxetine haloperidol methadone mibefradil paroxetine quinidine ritonavir Adapted from Flockhart DA. P450 Drug Interaction Table

19 CYP2C19 Below are examples of drugs that are metabolized by CYP2C19. A poor metabolizer may respond to these drugs in an unexpected way. Ulcer / Reflux Drugs Antiepileptics / Anticonvulsants Psychotherapeutic Drugs omeprazole lansoprazole pantoprazole rabeprazole diazepam phenytoin amitriptyline clomipramine Others clopidogrel cyclophosphamide progesterone Adapted from Flockhart DA. P450 Drug Interaction Table The following are some drugs that keep CYP2C19 from working normally. These are called inhibitors. CYP2C19 Inhibitors fluoxetine fluvoxamine ketoconazole lansoprazole omeprazole ticlopidine Adapted from Flockhart DA. P450 Drug Interaction Table