AUGUST 2006 IMPROVING PATIENT CARE THROUGH ESOTERIC LABORATORY TESTING VOLUME 31, NO. 8 Update on Serotonin Serotonin pathways regulate many systems in neuromuscular activity, cognitive function, the body, and disturbances in the serotonergic and mood control. Serotonin is released from (activated by or capable of liberating serotonin) presynaptic neurons and binds to postsynaptic system result in a wide range of problems. Drugs serotonin receptors, thereby exciting the that affect the serotonergic system are commonly postsynaptic neurons. The serotonin transporter used to treat psychiatric disorders, and inherited then carries serotonin back into the presynaptic differences in serotonin metabolism may alter neuron for subsequent reuse. Conversely, the patients’ responses to these drugs. In this review, enzyme monoamine oxidase (MAO) reduces we discuss serotonin metabolism, serotonin presynaptic serotonin levels by deamination syndrome, and new serotonin-related genetic (Figure 1). tests (pharmacogenetics). Serotonin in Enterochromaffin Cells Serotonin Metabolism Serotonin released from enterochromaffin cells Serotonin (5-hydroxytryptamine; 5-HT) is exerts a strong influence on the GI tract by synthesized from the amino acid tryptophan. increasing GI blood flow, motility, and fluid The body has 3 main serotonin pools: the central secretion. On its first pass through the liver, 30% nervous system (CNS), gastrointestinal (GI) to 80% of serotonin is metabolized, predominately enterochromaffin cells, and platelets. to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted by the kidneys. Most of the remaining Serotonin and the Central Nervous System serotonin (90%) is metabolized in the lungs, also to 5-HIAA. Approximately 10% is taken up by Serotonin, a neurotransmitter, is an important platelets, where it remains until it is released regulator of the autonomic nervous system during the coagulation process. (including temperature regulation and GI motility), INSIDE THIS ISSUE Feature Psychiatric Genomic Tests New Test Announcements Update on Serotonin Quick Reference Guide • #88672 API2/MALT1, mRNA Detection by Reverse 2006 Education Calendar Ask Us Transcription-PCR • #80678 Chorionic Gonadotropin for Pregnancy, Serum AUGUST 2006 • WWW.MAYOREFERENCESERVICES.ORG/COMMUNIQUE/ • PAGE 1 Figure 1. Diagram of neurosynaptic serotonin (5-HT). Serotonin in Platelets Serotonin and Psychiatric Disorders Serotonin is stored in the platelets’ dense granules Anxiety and depression are often treated with drugs and released during platelet activation. It stimulates that increase CNS serotonin levels, either by: platelet aggregation and causes other local and • Reducing serotonin deamination (eg, monoamine systemic effects including vasodilation and oxidase inhibitors [MAOI]) constriction, blood pressure changes, and • Increasing serotonin precursors (eg, lithium) bronchoconstriction. • Acting as serotonin agonists (eg, trazodone) PAGE 2 • WWW.MAYOREFERENCESERVICES.ORG/COMMUNIQUE/ • AUGUST 2006 • Increasing serotonin levels in the nerve synapses drug. Other individuals demonstrate accelerated (eg, tricyclic antidepressants [TCAs], such as metabolism and may not experience the desired amitriptyline [Elavil], imipramine [Tofranil], therapeutic effects because the drug is rapidly and desipramine [Norpramin], and the selective inactivated and/or eliminated. Individuals with serotonin reuptake inhibitors [SSRIs], such as extra copies (duplication) of the functional CYP2D6 citalopram [Celexa], fluoxetine [Prozac], gene demonstrate accelerated metabolism (ultrarapid paroxetine [Paxil], sertraline [Zoloft], and metabolizers). escitalopram [Lexapro]). A number of polymorphisms have been identified Use of these drugs has become increasingly in the CYP2D6 gene that result in enzymatic widespread. However, some patients are deficiencies (Table 2). The frequency of these nonresponsive or respond slowly to these polymorphisms varies within major ethnic groups. medications, while other patients may develop CYP2D6 polymorphisms that result in poor serious side effects (eg, serotonin syndrome, metabolism are found in 7% to 10% of Caucasians, cardiac dysrhthmias, hypotension, convulsions, 2% of Africans and African Americans, and 1% of CNS depression, or worsening of depression). Asians. Individuals who are homozygous (2 copies Antidepressant drug selection may be more of 1 abnormality) or compound heterozygous effectively guided by pharmacogenetic testing. (1 copy of 2 different abnormalities) for the Molecular tests are currently available for genes polymorphisms associated with reduced enzyme encoding the hepatic enzymes responsible for activity are poor metabolizers. Individuals who are drug metabolism (cytochrome P450 enzymes), heterozygous, with 1 normal gene and 1 polymorphic for the serotonin receptor, and for the serotonin gene, will have a metabolism that is intermediate, transporter.1 between the extensive and poor metabolizers. Cytochrome P450-mediated Metabolism Identification of a patient’s CYP2D6 genotype of Serotonergic Drugs may allow appropriate dosing adjustments (#83180 Cytochrome P450 2D6 Genotyping). Patients who Metabolism of many drugs is accomplished by are poor metabolizers may need lower than usual cytochrome P450 (CYP) enzymes, a group of enzymes doses to achieve optimal response while avoiding located predominantly in the liver (Table 1). Of the toxicity. Patients who are ultrarapid metabolizers CYP enzymes, CYP2D6 is primarily responsible for may benefit from increased doses or conversion to the metabolism of a large number of commonly other drugs that are not primarily metabolized by prescribed drugs, including the SSRIs and TCAs. CYP2D6. A complicating factor in correlating CYP2D6 genotype with phenotype is that many CYP2D6–mediated drug metabolism is highly drugs (or their metabolites) may reduce CYP2D6 variable, and inherited differences have been catalytic activity (Table 1). For example, an described. Individuals without inactivating individual with an inherited pattern consistent polymorphisms, deletions, or duplications are with intermediate metabolizer status for the considered normal (referred to as extensive antidepressant amitriptyline (metabolized by metabolizers), designated as CYP2D6*1/*1. CYP2D6) may act as a poor metabolizer if he Some individuals have altered CYP2D6 gene or she also is taking a drug that decreases CYP2D6 sequences (polymorphisms) that result in synthesis activity such as celecoxib or quinidine. Consequently, of enzyme with decreased or absent catalytic activity. it is important to interpret the results of CYP testing These individuals metabolize SSRIs and TCAs poorly in the context of other coadministered drugs, as and may experience significant medication side effects individuals may require dosing changes greater or due to prolonged exposure to the active form of the less than predicted based upon genotype alone. AUGUST 2006 • WWW.MAYOREFERENCESERVICES.ORG/COMMUNIQUE/ • PAGE 3 Drugs That Undergo Metabolism By CYP2D6: Alpha-blocker: alprenolol, timolol Analgesic: codeine, oxycodone, tramadol Anticonvulsant: felbamate, mephobarbital Antidepressant: amitryptyline, clomipramine, desipramine, duloxetine, fluoxetine, fluvoxamine, imipramine, mirtazapine, nortriptyline, paroxetine, sertraline, venlafaxine Antidiabetic: phenformin Antiestrogen: tamoxifen Antihypertensive: diltiazem Antipsychotic: aripiprazole, chlorpromazine, haloperidol, perphenazine, risperidone, thioridazine Antitussive: dextromethorphan Beta-blocker: labetalol, metoprolol, propranolol Cardioactive: disopyramide, encainide, flecainide, lidocaine, mexiletine, propafenone Norepinephrine reuptake inhibitors: atomoxetine Stimulant: amphetamine Coadministration may decrease the rate of elimination of other drugs metabolized by CYP2D6 Drugs Known To Increase CYP2D6 Activity: Dexamethasone Coadministration of this drug increases the rate of excretion of CYP2D6-metabolized drugs, reducing the other drugs’ effectiveness. Drugs Known To Decrease CYP2D6 Activity: Analgesic: celecoxib, methadone Antidepressant: bupropion, clomipramine, citalopram, duloxatine, fluoxetine, paroxetine, and sertraline Antiemetic: metoclopramide Antineoplastic: doxorubicin Antipsychotic: chlorpromazine, haloperidol Antiretroviral: indinavir, ritonavir Antistroke: ticlopidine Cardioactive: amiodarone, quinidine H-1 blocker: cimetidine, ranitidine Stimulant: cocaine Sympathomimetic: chlorpheniramine Coadministration will decrease the rate of metabolism of CYP2D6-metabolized drugs, increasing the possibility of toxicity. Table 1. Some of the known CYP2D6 metabolism and drug relationships. PAGE 4 • WWW.MAYOREFERENCESERVICES.ORG/COMMUNIQUE/ • AUGUST 2006 Serotonin Receptor Genotype response to SSRIs, putting the patient at increased risk for adverse drug reactions.3 The effects of serotonin occur after it binds Variations in the HTR2A and HTR2C genes to serotonin receptors, a large and diverse have been associated with increased risk of family of G protein-coupled receptors.2 At least tardive dyskinesia, a common and troubling 7 groups of serotonin receptors, each with medication side effect, in schizophrenic multiple polymorphisms, have been described.2 patients.4,5 Conversely, the presence of the Receptor proteins encoded by these gene HTR2A allele and HTR2C allele have been variants may demonstrate differing serotonin reported to predict favorable response to therapy binding affinity, differing signal transduction with clozapine, an antipsychotic agent.6 A capabilities,