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Psychiatric Pharmacogenomics. Genetic Testing in Psychiatry Beverly Bryant, M.D. Connections 10/25/13. The Human Genome Project.
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Psychiatric Pharmacogenomics Genetic Testing in Psychiatry Beverly Bryant, M.D. Connections 10/25/13
The Human Genome Project In 1990, the National Institute of Health and the U.S. Department of energy began the process of identifying all 30,000 genes in the human body . The project was completed in 2003. Among many other things, this has allowed us to identify the genes that control the metabolism and therapeutic results of certain medications as well as genes that contribute to the development of certain diseases.
DNA DNA contains the genetic blueprint for all life. Every physiological process is governed by it. We inherit half of our DNA from each parent and we get two copies of each gene. The expression of the gene products govern all bodily functions.
Genetic testing • The testing generally falls into two categories: • Testing for differences in the way that individuals respond to medications • Testing for differences in the way individuals metabolize medications.
Psychiatric Genes • There are 10 “psychiatric genes” that have been identified that are routinely tested at the Mayo Clinic. • What clinical questions can they help to answer? • Analysis of these genes can help to determine who is most likely to respond to specific medications for depression and ADHD, who is most at risk for tardive dyskinesia and who has increased risk of side effects such as weight gain and neuroleptic malignant syndrome.
Personalized medicine • Therefore, genetic testing has introduced the era of “personalized medicine” and based on our genetic profile, medical treatments can be customized to fit our individual needs. • Eventually, genetic testing may aid in the early identification and treatment of psychiatric illness
Ethical Considerations • But, genetic testing has also introduced a myriad of ethical issues. • Genetic testing does NOT take the place of good clinical judgment and there is not enough evidence currently to use it for diagnosis in psychiatry • Protection under the law is afforded by the Genetic Information Nondiscrimination Act (GINA) which became effective in 2009.
STIGMA Patients suffering from psychiatric illnesses are routinely stigmatized, partially due to the subjective nature of psychiatric diagnoses. Traditionally, criteria for psychiatric diagnoses have been based on the description of symptoms, leaving a wide margin for error and interpretation.
Diagnosis by committee We don’t refer to pneumonia as “coughing disorder” and the decision of how to treat it does not depend on the opinion of a committee. Yet, this is precisely the case for bipolar disorder, which carries a 20% mortality rate.
Wanting to be sick? • This leads to a common practice of seeing psychiatric diagnoses as being “fake” or fabricated. • Psychiatric patients are seen as being self-indulgent, selfish or weak. • Some are even accused of “wanting to be sick.” • Rarely do we accuse people of “wanting to get cancer” or “wanting to die of a heart attack” even though personal choices such as smoking can contribute to these diagnoses.
Once a psychiatric diagnosis is made, treatment is often a matter of trial and error. Choosing the correct medication is a gamble.
This is complicated by the fact that many psychiatric medications do not have therapeutic effects for several weeks.
If the first medication trial fails, the patient feels more hopeless and the family doubts the validity of the patient’s symptoms.
Psychiatric Genes The neuron and the synapse How neurons talk to each other
The synapse Proteins that transport neurotransmitters Proteins that receive neurotransmitters Proteins that synthesize neurotransmitters
Serotonin Transporter Gene (5HTT or SERT) • An allele is a variation in a gene. For example there is an allele for blue eyes and an allele for brown eyes. Brown is dominant over blue so to have blue eyes, one must have a blue eyed allele from each parent. • There is a “short” allele (S) and a “long” allele in the SERT. One can have two short alleles, two long alleles or a long and a short allele.
Short allele • The S/S form is associated with a better response to nortriptyline as well as lithium augmentation. • The short allele is associated with a poorer response to treatment with Selective Serotonin Reuptake Inhibitors (SSRIs),such as fluvoxamine (Luvox), sertraline (Zoloft), and fluoxetine (Prozac), especially for symptoms of depression and somatic anxiety. • The short allele is also associated with increased side effects to antidepressants including gastrointestinal side effects, antidepressant induced mania and lifetime history of rapid cycling mood swings.
Long allele • The L/L form of the gene is associated with an improved response to citalopram (Celexa) and escitalopram (Lexapro) in caucasians. • A copy of the long form of the allele is also associated with a better response rate to sertraline (Zoloft) and fluoxetine (Prozac) in patients of European ancestry.
Other variants • Other variants have been associated with a 77% successful prediction of response to the antipsychotic medication clozapine. • Some variants have been associated with a better response to methylphenidate.
NET1 DAT1 Neurotransmitter transporter genes Norepinephrine and Dopamine
Norepinephrine transporter gene (NET1) • The mechanism of a number of antidepressant medications involves inhibition of the norepinephrine transporter. Cocaine and amphetamines also inhibit this transporter. • Variants in this gene can predict a positive response to tricyclic antidepressants such as nortriptyline.
Norepinephrine transporter gene (NET1) • Variants in NET1 have also been associated with the degree of improvement of psychotic symptoms when treated with risperidone or olanzepine. • Response to methylphenidate has also been associated with variations in the NET1 gene. Likewise, certain variants are associated with a more euphoric response to amphetamines.
Dopamine transporter gene (DAT1) • Variants of this gene have been associated with response to a variety of antidepressants such as SSRIs, tricyclics, venlafaxine (Effexor) and mirtazepine (Remeron). • Certain forms of the gene may serve as genetic markers for ADHD and predict response to stimulants.
Receptor Genes Serotonin, Dopamine and Norepinephrine Predictors of treatment response
Serotonin and Dopamine Receptor Genes • There are genes that code for a variety of receptor proteins that bind to serotonin and dopamine. • Variations in these genes have also been associated with the therapeutic response to specific antidepressants, the risk of tardive dyskinesia and weight gain with the use of antipsychotic medications. • These variants can also predict intolerance to certain antidepressants and the risk of sexual side effects.
Serotonin and Dopamine Receptor Genes • The haplotype of rs6313 cytosine and rs6314 thymine allele is especially predictive of tardive dyskinesia • The following haplotypes are associated with weight gain with atypical antipsychotics: rs3813929 -759 C allele plus rs3834996 -1027 Long GT repeat allele plus rs6318 69 G allele Above plus 2565 C allele Gly 855 Ser rs1414334
COMT Protein that inactivates L- dopa, precursor to dopamine and norepinephrine
Catechol O Methyltransferase (COMT) • Variations in the COMT genotype have been linked to the response to ECT, response to antipsychotic medication and risk for tardive dyskinesia. • Likewise, there are variations associated with the response to stimulant medications, anti-Parkinson medications and morphine. • Variations in this gene have even been associated with the success of smoking cessation with bupropion.
Catechol O Methyltransferase (COMT) • Variations in this gene have even been associated with the success of smoking cessation with bupropion (Zyban.) • The haplotype of rs737865 -19847 G/T plus rs16599 1338 G/A is associated with decreased smoking cessation with bupropion (Berrettini 2007)
Metabolic Testing To the human body, medications are seen as foreign substances that need to be eliminated. Most medications are processed and disposed of by the liver and/or kidney. Some drugs are converted to their active form before being eliminated.
PRODRUG A “prodrug” is a drug that is converted to its active form by a metabolic process. For example, if your system is faster than the average person, you will rapidly convert to active drug and you may need lower doses. If your system is slower than average, you may need a higher dose of the drug than others in order to get benefit.
Cytochrome P450 System Many medicines are processed by what is known as the Cytochrome P450 system in the liver. There are a number of different pathways in this system that are responsible for metabolizing different drugs. An individual can be slow in one pathway but fast in another.
“Average Dosing” Drug companies calculate the recommended dosage of a drug based on the “average” person. Yet, very few people are actually “average” in every pathway.
Rapid Metabolizers Rapid metabolizers process a drug faster than the average person. This means that they clear the drug more quickly from their system, so they may need higher doses to be effective. On the other hand, if the drug is a “prodrug”, they need lower doses.
Slow Metabolizers Slow metabolizers are slower to clear a drug from their system. This means they may need lower doses of the drug to get benefit. If the drug is a “prodrug”, they may need higher doses.
Rapid Metabolizer Active Drug Prodrug • RAPID METABOLIZER= MORE ACTIVE DRUG • RAPID METABOLIZER= LESS PRODRUG
Slow Metabolizer Active Drug Prodrug SLOW METABOLIZER = LESS ACTIVE DRUG • SLOW METABOLIZER= MORE PRODRUG
Best guess Without genetic testing, doctors have to assume everyone is “average” unless they can make a guess based on racial differences.
2D6 • This is an important pathway for many antidepressants, such as venlafaxine, nortriptyline and others. • Also, some drugs such as fluoxetine (Prozac), bupropion (Wellbutrin) or paroxetine (Paxil) inhibit this pathway, making slow or intermediate metabolizers more at risk • A slow metabolizer is more vulnerable to side effects at lower doses and less responsive to prodrugs such as codeine.
Slow metabolizers • Codeine and Tamoxifen are both prodrugs that depend on 2D6 to be converted to active drug. • Slow or intermediate metabolizers will be less responsive to certain pain medications (often leading to accusations of drug seeking). • Likewise, if these patients are being treated for breast cancer, they are less likely to get adequate response to Tamoxifen at usual doses.
Common problems for slow metabolizers • Antipsychotics: increased risk of hyperprolactinemia due to accumulation of 9-hydroxyrisperdone • Aripiprazole (Abilify) is metabolized by 2D6 but also has a secondary pathway (3A4) so it can be tolerated at reduced dosages. • Dextromethorphan (found in over the counter cold medications) can build up to high levels causing a sense of altered awareness and increasing the risk of abuse. • Ecstasy (MDMA): increased risk of toxicity.
2D6 and endobiotic metabolism • In addition to clearing external substances from the body, the 2D6 pathway is also involved in transforming endogenous substances. • For example, it is believed that 2D6 is involved in the conversion of tyramine to dopamine and the regeneration of serotonin. • Some studies suggest that slow metabolizers of 2D6 may have certain personality traits such as “perfectionism” and anxiety, but the results of these studies are mixed.
2C19 • Citalopram (Celexa) and escitalopram (Lexapro) are cleared by this pathway. • Rapid metabolizers clear these drugs quickly and will not respond to the usual doses. • Yet, citalopram has an FDA warning against the use of high doses due to the risk of a heart arrythmia. • Rapid metabolizers are unlikely to receive the dose they need.