Major depressive disorder (MDD) is present in a variety of healthcare settings and is a chronic condition for many patients. Depression is a complicated and pervasive disease and current treatment modalities are successful in only two-thirds of patients.1 Genes, the fundamental unit of heredity, play a major role in MDD particularly in treatment outcomes. Some unsuccessful depression treatment outcomes are due to cytochrome P450 (CYP450) phenotype, or the physical manifestation of the genetic composition of the CYP450 metabolic enzymes. This concept is known as pharmacogenetics, or the effect of genetic variation on drug response.
In 2006, the World Health Organization reported that MDD is the leading cause of disability worldwide and that currently 1 in 20 Americans experience depression.2 The estimated cost of depression in the United States, including treatment, social services, disability payments, lost productivity, and premature mortality, is roughly $200 billion.3 The gold standard for diagnosing depression is found in the Diagnostic and Statistical Manual of Mental Disorders Revised 4th edition (DSM IV-TR).4 The criteria for depression as defined by the DSM IV-TR include at least five symptoms of depression lasting for at least 2 weeks and which cause impairment in daily functioning. Symptoms for depression include but are not limited to feeling depressed, feeling sad, irritable mood, or loss of interest in usual activities.4
The incidence of depression varies by age, race, sex, and socioeconomic status. The highest incidences of depression were found in 40- to 59-year-olds, women, non-Hispanic Blacks, and persons earning below the federal poverty level (FPL).2 Despite the negative effects in one's life, individuals with depression do not always seek healthcare. Pursuing treatment varies depending on the severity of one's symptoms; those with mild depression seek treatment 15.6% of the time contrasted with moderate, 24.3%, and severe, 39% (see National Center for Health Statistics Incidence of Depression Data).2
The guidelines for pharmacologic modalities for MDD, as defined by the American Psychiatric Association (APA), include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine, and bupropion as mainstays for treatment used alone or in addition to other nonpharmacologic treatment options.5 For those patients whose depression does not respond to the before-mentioned antidepressant drug classes tricyclic antidepressants (TCAs) and nonselective monoamine oxidase inhibitors (MAOIs) should be considered.5 The APA further recommends practitioners consider adverse reactions, safety, tolerability, and pharmacologic properties including actions on CYP450 enzymes when choosing an antidepressant medication.5 Antidepressants are widely utilized in clinical practice. Twelve antidepressants made the list of top 200 drugs prescribed in 2008, and were responsible for $11 billion in revenues for pharmaceutical companies in 2008.6–10
Complexity of treatment
Depression has several proposed pathologies, including the monoamine-deficiency hypothesis, the hypothalamic-pituitary-adrenal axis and stress hypothesis, and the decreased neurogenesis hypothesis.1,9–12 The monoamine-deficiency hypothesis proposes that there is a lack of serotonin and norepinephrine in the synaptic cleft resulting in depression symptoms. Evidence linking the hypothalamic-pituitary-adrenal axis to depression includes all the following signs found in patients with depression: elevated plasma cortisol levels, elevated cerebrospinal fluid corticotrophin-releasing hormone (CRH) levels, increased levels of CRH messenger ribonucleic acid (mRNA), and CRH protein in the limbic regions of the brain.1 In depressed patients, magnetic resonance imaging (MRI) shows a hippocampus decreased in normal size, and evidence of decreased neurogenesis.1 Additionally in depressed patients, there are reduced levels of brain-derived neurotrophic factor (BDNF), a neuropeptide associated with neurogenesis.1
The exact physiologic mechanism for depression is unknown and in turn there is no cure for depression, only symptom management.1 This highlights the current dichotomy in managing depression: with widely utilized screening tools there is an increased ability to diagnose MDD but little success in treating it. Furthermore, remission of depressive symptoms is frequently delayed in patients, which prolongs suffering and increases the risk for suicide.11,12 The National Institute of Mental Health funded a large clinical trial for adults with treatment-resistant depression. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study used a treatment algorithm of several steps to evaluate the most effective course of treatment in patients who have already tried to treat their depression. The STAR*D study was well conducted with high external validity. Researchers selected a patient population often excluded from most studies. The inclusion criteria allowed patients with comorbid conditions, taking medication other than antidepressants, with chronic conditions, and with current suicidal ideation.9 In addition to the broad inclusion criteria the study also enrolled patients from both primary care and specialty clinics, and included a racial-ethnic composition of patients that is similar to that of the United States.
The treatment algorithm began with citalopram, an SSRI, and progressed through four steps where one could choose to augment their current treatment or to switch treatments. Successful outcomes were measured by remission of depressive symptoms. Overall trends of the STAR*D study illustrated that patients who require more treatment steps tended to have greater depressive illness burden and more concurrent psychiatric and general medical disorders.10 Times to remission were 5.4 to 7.4 weeks across the four treatment steps, and remission was associated with a better prognosis even if remission was reached after several treatment steps.10 One of the most concerning results was that after all four treatment steps the cumulative remission rate was 70%.10 Of patients who completed the treatment program 30% were left without remission of their depression.10 It is also important to note that a considerable number of patients dropped out after each treatment step: of the patients remaining 20%, 30%, and 42%, respectively, left after each step of the trial.10 The STAR*D study illustrated that there is a need for several steps to achieve remission in some patients with depression and that treatment will not be successful for every patient.
Another point that can be concluded from the STAR*D trial is that there was no clear medication "winner" for those whose depression did not remit after one medication trial.9 The chance of remission did not clearly differ by medication choice. The results of the study implied that antidepressant medication effects are not universal for all patients and that there are extraneous factors contributing to the complexity of depression treatment.
Genotyping, which is the process of determining a person's genetic composition, can be utilized for personalized medicine. Knowing the genetic variations, which are called alleles, in a patient's CYP450 metabolic profile allows for optimal prescribing and dosing of medications. Recent studies have profiled CYP450 enzymes in relation to metabolism of medications, in particular antidepressants. Correlations have been found among CYP450 metabolic allelic variation and success, tolerance, and compliance with antidepressant medications.13–15 Genomic evaluation of patients would allow nurse practitioners (NPs) and physicians to tailor treatment options to achieve better rates of symptoms remission. This is the objective of personalized medicine (see Pharmacogenetic terms).
There are 50 different CYP450 enzymes found in the smooth endoplasmic reticulum of liver and intestinal cells.17 CYP450 enzymes interact with drugs in two ways: phase I metabolism and phase II metabolism. In phase I metabolism, CYP450 enzymes take lipophilic compounds, a chemical property of antidepressants, and convert them into polar moieties. Polar moieties are pieces of a molecule that aid in the interaction with water, which can activate or inactivate the antidepressant. In phase II metabolism, the enzymes conjugate the antidepressants into a water-soluble form to allow for excretion via the kidneys. These phases can happen either individually or successively. CYP450 enzymes are important to take into account when prescribing because 7 of the 50 different kinds of CYP450 enzymes are responsible for metabolizing 90% of all drugs.17 One CYP450 enzyme, CYP2D6, is responsible for the metabolism of 30% of all drugs including many antidepressants.17
Drugs interact with CYP450 enzymes in several ways. Drugs can be substrates, inhibitors, inducers, or a combination of both for CYP450 enzymes. Drug substrates are compounds that require metabolism by a certain enzyme but have no effect on the enzyme's overall activity. Inhibitors block enzyme function while inducers enhance enzyme activity. Drugs can also be autoinducers or autoinhibitors meaning that the drug can either inhibit or induce the enzyme for which it is a substrate. SSRIs, SNRIs, and TCAs are classes of antidepressants that are substrates for CYP2D6 (see Antidepressants and CYP2D6 metabolism).
CYP2D6, a highly variable gene with 77 different alleles, is a major determinant of the interindividual variability among patients in plasma concentrations of TCAs and many SSRIs.18 Some of the CYP2D6 alleles are not functional; therefore, the quantity of CYP2D6 alleles in the genome does not necessarily translate into a phenotype of increased metabolic function. There are four phenotypic profiles for CYP2D6: poor metabolizer (PM), no metabolic function; intermediate metabolizer (IM), some metabolic function; extensive metabolizer (EM), normal metabolic function; and ultra metabolizer (UM), too much metabolic function. This phenotypic function interacts with the three activities of CYP2D6 enzymes: inactivation of active drug, activation of a prodrug, and converting a drug to a metabolite.19 Depending on the CYP2D6 phenotype patients will react differently to each of the three enzymatic activities. For example, when CYP2D6 is responsible for inactivation of a drug UMs may not achieve therapeutic plasma concentrations because they will inactivate the drug too quickly, and PMs may suffer adverse drug reactions (ADRs) because they will not inactivate the drug.19 During activation of a prodrug PMs will have reduced conversion from drug to prodrug and therefore low effectiveness of treatment; for UMs there is greater risk for drug reaction because of increased conversion from prodrug to an active form.19 When CYP2D6 enzymes convert a drug into a metabolite, the target site and plasma concentration are affected; in PMs, there will be decreased plasma concentrations and inversely in UMs, there will be increased plasma concentrations.19 However, antidepressants do not follow linear pharmacokinetics, meaning the serum concentrations of antidepressants do not directly correlate to effectiveness of treatment.20
Studies that evaluated patient response to antidepressants attempted to design a prescribing algorithm based on the CYP2D6 metabolic profile (PM, IM, EM, and UM).13,20 In current practice, when prescribing an antidepressant, NPs and physicians estimate systemic concentration of a drug based on individual patient factors such as age, body mass index, and sex. However, both environment (age, body mass index, sex) and genetics (CYP2D6) need to be taken into account when prescribing. A group working with dosing warfarin, an anticoagulant drug with unpredictability when dosing, compared two algorithms. The first dosing algorithm took age, weight, race, and ethnicity into consideration, while the second dosing algorithm included CYP450 phenotypes in addition to the previously mentioned variants. Researchers found the algorithm that included genetics greatly out-performed the basic clinical algorithm and they were able to asses this by using patients who already had an established warfarin dose.21 Therefore, genotyping a patient's CYP2D6 profile is important in order to give practitioners clues about how a patient will respond to antidepressants. The frequency of each CYP2D6 phenotypic profile is variable among different ethnicities (see CYP2D6 status and race/ethnicity).
Metabolic phenotypes vary among patients, and genotyping is the best way to determine CYP2D6 phenotypes. There are several diagnostic tests available for determining CYP2D6 phenotype; the AmpliChip CYP450 test directly identifies 29 allelic variations in CYP2D6 and 3 for CYP2C19 in a single test in addition to measuring allelic activity in order to accurately predict phenotype.24 Measuring allelic function compared to number of present alleles accurately determines phenotype. TM Bioscience Tag-it Kit is another CYP450 genotyping test, but it is unable to predict allelic functioning, which is important because alleles of CYP2D6 genes may be present but not functioning.22
CYP450 genotype testing is readily available in clinical laboratories and cost for each test ranges from $422 to $1600 depending on the size of the lab. CYP450 genotyping tests are not covered by any major insurance companies, which claim that genotyping CYP450 enzymes is not cost-effective enough to allow coverage. There are many studies with supportive data for the improved clinical outcome associated with genotyping CYP2D6 prior to antidepressant treatment.15,19,25–28
A cohort of 1,198 elderly Dutch patients was genotyped for their CYP2D6 metabolic profiles prior to their first antidepressant treatments. Researchers found that PMs were more likely than EMs to switch TCA treatments due to ineffectiveness of treatment and ADRs.15 In addition, the maintenance dose of antidepressants was significantly lower in PMs.15 In clinical practice patients identified as PMs may require adjusted doses of antidepressants to optimize efficacy and avoid ADRs. A second study found the incidence of hyponatremia, an adverse reaction with TCAs and SSRIs, was more frequent in PMs than in EMs and IMs.25 These studies illustrated both the ineffectiveness of current treatment modalities and the increased incidences of ADRs based on metabolizer status phenotypes. This shows that CYP2D6 genotyping may be associated with safer administration of antidepressants.
A way to monitor safe administration of antidepressants is to measure serum concentrations of antidepressants. A study in 2004 analyzed 136 White hospitalized patients with depression. Data from the study indicated a significant influence of the CYP2D6 genotype on plasma concentrations of patients who received second-generation antidepressants, which included mirtazapine, paroxetine, sertraline, and venlafaxine.26 The study also found that PMs and patients who received pharmaceutical inhibitors of CYP2D6 had significantly higher mean dose-corrected plasma concentrations, which is the plasma concentration of the antidepressant or antidepressant plus active metabolite by daily dose, than the drug-specific median.26 PMs did not metabolize and excrete the drug as quickly from their system as IMs or EMs. A systematic review reported similar results that described a close correlation between the number of functional CYP2D6 gene copies and plasma levels of nortriptyline, paroxetine, and venlafaxine.19,27 The review also found evidence that PMs had greater than 50% decreased clearance for amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, doxepin, and trimipramine.19 This may result in both PMs and UMs being overrepresented in antidepressant ADR studies, with PMs particularly vulnerable to an increased occurrence of cardiovascular adverse reactions.27
Despite multiple studies supporting a correlation between CYP2D6 phenotypes and treatment outcome in depressed patients the data are still considered controversial. Some researchers accept that CYP2D6 status is helpful when prescribing TCAs but not SSRIs.27,28 SSRIs are frequently prescribed in the clinical setting and are considered first-line treatment for depression.10,29,30 Therefore, some researchers feel that CYP2D6 genotyping is not necessary because SSRIs are more commonly used than TCAs. From 37 studies a systematic review found marginal evidence of an association between CYP450 variants and SSRI metabolism, and tolerability in the treatment.12,31 De Leon concluded there are no data suggesting CYP2D6 PM phenotype has significance for treatment with SSRIs.11 However, applying the studies reviewed in Thakur et al. and De Leon to primary care practice is questionable because of narrow inclusion criteria.12,30 The clinical utility of CYP2D6 genotyping may appear uncertain, but these trials do not take into account polypharmacy and comorbid conditions, which are frequent in depressed patients.17
For example, Thakur's (2009) systematic review did not find any studies that performed a randomized control trial that compared CYP450 genotyping with SSRI treatment against the empirical standard.28 These trials have strict inclusion and exclusion criteria, which reduce the number of variables often found in patients treated in primary care settings. The Treatment for Adolescents with Depression Study, the Treatment for Adolescent Suicide Attempters study, and the STAR*D study each concluded that depression was often associated with comorbid conditions, taking medication other than antidepressants, chronic conditions, and current suicidal ideation.10,29,30 All of these variables complicate the treatment of depressed patients in clinical practice. So while the benefit of CYP2D6 genotyping may not be evident with all study criteria, it may be beneficial for the majority of "real-world" patients with depression.
Polypharmacy among depressed patients is common.10 Thakur's (2007) systematic review suggested that identification of PMs may prevent overdosing and the occurrence of specific adverse reactions with SSRIs, such as the previously mentioned cardiotoxic ADRs.31 A majority of SSRIs are CYP2D6 inhibitors and, when taken with other drugs that are CYP2D6 substrates, may result in toxicity. This indicates a difficulty in treating UMs and PMs because of the atypical response to drugs, including an increased rate of ADRs. It has been reported that CYP2D6 PMs have a three to six times greater increased risk of ADRs compared to IMs and EMs.23 Further evidence supporting a correlation between CYP2D6 genotype and antidepressant treatment outcome was reported in a study that found a trend toward longer hospital stay and higher treatment costs in inpatient UMs and PMs.23 In 2007, the estimated cost in the U.S. ambulatory care environment for adverse drug events was estimated to be $8 billion annually.32
Ordering the CYP450 genotyping tests falls within the advanced practice nurse scope of practice under the diagnosing, treating, and interpreting lab results responsibilities.33 Furthermore, the International Society of Nurses in Genetics (ISONG) recommends as part of the essential competencies for all nurses to develop plans of care that incorporate genetics and genomic assessment information.33 The APA recommends considering CYP450 pharmacokinetic actions when initially prescribing an antidepressant in the MDD treatment guidelines.5 As previously discussed, there is evidence showing a correlation between CYP2D6 genotyping and poor antidepressant treatment outcomes, including ADRs, longer hospital stay, and increased costs.15,17,23,27,31 Therefore, CYP450 genotyping should also be considered in patients with antidepressant treatment failure, polypharmacy, and ADRs. CYP450 genotyping tests have been FDA-approved since 2005, are easily administered with a buccal swab or blood draw, are readily available in many diagnostic labs, and are relatively inexpensive. CYP450 genotyping could be a cost-effective way to avoid poor antidepressant treatment outcomes and optimize care for the patient.
More information regarding the ISONG Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics can be accessed via: http://www.isong.org/pdfs2010/genetics_competencies.pdf.
Allele—the different sequences, that a gene can have in a population
Autoinducer—induces or enhances the activity of the enzyme for which it is a substrate
Autoinhibitor—inhibits or blocks the activity of the enzyme for which it is a substrate
CYP2D6—a CYP450 enzyme responsible for the metabolism of 30% of available drugs
CYP450 enzymes—a family of 50 enzymes responsible for the metabolism of 90% of available drugs
Gene—the fundamental unit of heredity
Genetics—the study of the roles and functions of single genes
Genome—the totality of an organism's DNA
Genomics—the interaction and function of all genes within the genome
Genotyping—act of determining genetic composition
Inducer—substance that increases enzyme activity
Inhibitor—substance that decreases enzyme activity
Personalized medicine—tailoring medical diagnostics and treatments to meet an individual patient's needs
Pharmacogenetics—study of genetic variation in drug response
Phenotype—the physical characteristics of an individual as produced by the interaction between functioning genes and environment
Substrate—a molecule that is acted upon by an enzyme
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