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Pharmacogenomics

Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders

While antidepressants are widely used to treat major depressive disorder and anxiety disorders, only half of the patients will respond to antidepressant treatment and only a third of patients will experience a remission of symptoms. Identification of genetic biomarkers that predict antidepressant treatment response could thus greatly improve current clinical practice by providing guidance on which drug to use for which patient. Most antidepressant drugs for the treatment of depression and anxiety disorders have effects on the serotonergic neurotransmitter system; thus, genetic polymorphisms in the genes involved in this pathway represent logical candidates for investigation. This article reviews recent findings on the pharmacogenetics of antidepressant drugs with a focus on serotonergic pathway polymorphisms and discusses future clinical applications.

Sarah G Helton1 & Falk W Lohoff*,1 Section on Clinical Genomics & Experimental Therapeutics (CGET), Laboratory of Clinical & Translational Studies (LCTS), National Institute on Alcohol Abuse & Alcoholism (NIAAA), NIH, Bethesda, MD 20892-1540, USA *Author for correspondence: Tel.: +1 301 827 1542 [email protected] nih.gov 1

Keywords:  antidepressants • anxiety disorders • biomarker • genetics • pharmacogenetics • serotonin • treatment response

Antidepressant drugs are often prescribed for the treatment of major depressive disorder (MDD) and anxiety disorders. However, in general only a third of patients treated with antidepressants show a positive therapeutic response [1] . Treatment response and side effects for the same drug, and even at the same dose, often differ between patients, with some patients responding favorably to one treatment but not another. There are several factors that influence drug response rates, such as clinical, environmental and social factors, as well as genetic factors. Isolating variables that could predict a more beneficial therapeutic response to a particular drug would allow the potential to use a medication with greater certainty and efficiency. Pharmacogenetics, a predictive tool used to identify and develop genetic biomarkers that can predict a patient’s therapeutic response and risk of side effects, will help the practitioners choose effective and safe treatment for patients suffering from p ­sychiatric ­d isorders.

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Serotonergic drugs for the treatment of MDD & anxiety disorders According to The Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5; American Psychiatric Association, 2013), MDD is characterized by exhibiting a depressed mood most of the day for nearly every day for a 2-week period and/or having a diminished interest or pleasure in almost all activities nearly every day for the same 2-week period. However, individual symptoms can vary across patients substantially. Risk factors for an MDD diagnosis include genetic, environmental and social factors, as well as having a history of a major depressive episode. In the United States, MDD has a lifetime prevalence of approximately 16% in the adult population [2] . Anxiety disorders comprise a heterogeneous group of illnesses that have in common heightened and excessive levels of ‘fear,’ which often leads to functional impairment and adverse physical symptoms. The most common disorders include generalized anxiety disorder

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Review  Helton & Lohoff (GAD), panic disorder (PD), social anxiety disorder (SAD) and now reorganized for DSM-5 as separate categories post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). As a group, anxiety disorders represent the most common psychiatric disorder, affecting about 18% of the general population 18 years and older in a given year [3] . Anxiety disorders are highly comorbid among themselves and with major depression  [3] . It is thus not surprising that antidepressant drugs are effective in the treatment of both disorders, which might actually reflect some shared biological mechanisms for depression and anxiety. Treatments for MDD and anxiety disorders usually span the spectrum from cognitive, behavioral and pharmacological interventions, often resulting in combinations. In general, treatment involves a sequential process that focuses first on remission of symptoms and long-term on maintaining suppression of depression and anxiety symptoms and functional recovery. Initially, monoamine oxidase inhibitors and tricyclic antidepressants were used to treat depression, while benzodiazepines were prescribed for the treatment of anxiety disorders. However, benzodiazepines did not treat comorbid depression and often caused unwanted side effects and dependence when used for long term. In accordance with the serotonin (5-HT) dysregulation hypothesis of depression, selective serotonin reuptake inhibitors (SSRIs) were discovered and found to offer similar treatment responses but markedly improved safety and tolerability profiles compared with previous antidepressants. In the 1960s, the anxiolytic properties of serotonergic antidepressant drugs were discovered [4] . With the introduction of SSRIs, the pharmacological treatment of depression and anxiety disorders changed dramatically, and they are now recommended as the first-line medications for MDD, GAD, PD, SAD, OCD and PTSD. While antidepressants such as SSRIs may be the most efficacious method of long-term treatment in MDD and anxiety disorders, individual drug treatment response varies among anxiety patients similar to what has been observed in depression [5] . Although depression and anxiety may have shared genetic susceptibility factors, it remains unclear, though likely, that they also share genetic alleles that predict treatment response to antidepressant drugs. Therefore, pharmacogenetic studies of antidepressant medications in anxiety disorders are needed to elucidate the underlying neurobiology of antidepressant treatment response and to improve clinical treatment by using genetically informed precision medicine. Genetics of antidepressant drug pharmacokinetics Pharmacogenetics refers to both studies concerned with pharmacokinetics and pharmacodynamics of a

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given drug. Pharmacokinetics involves the mechanisms controlling the absorption, distribution, metabolism and excretion of a drug. The most studied system includes the influence of genetic traits on the metabolism of antidepressant drugs, which is discussed in the following. CYP450

Toxicity and tolerability of antidepressant drugs, most notably tricyclic antidepressants, is to some extent influenced by differences in the activity in the CYP450 enzymes that metabolize antidepressants. CYP450 enzymes are drug-metabolizing hemoproteins residing in multiple tissues, with the highest prevalence in the liver. There are more than 63 CYP450 genes that encode over 50 enzymes. However, the primary P450 enzymes involved in antidepressant drug metabolism are CYP2D6, CYP2C19, CYP3A4 and CYP1A2 [6] . The CYP2D6 enzyme system has been characterized extensively, and experiments with debrisoquin and nortriptyline show that patients fall into different categories: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultra-rapid (UM) metabolizers [7] . Cloning and characterization of the CYP2D6 gene led to the identification of over 75 CYP2D6 alleles that control metabolizer status [8,9] . Studies with nortriptyline demonstrated that patients with zero to one functional copy of this gene reach therapeutic plasma levels with only starting doses, while high-normal doses would possibly cause toxic plasma levels; alternatively, patients with two to four copies need high-normal doses in order to obtain therapeutic plasma levels [10] . Consistent CYP2D6-allele/plasma level concentration correlations have been shown for SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs)  [11–13] . A recent meta-analysis of the CYP2D6 gene showed that 95% of included studies that assessed antidepressant response demonstrated a significant association with pharmacokinetic outcomes, with PM/IM participants having higher blood levels of antidepressant medications than their UM counterparts [14] . Along with the CYP2D6 gene, variations in the CYP2C19 gene are related to antidepressant metabolizer status. Various alleles of the CYP2C19 gene allow for grouping of poor, extensive and ultrarapid metabolizers, comparable to the CYP2D6 alleles [15–17] . Additionally, the side effect profile of amitriptyline seems to depend on a combination of alleles coding for CYP2D6 and CYP2C19  [18] . Clinicians can utilize a patient’s genetic metabolizer status to make an informed decision when prescribing a medication that could reduce potential side effects and obtain therapeutic levels more rapidly; however, the overall effects on improved efficacy are still unclear and need to be established.

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Serotonin pathway polymorphisms & the treatment of major depressive disorder & anxiety disorders 

Genetics of antidepressant drug pharmacodynamics Pharmacodynamics refers to the effects of a drug on the body. Pharmacodynamics consists of interactions of a drug with receptors, transporters and downstream targets. While the precise mechanisms of antidepressants remain fairly unknown, they are hypothesized to involve primarily the serotonergic neurotransmitter systems. Thus not surprising, most pharmacogenetic studies in MDD and anxiety disorders have focused on serotonergic pathway genes. Given that the majority of studies of pharmacodynamic candidate genes were initially conducted in patients with depression, we have included findings for depression and extended our review to anxiety disorders. Monoamine metabolic genes

There are three key metabolic enzymes in the monoamine pathways that are associated with depression: TPH, MAOA and COMT. TPH is involved in 5-HT biosynthesis. It has two isoforms, TPH1 and TPH2, the genes for both of which have been implicated in the pharmacogenetics of antidepressants. A functional SNP in the TPH1 gene, rs1800532, is related to a worse response to SSRIs in depressed Caucasians [19–22] , although this finding has not been replicated in other ethnic groups [23–26] . An earlier meta-analysis of this SNP and antidepressant treatment efficacy showed a correlation between the C/C genotype and remission rate in MDD [27] . However, a recent meta-analysis of this SNP and antidepressant response did not find an association in either all ethnicities examined or Caucasian or Asian populations specifically [28] . Interestingly, the rs1800053 SNP of this gene was associated with a specific MDD subtype that included melancholic and psychotic symptoms [22] . Additionally, genetic variation in TPH2 is related to antidepressant treatment response in patients with MDD. Zhang et al.  [29] showed an association between Arg441His, a nonsynonymous coding SNP and reduced response to SSRI treatment. They further demonstrated that this was a functional SNP, with 80% loss of function in TPH2. Another study showed a relationship between intronic SNP rs10897346 and treatment response to various antidepressants in MDD  [30] . This SNP is fully linked to the functional SNP Pro312Pro in the TPH2 gene, which is known to affect TPH2 expression levels. Other SNPs with unknown function effect have been shown to be associated with antidepressant treatment response [30–32] . On the other hand, several reports failed to replicate these results [33,34] . MAOA is an important degrading enzyme in the 5-HT, dopamine (DA) and norepinephrine (NE) path-

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ways. One interesting polymorphism in the MAOA gene, a variable number tandem repeat (VNTR) upstream of the gene, appears to influence the transcription efficiency of MAOA [35] . Additional pharmacogenetic studies have shown an association between this VNTR and anti­ depressants in MDD. One study demonstrated a positive correlation with the long form of the VNTR and poor antidepressant treatment response [36] . Controversially, some studies found an association with the VNTR, but only in females [37,38] , while others did not find significant associations [39–41] . This gender-specific effect is not completely surprising, considering that the gene is located on the X chromosome. Yoshida et al.  [42] reported that the MAOA VNTR might also play a role in SSRI-induced nausea, although this finding is yet to be replicated. Another variant in the MAOA gene that has been associated with antidepressant treatment outcome is rs6323, which is a functional coding SNP that is associated with decreased MAOA activity [31,43,44] . Recently, a haplotype containing this SNP was found to have an effect on antidepressant response [45] . Taken together, more recent and comprehensive studies of the MAOA VNTR are needed to assess the association between genetic variation in this gene and antidepressant treatment response. COMT is involved directly in the catabolic pathway of both DA and NE and indirectly in the 5-HT pathway. Several studies have investigated the role of COMT variants in antidepressant treatment response, in particular the functional variant rs4680 (Val158Met) [46] , which is known to change enzymatic levels of COMT three- or fourfold [47] . Perlis et al.  [48] investigated 19 candidate genes in response to duloxetine and found the most significant associations for variants rs165599, rs165774 and rs174696. However, other smaller studies have investigated the pharmacogenetic role of rs4680 in antidepressant treatment, with controversial results. Benedetti  et al.  [49] reported a positive association for treatment response to paroxetine and later found a significant association to fluvoxamine treatment response in MDD [50] . Other studies supported this association with other antidepressant medications [43,51–54] . However, Yoshida et al.  [55] did not find an association between rs4680 and final therapeutic response to milnacipram, but demonstrated an association between this variant and a faster therapeutic effect. Conversely, a recent study in a Korean population did not find an association with rs4680 and treatment response to either paroxetine or venlafaxine [56] . Taken cumulatively, these studies illustrate a potential role of the COMT gene and antidepressant treatment response in MDD. All three monoamine metabolic enzymes have also been studied in various anxiety disorders. One study investigated the 218A/C SNP in the TPH1 gene in a PD population, but did not find an association [57] , and

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Review  Helton & Lohoff no studies have looked at any variations in the TPH2 gene in anxiety disorders yet. MAOA and COMT variants were studied in OCD and PD with respect to antidepressant anxiolytic effects [58–63] ; however no clear genetic predictor could be identified. For GAD, only COMT was investigated, and the data suggest a possible dominant effect of the A-allele and reduction of anxiety symptoms when subjects were treated with venlafaxine XR [64] . Serotonin transporter gene

Although the exact mechanisms of antidepressants are unknown, the majority of research focuses on the serotonergic pathway, particularly the 5-HT transporter and the 5-HT receptors. One of the most widely studied genes in pharmacogenetic studies of antidepressant drugs is the serotonin transporter gene (SLC6A4). One polymorphism in the promoter region of the gene (5-HT transporter gene linked polymorphic region: 5-HTTLPR) includes an insertion or deletion of a repetitive sequence, producing a short allele (S) or a long (L) allele [65] . The long version of this 5-HTTLPR has been shown to affect transporter function, resulting in higher serotonin reuptake by the transporter [65] . Given high a-priory plausibility, numerous pharmacogenetic studies have investigated this polymorphism with regards to risk for illness and for antidepressant treatment response in MDD [66] . A vast majority of the studies found an effect of the L-allele and better treatment outcome [67–82] . This finding was supported by two meta-analyses indicating that there was a significant association between the L-allele and superior treatment response to SSRIs in depression [27,83] . Two smaller studies [84,85] and two more recent metaanalyses  [86,87] confirmed this finding, but only in Caucasians. However, other studies found no effect of the 5-HTTLPR on antidepressant treatment outcome [39,88–90] , particularly in Asian populations [91,92] . This finding was confirmed by a meta-analysis showing no association between this variant and antidepressant treatment response [93] . Conversely, many studies in Asian populations reported better treatment outcome associated with the S allele, although this may be due to the infrequency of the L allele in this population  [94–97] . In an attempt to explore clinical utility of this polymorphism, early studies have shown that a pretreatment test of 5-HTTLPR genotype may be associated with better clinical outcome [79,86] . However, randomized clinical trials with a pharmaco­ genetic component are needed before this genotype can be used widely in clinical practice. The 5-HTTLPR has also been associated with antidepressant-induced side effects. Studies have shown the S allele to be associated with worse toler-

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ability to antidepressant medications [81] . Other studies also found the S allele to be associated with SSRIinduced side effects [72,76,79,98,99] . A meta-analysis of 5-HTTLPR genotype on antidepressant side effects showed a significant association, with a trend in association with gastrointestinal side effects [27] . However, a more recent study did not find a significant association between genotype and adverse side effects to escitalopram or venlafaxine in either Caucasian or Han Chinese populations [85] . The presence of an A/G SNP (rs25531) within the 5-HTT promoter region forms a haplotype with the 5-HTTLPR that may be associated with antidepressant treatment outcome in MDD. Hu et al. [98] showed that this haplotype is functional, with La carriers showing the highest transcription of 5-HTT. Studies have shown that in the presence of the g SNP, the L allele of 5-HTTLPR is related to nonresponse to antidepressant treatment [100] . One study additionally found an association with the S allele and the Lg allele and adverse effects from antidepressants [98] . Future pharmaco­genetic studies with the 5-HTLLPR should also consider this SNP in a haplotypic analysis. Another VNTR polymorphism in intron 2 (STin2) of the 5-HTT gene has been implicated in antidepressant response [31,76,94,100,101] , although some studies did not find an association [24,91] . A meta-analysis of pharmacogenetic studies with this VNTR reported a significant association with antidepressant treatment outcome [27] . Furthermore, Kim et al. [96] showed that within an Asian population, the haplotype of STin2 12/12 and 5-HTTLPR S/S genotype had the highest response rate to antidepressants. One study found an association between the STin2 10/10 genotype and greater side effects [102] , yet other studies did not report this relationship [76,103,104] . There are only a few studies that have investigated the 5-HTTLPR in anxiety disorders. Stein et al.  [105] investigated this polymorphism in a sample of SAD and showed that the S-allele was associated with poorer treatment response. They additionally investigated the haplotype of rs25531 and 5-HTTLPR and discovered a trend in association; however, their results have yet to be replicated. In PD one study reported an association of L carriers and better treatment response, a relationship which appeared to be driven by females and did not seem to be a result of clinical or demographical differences in the population [106] . However, their findings were not replicated in a later study [57] . Studies in OCD have reported positive associations with 5-HTTLPR, with one study showing a positive association with L/S heterozygotes and better response to venlafaxine [107] , and another demonstrating a trend in association with the L allele and poorer antidepressant

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Serotonin pathway polymorphisms & the treatment of major depressive disorder & anxiety disorders 

treatment response [108] . Controversially, other studies have reported no association with this poly­morphism and antidepressant treatment in OCD [109–111] . Another recent study in GAD did find an association with the rs25531 and 5-HTTLPR haplotype and antidepressant treatment outcome, with La carriers showing better response to escitalopram [112] . Interestingly, Lohoff et al. [113] confirmed this finding in an independent sample of GAD patients treated long-term with venlafaxine XR. Taken together, studies of antidepressant treatment response based on 5-HTTLPR polymorphism status in depression and anxiety disorders point to a modest effect of the L-allele resulting in better treatment response. This effect seems to cross-diagnostic categories and might be more relevant to the drug class then psychiatric phenotype. Serotonin receptor genes

Serotonin receptor genes have been of great interest for pharmacogenetic investigation of antidepressant drugs given that several antidepressants desensitize these inhibitory autoreceptors. The 5HTR1A, 5HTR2A, 5HTR3A, 5HTR3B and 5HTR6 receptor genes have been the most studied. The 5HT-1A receptor is located both pre- and post-synaptically. A functional SNP in the upstream regulatory region of this gene, rs6295, is associated with increased expression of the gene. This variant was investigated in clinical samples, and a positive association with rs6295 and better antidepressant treatment outcome was observed [24,114–118] . However, a recent study did not find an effect of this SNP on antidepressant treatment response in depressed patients  [119] . Interestingly, a meta-analysis of rs6295 and antidepressant treatment response in MDD failed to find a significant association in all studies, but it did note a significant outcome in studies with Asian populations [27] . Another SNP, which changes an amino acid at position 272 from glycine to aspartate, was found in one study to be associated with better antidepressant treatment response [120] , but this finding was not replicated in later studies [121,122] . Kato et al. [115] also found significant associations between SNPs rs10042486 and rs1364043 and better antidepressant response. The 5HTR2A gene is another highly studied candidate gene for the antidepressant response phenotype. Three coding SNPs in particular have been associated with antidepressant treatment response in MDD in several studies: rs6311 (102T/C), rs6313 (1438A/G) and rs6314 [76,88,123–125] . The rs6311 and rs6313 variants are in linkage disequilibrium (LD) and can be considered together [126] ; these variants were reported to be associated with drug-induced side effects, including nausea, gastrointestinal side effects and sexual dys-

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function  [124,127–129] . A meta-analysis of 1438A/G did not find a significant association with antidepressant treatment outcome, yet it did find a significant association with adverse events [27] . In addition, an important pharmacogenetic study of the large STAR*D sample demonstrated a robust association between SNP rs7997012 (located intronically) and citalopram treatment response [130] . Other studies later successfully replicated this association [34,131,132] . However, a recent study did not find an association between rs7997012 and antidepressant treatment response in depressed patients [119] . Two genes for subunits of the 5HT3 receptor have been implicated in treatment outcome and side effects of antidepressant medications in MDD: 5HTR3A and 5HTR3B. 5HTR3A SNP 178C/T was associated with treatment outcome in an Asian sample, although there were no findings of an association with side effects  [124] . An AAG deletion in the 5HTR3B gene (100–102 AAG del) was reported to be associated with better treatment outcome [124] . This deletion and another non-synonymous coding SNP, 129Tyr/Ser, was additionally demonstrated to be associated with antidepressant-induced nausea [133,134] . One variant in the 5HTR6 gene, rs1805054, is potentially involved in antidepressant treatment outcome. This variant is a silent polymorphism in exon 1 (267T/C) and has been related to greater efficacy of antidepressant medications  [135] ; however, other studies failed to find this association [76,136] . Furthermore, a recent metaanalysis including rs1805054 did not find an association between this SNP and response to antidepressant treatment  [137] . Additional studies of this gene are needed to understand its role in the pharmacogenetics of antidepressant treatment response. The serotonin receptor family has been a logical target for pharmacogenetic investigation of antidepressants in anxiety disorders as well. OCD studies have examined variants in the 5HTR2A gene and anti­depressant treatment outcome. A few studies found a positive association with rs6313 (1438A/G) [111] , although another study did not find an association [138] . One study investigated another variant, rs6311 (102T/C), in OCD, but did not find an association [138] . More recently, based on findings of the HTR2A intronic variant rs7997012 with treatment response to citalopram in MDD [130] , Lohoff et al. [139] investigated this variant in a large sample of patients with GAD that were treated 6 months open-label with venlafaxine XR. They found that GAD patients with the G-allele had significantly better treatment outcomes compared with the A/A genotype group. Similar findings in depression were observed by Horstmann et al. [131] and Lucae et al. [132] , suggesting that this variant might pre-

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Review  Helton & Lohoff dict response to drug class independent of psychiatric diagnosis. A recent combinatory analysis of the HTR2A rs7997012 variant and the 5-HTTLPR haplotype in GAD patients revealed a large additive effect, with ‘G + La’ carriers experiencing the most benefit from antidepressant treatment, whereas ‘A/A + S’ did not [113] . These data support the notion that some patients do very well on SNRI therapy while others exhibit almost no benefit, perhaps modulated by genetic difference in the serotonin-signaling pathway. Consequently, if confirmed, these SNRI nonresponder patients might represent a group for which other interventions should be considered first, such as cognitive behavioral therapy or other pharmacological interventions. Discussion & future perspective Serotonergic drugs have become the first-line treatment options for both depression and a variety of anxiety disorders, yet the exact mechanism of action remains elusive, despite decades of research. The rapid development of personalized medicine in psychiatry might offer new insights into the pathophysiology of these disorders, and more importantly has the potential to provide immediate benefits for patients. Multiple studies in MDD, and more recently in anxiety disorders, have shown that genetic considerations in the prescription of antidepressant medications can be crucial to determining individual treatment outcome. For the practitioner, there are currently two main pharmacogenetic testing panels available, which can be ordered through a few selected commercial and academic laboratories. The Roche ‘AmpliChip’ test was the first US FDA-approved pharmacogenetics test available, and it provides genotypes for the two cytochrome P450 genes, CYP2D6 and CYP2C19. By genotyping patients for variation in these genes, the clinician should be able to predict a patient’s metabolizer status, which could influence medication choice and dosing. In addition, the FDA has approved several drug labels to contain pharmacogenetic biomarker information. Currently, approximately 17% of these pharmacogenetic labels are for psychiatric drugs, and most of them present information about the CYP450 enzymes [140] . However, most of these labels only offer pharmacogenetic information for the specific drug and neither provide any clinical recommendations nor require the use of this information before treatment prescription. Thus, although this panel has beneficial clinical implications and utility, clinicians should proceed with caution when using the panel to prescribe psychiatric drugs. Another psychiatric pharmacogenetic test has recently become available. The AssureX ‘GeneSight’ test is a pharmacogenomics test that combines allelic

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variation in four cytochrome P450 genes (CYP2D6, CYP2C19, CYP2C9, CYP1A2) and genes for the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A). The combinatorial genotyping method categorizes each patient as a green (Use as directed), yellow (Use with caution) or red bin (Use with increased caution and with more frequent monitoring) phenotype for relevant medication. Although no large-scale clinical studies are available to investigate the usefulness of this test, some small-company-sponsored studies suggest clinical utility both for patient outcome and effects on prescribing costs [141–143] . It is clear that future studies are needed to elucidate the exact clinical practicalities of this panel. Although current research on the pharmaco­genetics of antidepressant medications has been promising, there are several limitations that need to be considered before this field can advance. The primary concern with current pharmacogenetic studies is the lack of standardization, making it difficult to distinguish between positive and negative findings in the same candidate gene. Current studies often have discrepant inclusion criteria, treatment length, use of medications, outcome measures, recording of side effects, ethnicity of population and genetic coverage. Furthermore, many of these studies have small sample sizes with limited power, leading to possibilities of either false negative or false positive results. Thus, much of future research will be devoted to replication of these results in large prospective trials with standardized designs, like the GENDEP project [144] . Additionally, there needs to be better diagnostic criteria for psychopathologies. Currently, the DSM relies on an amalgamation of scientific studies to create a set of guidelines for classifying disorders. Thus, an alternative method to progress the reliability of psychopharmalogical interventions is to shift from evidence-based clinical trials to the more individualfocused functional psychopharamacology. According to Loonen and Stahl [145] , instead of relying on placebo-controlled studies, clinicians should focus on treating specific symptoms of a patient’s disorder with specific psychotropic drugs. When paired with pharmacogenetics, functional psychopharmacology may revolutionize the treatment of individual patients, ideally providing more accurate therapies with reduced costs and side effects. Another limitation of all pharmacogenetic studies to date is that the majority of studies only investigated very few, a priori selected genetic variants and only a few genome-wide attempts have been made. Three separate, large-scale GWAS have been conducted on antidepressant pharmacogenetics in MDD patients: The Sequenced Treatment Alternatives to Relieve Depres-

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Serotonin pathway polymorphisms & the treatment of major depressive disorder & anxiety disorders 

sion (STAR*D) [130,146] , the Munich Antidepressant Response Signature (MARS) [147] and the Genomebased Therapeutic Drugs for Depression (GENDEP) [148] . Generally speaking, these studies measured response and remission phenotypes following antidepressant treatment. However, these studies had neither standardized study designs nor standardized outcome measures, and as a result the findings were inconsistent, and none reached genome-wide significance. For anxiety disorder, no genome-wide analysis exists yet. With the rapid advancement of genomics, it will be soon possible to obtain whole genome sequence data for each patient at low costs, thus opening possibilities of a more comprehensive genetic analytic approach by including rare and structural variants, such as de novo mutations and copy number variants. It is apparent that the field of pharmacogentics needs more standardized studies. An ideal study is possible to design, and prospective studies should attempt to include the following elements. First, pharmaco­genetic studies should use a standardized set of outcome measures to assess the efficacy of treatment response. Much of the controversy in assessing positive or negative findings derives from discrepant outcome measures between studies. Second, the trial design should

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incorporate a standardized assessment schedule for the assessment of patients. This standardization will not only help clinical management of patients, but also provide a more uniform method for reporting adverse side effects to medications. A further problem with current studies is lack of power. Future studies should use adequate sample sizes to ensure that the results will not be underpowered. With larger sample sizes, it will be possible to control for population stratification, an additional problem with current pharmacogenetic studies. Lastly, there should be a standard for minimum gene coverage, and gene-X-environment inter­actions should be assessed to strengthen potential genetic findings. In the future, more studies should be conducted on antidepressant use in not only MDD and anxiety disorders, but other disorders as well. Ultimately, large prospective clinical trials will be the goal, but they must not exhibit the same lack of standardization currently seen in the field of pharmacogenetics. As discussed in this review, most of the antidepressant pharmacogenetic studies have focused on MDD, despite the fact that antidepressants are widely used in other disorders as well. The use of antidepressants across disorders, specifically MDD and anxiety disorders, suggests at least partially shared underlying neu-

Executive summary Serotonergic drugs for the treatment of major depressive disorder & anxiety disorders • Major depressive disorder (MDD) and anxiety disorders are highly co-morbid. • Antidepressant drugs are used to treat both disorders, suggesting shared biological mechanisms. • Treatment response to specific drugs may depend on genetic factors.

Genetics of antidepressant drug pharmacokinetics • CYP450 –– Pharmacokinetic gene studies have centered around CYP450 enzymes, which metabolize antidepressants. –– CYP2D6 alleles characterize individuals based on metabolizer status, which can be clinically used to determine toxicity and tolerability of drugs.

Genetics of antidepressant drug pharmacodynamics • Monoamine metabolic genes –– Pharmacodynamic studies of the monoamine pathways have focused on TPH, MAOA and COMT in MDD and anxiety disorders. –– Results have been inconsistent, and additional replication studies are needed of the genetic effects of these genes in determining antidepressant treatment response in MDD and anxiety disorders. • Serotonin transporter genes –– A polymorphism in the serotonin transporter (5-HTTLPR) generally is associated with treatment response in MDD and anxiety disorders. –– Controversial findings have been reported between Caucasian and Asian populations. • Serotonin receptor genes –– Pharmacodynamic studies have focused on variations in serotonin receptor genes, which are inhibitory autoreceptors that are desensitized by antidepressants. –– Findings in both MDD and anxiety disorders are inconsistent, and additional replication studies of these genes are needed.

Discussion & future perspective • The Roche ‘AmpliChip’ test and ‘GeneSight’ test are available for pharmacogenomics testing; however, their efficacy and clinical utility will need to be further examined through larger replication studies. • Future pharmacogenetic studies on the efficacy of antidepressants in MDD and anxiety disorders should be larger and more standardized.

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Review  Helton & Lohoff robiologies. Although this hypothesized shared etiological pathway between MDD and anxiety disorders is not fully understood, growing evidence indicates that genetic factors influence response to antidepressant treatment in both disorders [113] . While it is clear that the pharmacogenetics of antidepressants in various psychiatric disorders deserves greater attention in both future research and clinical practice, it is important to remember that genetic information is only one aspect of the complex history of psychiatric patients. Combination of genetic information and clinical data, such as family history, age, gender and presenting symptomatology will ultimately be necessary to

develop new treatment algorithms and to advance our understanding of the underlying pathology.

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Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders.

While antidepressants are widely used to treat major depressive disorder and anxiety disorders, only half of the patients will respond to antidepressa...
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