sign in sign up
<<
Home , Agomelatine

Overview Taiwanese Journal of Psychiatry (Taipei) Vol. 30 No. 2 2016 • 79 •

Pharmacogenetics of : Is There a Magic Bullet for Treating Depression?

Min-Soo Lee, M.D., Ph.D.1,2*

Depression is one of the most common mental disorders nowadays. Many researchers in psychiatry have investigated the cause of depression. Unfortunately, the problem of individual differences in response to treatment still lingers in the clinical fi eld. For setting up the stage for the main topics in the later part of this overview, I start introducing the topics of monoamine hypothesis, the rôle of in causing clinical depression, as well as advents of antidepres- sants (briefl y describing antidepressants, the arrival of selective serotonin- inhibitor, and novel antidepressants). Then, I introduce the concept of pharmacogenetics, the candidate genes. Afterwards, I consider that genetic factors are recognized to have an independent effect on drug responses. To demonstrate, I highlight fi ve gene studies ‒ serotonin transporter (5-HTT/SLC6A4), serotonin receptor 2A (HTR2A), G-protein β3 subunit (GNB3), brain-derived neurotrophic factor (BDNF), and hydroxylase (TPH). But some of candidate gene studies have been conducted, but results were not consistent. Since 2009, Genome- wide Association Studies (GWAS) has provided further grounds for understanding the pharmacogenetic mechanisms of antidepressants and depression treatment. Further research and technological development are still needed.

Key words: antidepressants, monoamines, pharmacogenetics, Genome-wide Association Studies (GWAS) (Taiwanese Journal of Psychiatry [Taipei] 2016; 30: 79-90)

Organization predicts that depression is going to Introduction take the fi rst place in the burden of mental disor- ders. The signifi cant danger of depression is that it Depression is one of the most common men- lowers the quality of life considerably. Depression tal disorders nowadays. In the US, 9% of men and can affect one’s life in various aspects. It impairs 18% of women experience depression once in the ability to eat, sleep, work, and socialize [2-5]. their lifetime, and more than 10% of the total pop- A depressive patient loses interest and motivation ulation experiences another episode of depression in life, which can damage one’s self-esteem. Since more than twice [1]. The World Health worsened depression can develop physical prob-

1 Department of Psychiatry, College of Medicine, and 2 Pharmacogenomic Research Center for Psychotropic Drugs, Korea Univer- sity, Seoul, Republic of Korea Received: March 29, 2016; revised: April 28, 2016; accepted: May 1, 2016 *Corresponding author. 126-1 Anam-dong 5 ga Seongbuku-gu, Seoul 136-705, Republic of Korea E-mail: Min-Soo Lee • 80 • Pharmacogenetics of Antidepressants

lems or lead to suicide, researchers and clinicians the neurobiological mechanism of developing in psychiatry have put much effort in investigating depression. the cause and developing the treatment of Amines are chemical compounds that have depression. similar amino group to ammonia, and there are many different types of amines. Among them, a Monoamine Hypothesis chemical compound, being also a neurotransmit- ter in the brain, which has only one amino group Before 1950, the psychiatrists did not explain is called monoamine. Because there are many dif- the cause of depression clearly except genetic fac- ferent types of monoamines, many researchers tor. The person who tends to be depressive among tried to fi nd out which monoamine plays a critical family members is considered to be highly possi- rôle to develop depression by experimenting on ble to have depression. But in the early 1950s, animals [13-15]. With all those efforts, it turned many psychiatrists asserted that depression is not out that serotonin and noradrenalin (norepineph- just because of congenital or innate tendency and rine) are the substances. Through a narrow gap of environmental stress. Instead, the psychiatrists synapse which is closely connected by neurons, considered depression as neurophysiological ab- nerve cells in the brain, the substances transmit normality of the brain. The reason why this theory information from brain by being sent from one is brought up is that many patients who have hy- place and being accepted to other place. If depres- pertension and tuberculosis showed prominent sion is developed because the amount of substanc- symptoms. Several cases from many medical in- es released is scarce or the released substances stitutions have been reported that the patients who become scarce due to absorption by the original have hypertension and take anti-hypertensive neurons, in a simple logic, depression would be drugs over long periods of time generate severe treated if these substances could be fully depression [6, 7], or that the patients who have supplied. tuberculosis treated with show improved depressive symptoms [8]. From those results, the Serotonin and Depression argument that the main components in anti-hyper- tensive drugs or tuberculosis medicines might af- After serotonin (5-hydroxy-trytophan) is re- fect brain and cause or improve depressive symp- leased from neurons in the brain, it is absorbed by toms is emboldened. At this time, uprising the receptor of neighboring neuronal cells though causative agent of depression is monoamine be- a gap of synapse. By this process, the information cause several research showed that the fact which is transmitted from one neuronal cell to another. anti-hypertensive drugs decrease monoamine in But all released are not absorbed by the brain [9, 10] and tuberculosis medicines in- neighboring neuronal cells. Large amount of sero- hibit breakdown of monoamine [11, 12] is true. tonins are re-absorbed by receptors of the original Therefore, the theory that depression occurs due presynaptic neuronal cells. At this moment, if the to decreased monoamine transmission in the brain amount of serotonins are abnormally re-absorbed was raised. Since then, the psychiatry group called too much, serotonin in the postsynaptic neurons is this theory as “monoamine hypothesis” and the lacking and this seriously infl uences on various theory has been well-established to explain about functions of body and mind. Serotonin is pro- Lee MS • 81 •

duced when tryptophan, one of the essential ami- ciple of is to inhibit re- no acids which is not synthesized in the body, is absorption of serotonin by blocking the receptor metabolized in the brain [16]. that helps re-absorption. Most of the released se- In the body, about 10 mg of serotonin exists, rotonins move to the opposite side of receptors of and only 1% of them exists in the brain as a neu- postsynaptic neuronal cell, and the information is rotransmitter [17, 18]. The rest is staying in stom- more easily transmitted without stagnation. ach and intestines to help digestion. Serotonin Among tricyclic antidepressants, , exercises a far-reaching infl uence on our body and , etc., are developed and widely used. mind because it has various functions that modu- Some drawbacks existed for those antide- late body in so many different ways. Because it pressants. Although they are daily administered has functions to regulate autonomic nervous sys- for a patient, it takes about two to three weeks to tem, when the amount of serotonin in the brain is show their effects. Also, they can cause many dif- increased or decreased, it affects not only regula- ferent side effects by interrupting re-absorption of tion of body temperature, cardiovascular activity, besides serotonin. If a patient muscular contraction, vasoconstriction, and ac- takes massive dose of tricyclic antidepressants it tivities of endocrine glands, but also appetite, causes acute intoxication and increases mortality sleep, , mood, and behavior. rate by affecting cardiovascular side effects. For this reason, serotonin has much to do Because of this reason, this antidepressant could with depression. Also, it regulates and be lethal to the depressive patients who take mas- [19-21], which are also important sive dose to attempt suicide. Tetracyclic antide- neurotransmitters that control human’s behavior pressant (such as ) was once thought and emotion. Because serotonin controls afore- to have least potential in causing cardiotoxic side mentioned various parts and works on raphé nu- effects than TCAs. Even up to today, TCA short- clei, limbic system, and prefrontal area which is comings of tricyclic antidepressants are not com- the most important region, it is considered to be a pletely resolved. conductor of the orchestra toward the complex components of brain. Selective serotonin reuptake inhibitors: the arrival of fl uoxetine Advent of Antidepressant A new type of antidepressant that specifi cally Therapy inhibits serotonin reuptake was developed in the late 1980s to address the problems of then existing Tricyclic antidepressants (TCAs) tricyclic antidepressants. This novel class of anti- In the late 1950s, “tricyclic antidepressants” was named selective serotonin reup- were synthesized and became commoditized as take inhibitors (SSRIs). The most widely known the fi rst antidepressant. “Tricyclic” means that SSRI is Prozac®, which was launched by Eli Lilly three cyclic structures (annular or ring-shaped) in the United States in 1987. Prozac is by far the are in the molecular structure. Actually, the fact most popular antidepressant with over fi fty mil- that these antidepressants improve the effects of lion users worldwide (data from 2005, according serotonin in the brain is verifi ed, and they are used to Eli Lilly). The active ingredient in Prozac® is as treatment for depression. The functional prin- fl uoxetine hydrochloride (HCl) which has a dif- • 82 • Pharmacogenetics of Antidepressants

ferent chemical structure from the previously used patient. For example, the standard dose of a par- tricyclic and tetracyclic antidepressants, and it has ticular drug may not be suffi cient for one patient been found to strongly inhibit the reuptake of se- while inducing severe side effects in another pa- rotonin [22] and only partially that of noradrena- tient. Whichever the case, a more suitable treat- line (or norepinephrine). This property of fl uox- ment regimen is required to enhance the personal etine is thought to allow it not only to alleviate therapeutic effi cacy of the treatment. depression symptoms, but also to control the symptoms of other diseases induced by serotonin The Concept of or noradrenaline, such as obsessive-compulsive Pharmacogenetics disorder [23] or panic disorder [24]. Furthermore, fl uoxetine rarely acts on neurotransmitters other Although factors that infl uence responses to than serotonin, resulting in few side effects. But drugs are diverse and thought to interact in a com- Prozac® still has been associated with some minor plex manner, genetic factors are recognized to have and severe side effects. This has sparked fi erce de- an independent effect on drug responses. In fact, bate on its use due to unexpected side effects, such some studies reported that responses to antidepres- as inducing manic switch or suicidal impulses. sants show familial concordance in patients with depression [28-30]. The reason for investigating Development of novel Antidepressants genetic factors is due to the knowledge that there In 1993, six years after the advent of Prozac, should be reliable biological factors modulating the serotonin and norepinephrine reuptake inhibitors damage and pain infl icted on patients by the above- (SNRIs) were developed. SNRIs simultaneously mentioned insuffi cient treatment outcomes, and inhibit the reuptake of serotonin and noradrena- that genetic biomarkers can fulfi ll that rôle. line, which is a also thought to Many researchers and clinicians working on be associated with depression. The fi rst SNRI was depression have been conducting various studies manufactured by Wyeth in the United States, with using candidate genes since the 1990s, with the the trade name Effexor. In addition to SNRIs, oth- ultimate goal of allowing patients to select the er novel antidepressants, including norepineph- most personally effective drug. In the early days rine-dopamine reuptake inhibitors (NDRIs) and of pharmacogenetics research, most of these can- noradrenergic and specifi c antide- didate genes are selected among the key genes as- pressants (NaSSAs), were also developed. sociated with proteins having been involved in the Meanwhile antidepressants containing thyroid mechanisms of action of the antidepressants [31]. hormone, , or either have been recently developed or are underway [25-27]. Candidate Gene Studies in These drugs have been developed to improve the Treating Depression effi cacy and address the adverse effects of exist- ing drugs. Serotonin transporter (5-HTT/SLC6A4) Unfortunately, however, the problem of indi- and serotonin receptor 2A (HTR2A) vidual differences in response to treatment still The genes that have been most vigorously lingers in the clinical fi eld. Indeed, the dosage re- studied as candidate genes, and thus have the most quired for effective treatment is different for each accumulated evidence, are SLC6A4 and HTR2A, Lee MS • 83 •

which are associated with serotonergic transmis- those evoked by hormones and neurotransmitters. sion. SLC6A4 encodes a serotonin transporter (5- Researchers have long concentrated research ef- HTT or SERT) responsible for the reuptake of se- forts on G-proteins, because they are widely rotonin into the presynaptic neuron. Because of known to be associated with multiple pathways this function, it has been the target of many anti- responsible for controlling cellular responses. depressants, which have in turn sparked research Moreover, some studies have shown an associa- interest in polymorphisms associated with this tion between the levels of G-protein α subunit ex- gene. While some studies found signifi cant re- pression and depression. Immediately after these sults, others did not. The most investigated poly- studies, several researchers began to shed light on morphism thus far is a 44-bp repeat insertion/de- the association between genetic polymorphisms letion polymorphism in the promoter region of the of the G-protein β3 subunit and depression or the gene (5-HTTLPR); a meta-analysis study suggest- response to antidepressant treatment, and have ed that the long (L) allele of 5-HTTLPR is signifi - found signifi cant results. cantly associated with a better treatment response Thus far, the most investigated polymor- to SSRI compared to the short (S) allele, in a phism in the GNB3 gene is rs5443 (C825T), and Caucasian group [32, 33]. This is thought to result the main fi nding, including that of a meta-analysis from the S allele reducing the transcriptional ac- reported in 2014 [43], is that rs5443 T allele carri- tivity of the 5-HTT gene promoter, which in turn ers show better treatment responses [44-46]. But decreases 5-HTT expression, leading to reduced some studies actually reported signifi cantly better serotonin (5-HT) reuptake [34]. responses in patients with fewer T alleles [47-49], Many studies suggest that the 5-HT receptor while other studies on Asians, as with other simi- 2A gene (HTR2A) is associated with treatment re- lar genetic studies, reported no signifi cant associa- sponse to SSRIs. The Sequenced Treatment tion between the T allele and the treatment re- Alternatives to Relieve Depression (STAR*D) sponse [50-52]. trial is the most notable study; this large-scale study examined 1,953 patients with major depres- Brain-derived neurotrophic factor (BDNF) sive disorder (MDD) and showed the potential of Recently, evidence has been accumulating HTR2A as a signifi cant indicator of treatment out- for the rôle of brain-derived neurotrophic factor come [35]. There have been other studies suggest- (BDNF) in the pathophysiology of depression. As ing an association of this gene with the response several studies revealed that BDNF plays a pivot- to SSRIs [36, 37]. But some further studies report- al rôle in neurogenesis and neuroplasticity, as well ed that the results were more heterogeneous than as in the serotonergic system, which is the main those for SLC6A4, and others failed to fi nd a sig- target of antidepressants, BDNF has become the nifi cant association between HTR2A and other an- focus in studies on depression recovery. Indeed, tidepressants (other than SSRI), or showed mixed meta-analysis studies revealed that plasma BDNF results [38-42]. levels are signifi cantly lower in MDD patients in remission compared to those in acute depression G-protein β3 subunit (GNB3) [53]. Another meta-analysis study showed that se- The GNB3 gene is involved in the generation rum BDNF level after treatment for MDD is sig- of second messengers signaling cascades, such as nifi cantly higher in responders than that in non- • 84 • Pharmacogenetics of Antidepressants

responders [54]. Of about 3,000 reported single tween this genetic polymorphism and bipolar dis- nucleotide polymorphisms (SNPs), rs6265 order [63], which triggered many researchers to (G196A or V66M) is an SNP found in the BDNF begin studying the association between A218C gene that has been studied the most as it is known and major depression. Some studies have con- to have a functional rôle. A recent meta-analysis fi rmed the association between TPH1 and antide- reported that MDD patients with the Met/Met or pressant treatment response, and were found that Met/Val genotype for rs6265 show better respons- A allele carriers show poorer treatment responses es to antidepressants, especially SSRIs, and that [64-66]. Moreover, a haplotype analysis has re- this effect is more prominent among Asians [55]. vealed an association between major depression Similarly, studies conducted in Korea showed that and TPH1 [67]. patients with a Met allele showed better responses On the other hand, many other studies, espe- to and than those with a cially those on Asians, have failed to produce sig- Val allele [56, 57]. nifi cant results [50, 68-71]. The two TPH isoforms A study on fl uoxetine, another type of SSRI, are expressed at similar levels in areas of the brain could not confi rm that the different genotypes of such as the frontal cortex, the hippocampus, and the BDNF polymorphism have any differences in the amygdala. In particular, TPH2 has attracted treatment responses, despite the fact that the sub- much research interest, as it is predominantly ex- jects were Asian (namely Chinese patients and pressed in the central nervous system (CNS) [72, healthy controls). [58] In addition, a study on mir- 73]. Since Zill et al. [73] fi rst reported an associa- tazapine, an NaSSA, did not fi nd any association tion between the TPH2 gene and major depres- between the afore-mentioned polymorphism and sion, several studies have been conducted to repli- the treatment response [59]. Furthermore, most cate the results, with some having succeeded in studies have not shown an association between producing signifi cant results [74, 75], while others V66M and the risk of developing MDD [57, 60]. have failed [76, 77]. Such contrasting outcomes One meta-analysis in particular reported that have thwarted researchers’ efforts to draw a con- V66M has not been associated with an increased sistent conclusion. risk of developing MDD; however, they have not shown an association when the analysis was re- Genome-wide Association stricted to male subjects [61]. Studies (GWAS)

Tryptophan hydroxylase (TPH) Unfortunately, researches have yet to identi- Two isoforms of tryptophan hydroxylase fy a clear link between a specifi c gene and suscep- (TPH) are known to be important, and TPH1 is the tibility to depression. Rather than the possibility one that has been most studied in the psychiatric of only a single gene being responsible for the fi eld. TPH is the rate-limiting enzyme in the bio- development or treatment of depression, it is more synthesis of 5-HT [62]. The TPH1 gene has been likely that many genes acting together may cause the focus of many studies because one functional a patient to become susceptible to depression. SNP in this gene ‒ rs1800532 (A218C) - is located Several researchers had been struggling with in- in the potential GATA transcription factor binding consistent results and failed to replicate results on site. One study has been found an association be- several candidate genes. But the advancement of Lee MS • 85 •

DNA analysis technology introduced around upon which those studies are conducted. Another 2007, the concept of genome-wide association indication of the need to research rare variants is studies (GWAS), causing a paradigm shift in can- that common variants are usually shared by differ- didate gene research. Whereas previous studies ent ethnicities and cultures while rare variants are selected candidate genes based on a priori hy- not. Furthermore, GWA studies have limitations potheses, the development of hypothesis-free in analyzing diseases caused by different types of GWAS has enabled the launch of several studies genetic mutations, such as copy number variant focusing on depression and antidepressants (CNV). around 2009. Those studies have in turn provided further grounds for understanding the pharmaco- Conclusion genetic mechanisms of antidepressants and de- pression treatment. GWAS has opened doors to In this overview, I have pointed out the de- genotyping and analysis of millions of polymor- velopment of antidepressants and pharmacogenet- phisms throughout the whole genome. ics. Table 1 summarizes the current research fi nd- Theoretically speaking, GWAS is an appropriate ings of the candidate gene studies in treating strategy for analyzing the association between depression with support of being associated with diseases and genes because individuals share antidepressant effi cacy. What’s more, extended 99.9% of their genomes. Furthermore, GWAS is from genetics, fi elds such as epigenetics, pro- suffi cient to address the problem of small sample teomics, and metabolomics are being suggested sizes in candidate gene studies, especially the and researched in the biological ground. In addi- problem of a signifi cant reduction of sample size tion, the development of personal genomics which during follow-ups, and the resulting biases. uses the next generation sequencing, and the tech- There have been three major large-scale nological development including neuroimaging GWA studies: the Genome-based Therapeutic are widening the newest knowledges of biological Drugs for Depression (GENDEP; Uher, R., et al. psychiatry. [78]), the Sequenced Treatment Alternatives to Many other ongoing efforts exist to achieve Relieve Depression (STAR*D; Garriock, H.A., et better responses of antidepressants in depressive al. [79]), and the Munich Antidepressant Response patients. Sadly, despite the efforts of numerous re- Signature (MARS; Ising, M., et al. [80]). Although searchers and clinicians including myself, the de- GWA studies initially were considerably expen- velopment of the “magic bullet,” which diagnoses sive, scholars’ efforts to identify haplotypes and treats depression dramatically, seems so dis- through the HapMap Project markedly have low- tant. Does “magic bullet” ever exist? Although it ered the required costs. But the limitations of might seem like an illusion, such cravings and GWAS began to surface as more studies were con- faith have contributed largely to the current ad- ducted. GWA studies generally identify genetic vanced psychiatry, and I expect superior treat- mutations shared by at least 5% of the population. ments to be developed which enlighten the future But common variants alone cannot suffi ciently of treating depressive patients. explain the heritability of diseases because of “missing heritability” resulting from the so-called “common disease-common variant hypothesis,” • 86 • Pharmacogenetics of Antidepressants

Table 1. Summary of the major positive fi ndings of the candidate gene studies in treating depression with support of being associated with antidepressant effi cacy Gene Variants Main findings References SLC6A4 5-HTTLPR In a Caucasian group, the L allele is Serretti et al. 2007 [32], significantly associated with a better Porcelli et al. 2012 [33] treatment response to SSRI compared to the S allele. HTR2A rs7997012 A better response to SSRI of the A allele McMahaon et al. 2006 was reported in the STAR*D studies. [35], Peters et al. 2009 [36] GNB3 rs5443(C825T) The T allele carriers show better treatment Hu et al. 2015 [43] responses to antidepressant . Zill et al. 2000 [44] Lee et al. 2004 [45] Keers et al. 2007 [46] BDNF rs6265 (G196A; V66M) The patients with the Met allele show Yan et al. 2014 [55] better responses to SSRIs, especially more Chang et al. 2012 [56] prominent in Asians. Choi et al. 2006 [57] TPH1 rs1800532 (A218C) The A allele carriers show poorer treatment Serretti et al. 2001 [64] responses to antidepressant medication. Ham et al. 2007 [65] Arias et al. 2012 [66]

the National Comorbidity Survey Replication Acknowledgement (NCS-R). JAMA 2003; 289: 3095-105. 5. Insel TR, Charney DS: Research on major depres- The author declares no potential confl icts of sion: strategies and priorities. JAMA 2003; 289: 3167-8. interest in writing this invited overview. 6. Huapaya L, Ananth J: [Is there a relation between de- pression and hypertension?]. Rev Neuropsiquiatr References 1980; 43: 97-105. 7. Freis ED: Mental depression in hypertensive patients Hasin DS, Goodwin RD, Stinson FS, Grant BF: 1. treated for long periods with large doses of reserpine. Epidemiology of major depressive disorder: results N Engl J Med 1954; 251: 1006-8. from the National Epidemiologic Survey on 8. Oquendo MA, Ellis SP, Greenwald S, Malone KM, Alcoholism and Related Conditions. Arch Gen Weissman MM, Mann JJ: Ethnic and sex differences Psychiatry 2005; 62: 1097-106. in suicide rates relative to major depression in the Robins LN, Regier DA: Psychiatric Disorders in 2. United States. Am J Psychiatry 2001; 158: 1652-8 America: The Epidemiologic Catchment Area Study. 9. Nemeroff CB: The neurobiology of depression. Sci New York, Free Press, 1991. Am 1998; 278: 42-9. 3. Kessler RC, McGonagle KA, Zhao S, et al.: Lifetime 10. Shore PA, Silver SL, Brodie BB: Interaction of reser- and 12-month prevalence of DSM-III-R psychiatric pine, serotonin, and lysergic acid diethylamide in disorders in the United States: results from the brain. Science 1955; 122: 284-5. National Comorbidity Survey. Arch Gen Psychiatry 11. López-Muñoz F, Álamo C, Juckel G, Assion HJ: Half 1994; 51: 8-19. a century of antidepressant drugs: on the clinical in- Kessler RC, Berglund P, Demler O, et al. : The epide- 4. troduction of monoamine oxidase inhibitors, tricy- miology of major depressive disorder: results from clics, and tetracyclics. part I: monoamine oxidase Lee MS • 87 •

inhibitors. J Clin Psychopharmacol 2007; 27: 23. Tollefson GD, Rampey AH, Potvin JH, et al.: A mul- 555-9. ticenter investigation of fi xed-dose fl uoxetine in the 12. López-Muñoz F, Shen WW, Álamo C, Cacabelos R: treatment of obsessive-compulsive disorder. Arch Serendipitous discovery of fi rst two antidepressants. Gen Psychiatry 1994; 51: 559-67. Taiwanese Journal of Psychiatry [Taipei] 2014; 28: 24. Schneier FR, Liebowitz MR, Davies SO, et al.: 67-70. in panic disorder. J Clin Psychopharmacol 13. Carlsson A, Lindqvist M, Magnusson T: 3, 1990; 10: 119-21. 4-Dihydroxyphenylalanine and 5-hydroxytrypto- 25. Joffe RT, Sokolov ST: Thyroid hormone treatment of phan as reserpine antagonists. Nature 1957; 30; 180: primary unipolar depression: a review. Int J 1200. Neuropsychopharmacol 2000; 3: 143-7. 14. Hatotani N, Nomura J, Kitayama I: Changes of brain 26. Philip NS, Carpenter LL, Tyrka AR, Price LH: monoamines in the animal model for depression. In: Pharmacologic approaches to treatment resistant de- Shah NS, Donald AG, eds: Psychoneuroendocrine pression: a re-examination for the modern era. Exp Dysfunction. Berlin: Springer-Verlag, 1984: 331-42. Opin Pharmacother 2010; 11: 709-22. 15. Hatotani N, Nomura J, Kitayama I: Neuroendocrine 27. Olié JP, Kasper S: Effi cacy of agomelatine, a MT 1/ studies on the pathogenesis of depression. In: Hrdina MT 2 receptor with 5-HT antagonistic PD, Singhal RL, eds: Neuroendocrine Regulation properties, in major depressive disorder. Int J and Altered Behaviour. Berlin: Springer-Verlag, Neuropsychopharmacol 2007;10: 661-73. 1981: 187-203. 28. O’Reilly RL, Bogue L, Singh SM: Pharmacogenetic 16. Boadle-Biber MC: Regulation of serotonin synthesis. response to antidepressants in a multicase family Prog Biophysic Mol Biol 1993; 60: 1-15. with affective disorder. Biol Psychiatry 1994; 36: 17. Berger M, Gray JA, Roth BL: The expanded biology 467-71. of serotonin. Ann Rev Med 2009; 60: 355-66. 29. Pare C, Rees L, Sainsbury M: Differentiation of two 18. King M: Serotonin: The Medical Biochemistry Page. genetically specifi c types of depression by the re- Indiapolis, Indiana: Indiana University School of sponse to anti-depressants. Lancet 1962; 280: Medicine, 2009. 1340-3. 19. Sulser F: Serotonin-norepinephrine receptor interac- 30. Franchini L, Serretti A, Gasperini M, Smeraldi E: tions in the brain: implications for the pharmacology Familial concordance of fl uvoxamine response as a and pathophysiology of affective disorders. J Clin tool for differentiating mood disorder pedigrees. J Psychiatry 1987; 48 (Supp): 12-8. Psychiatr Res 1998; 32: 255-9. 20. Bymaster FP, Zhang W, Carter PA, et al.: Fluoxetine, 31. Fabbri C, Serretti A: Pharmacogenetics of major de- but not other selective serotonin uptake inhibitors, pressive disorder: top genes and pathways toward increases norepinephrine and dopamine extracellular clinical applications. Curr Psychiatry Rep 2015; 17: levels in prefrontal cortex. Psychopharmacology 1-11. (Berl) 2002; 160: 353-61. 32. Serretti A, Kato M, De Ronchi D, Kinoshita T: Meta- 21. Kapur S, Remington G: Serotonin-dopamine interac- analysis of serotonin transporter gene promoter poly- tion and its relevance to schizophrenia. Am J morphism (5-HTTLPR) association with selective Psychiatry 1996; 153: 466-76. serotonin effi cacy in depressed 22. Wong DT, Bymaster FP, Engleman EA: Prozac (fl uox- patients. Mol Psychiatry 2007; 12: 247-57. etine, Lilly 110140), the fi rst selective serotonin up- 33. Porcelli S, Fabbri C, Serretti A: Meta-analysis of se- take inhibitor and an antidepressant drug: twenty rotonin transporter gene promoter polymorphism years since its fi rst publication. Life Sci 1995; 57: (5-HTTLPR) association with antidepressant effi ca- 411-41. cy. Eur Neuropsychopharmacol 2012; 22: 239-58. • 88 • Pharmacogenetics of Antidepressants

34. Heils A, Teufel A, Petri S, et al.: Allelic variation of association between a G-protein β3-gene variant with human serotonin transporter gene expression. J depression and response to antidepressant treatment. Neurochem 1996; 66: 2621-4. Neuroreport 2000; 11: 1893-7. 35. McMahon FJ, Buervenich S, Charney D, et al.: 45. Lee HJ, Cha J, Ham BJ, et al.: Association between a Variation in the gene encoding the serotonin 2A re- G-protein β3 subunit gene polymorphism and the ceptor is associated with outcome of antidepressant symptomatology and treatment responses of major treatment. Am J Hum Genet 2006; 78: 804-14. depressive disorders. Pharmacogenom J 2004; 4: 36. Peters EJ, Slager SL, Jenkins GD, et al.: Resequencing 29-33. of serotonin-related genes and association of tagging 46. Keers R, Bonvicini C, Scassellati C, et al.: Variation SNPs to citalopram response. Pharmacogenet in GNB3 predicts response and adverse reactions to Genom 2009; 19: 1-10. antidepressants. J Psychopharmacol 2011; 25: 37. Kishi T, Yoshimura R, Kitajima T, et al.: HTR2A is 867-74. associated with SSRI response in major depressive 47. Joyce PR, Mulder RT, Luty SE, et al.: Age-dependent disorder in a Japanese cohort. Neuromol Med 2010; antidepressant pharmacogenomics: polymorphisms 12: 237-42. of the serotonin transporter and G protein β3 subunit 38. Fabbri C, Marsano A, Albani D, et al.: PPP3CC gene: as predictors of response to fl uoxetine and nortripty- a putative modulator of antidepressant response line. Int J Neuropsychopharmacol 2003; 6: 339-46. through the B-cell receptor signaling pathway. 48. Wilkie MJ, Smith D, Reid IC, et al.: A splice site Pharmacogenom J 2014; 14: 463-72. polymorphism in the G-protein β subunit infl uences 39. Fabbri C, Di Girolamo G, Serretti A: antidepressant effi cacy in depression. Pharmacogenet Pharmacogenetics of antidepressant drugs: an update Genom 2007; 17: 207-15. after almost 20 years of research. Am J Med Genet 49. Lin E, Chen PS, Chang HH, et al.: Interaction of se- Part B Neuropsychiatr Genet 2013; 162: 487-520. rotonin-related genes affects short-term antidepres- 40. Perlis RH, Fijal B, Adams DH, Sutton VK, Trivedi sant response in major depressive disorder. Prog MH, Houston JP: Variation in catechol-O-methyl- Neuro-Psychopharmacol Biol Psychiatry 2009; 33: transferase is associated with response in 1167-72. a for major depressive disorder. Biol 50. Hong C, Chen T, Yu YW, Tsai S: Response to fl uox- Psychiatry 2009; 65: 785-91. etine and serotonin 1A receptor (C-1019G) polymor- 41. Horstmann S, Lucae S, Menke A, et al.: phism in Taiwan Chinese major depressive disorder. Polymorphisms in GRIK4, HTR2A, and FKBP5 Pharmacogenomics J 2006; 6: 27-33. show interactive effects in predicting remission to 51. Kang RH, Hahn SW, Choi MJ, Lee MS: Relationship antidepressant treatment. Neuropsychopharmacology between G-protein beta-3 subunit C825T polymor- 2010; 35: 727-40. phism and responses in Korean patients 42. Anguelova M, Benkelfat C, Turecki G: A systematic with major depression. Neuropsychobiology 2007; review of association studies investigating genes 56: 1-5. coding for serotonin receptors and the serotonin 52. Kato M, Wakeno M, Okugawa G, et al.: transporter: I. Affective disorders. Mol Psychiatry Antidepressant response and intolerance to SSRI is 2003; 8: 574-91. not infl uenced by G-protein β3 subunit gene C825T 43. Hu Q, Zhang S-Y, Liu F, et al.: Infl uence of GNB3 polymorphism in Japanese major depressive patients. C825T polymorphism on the effi cacy of antidepres- Prog Neuro-Psychopharmacol Biol Psychiatry 2008; sants in the treatment of major depressive disorder: a 32: 1041-4. meta-analysis. J Affect Disord 2015; 172: 103-9. 53. Fernandes B, Berk M, Turck C, Steiner J, Goncalves 44. Zill P, Baghai TC, Zwanzger P, et al.: Evidence for an C: Decreased peripheral brain-derived neurotrophic Lee MS • 89 •

factor levels are a biomarker of disease activity in 265-8. major psychiatric disorders: a comparative meta- 63. Bellivier F, Leboyer M, Courtet P, et al.: Association analysis. Mol Psychiatry 2014; 19: 750-1. between the tryptophan hydroxylase gene and manic- 54. Polyakova M, Stuke K, Schuemberg K, Mueller K, depressive illness. Arch Gen Psychiatry 1998; 55: Schoenknecht P, Schroeter ML: BDNF as a biomark- 33-7. er for successful treatment of mood disorders: a sys- 64. Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, tematic and quantitative meta-analysis. J Affect Smeraldi E: Infl uence of tryptophan hydroxylase and Disord 2015; 174: 432-40. serotonin transporter genes on fl uvoxamine antide- 55. Yan T, Wang L, Kuang W, et al.: Brain-derived neu- pressant activity. Mol Psychiatry 2001; 6: 586-92. rotrophic factor Val66Met polymorphism association 65. Ham BJ, Lee BC, Paik JW, et al.: Association be- with antidepressant effi cacy: a systematic review and tween the tryptophan hydroxylase-1 gene A218C meta-analysis. Asia Pac Psychiatry 2014; 6: 241-51. polymorphism and citalopram antidepressant re- 56. Chang HS, Lee HY, Ham BJ, et al.: Association be- sponse in a Korean population. Prog Neuro- tween brain-derived neurotrophic factor V66M and Psychopharmacol Biol Psychiatry 2007; 31: 104-7. treatment responses to escitalopram in patients with 66. Arias B, Fabbri C, Gressier F, et al.: TPH1, MAOA, major depressive disorder. Asia Pac Psychiatry 2012; serotonin receptor 2A and 2C genes in citalopram re- 4: 241-9. sponse: possible effect in melancholic and psychotic 57. Choi MJ, Kang RH, Lim SW, Oh KS, Lee MS: depression. Neuropsychobiology 2012; 67: 41-7. Brain-derived neurotrophic factor gene polymor- 67. Gizatullin R, Zaboli G, Jonsson EG, Asberg M, phism (Val66Met) and citalopram response in major Leopardi R: Haplotype analysis reveals tryptophan depressive disorder. Brain Res 2006; 1118: 176-82. hydroxylase (TPH) 1 gene variants associated with 58. Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ: major depression. Biol Psychiatry 2006; 59: Association study of a brain-derived neurotrophic- 295-300. factor genetic polymorphism and major depressive 68. Yoshida K, Naito S, Takahashi H, et al.: Monoamine disorders, symptomatology, and antidepressant re- oxidase: a gene polymorphism, tryptophan hydroxy- sponse. Am J Med Genet Part B Neuropsychiatr lase gene polymorphism and antidepressant response Genet 2003; 123b: 19-22. to fl uvoxamine in Japanese patients with major de- 59. Kang R, Chang H, Wong M, et al.: Brain-derived pressive disorder. Prog Neuro-Psychopharmacol neurotrophic factor gene polymorphisms and mir- Biol Psychiatry 2002; 26: 1279-83. tazapine responses in Koreans with major depres- 69. Ham BJ, Lee MS, Lee HJ, et al.: No association be- sion. J Psychopharmacol 2010; 24: 1755-63. tween the tryptophan hydroxylase gene polymor- 60. Chen L, Lawlor DA, Lewis SJ, et al.: Genetic asso- phism and major depressive disorders and antide- ciation study of BDNF in depression: Finding from pressant response in a Korean population. Psychiatr two cohort studies and a meta-analysis. Am J Med Genet 2005; 15: 299-301. Genet Part B Neuropsychiatr Genet 2008; 147: 70. Kato M, Wakeno M, Okugawa G, et al.: No associa- 814-21. tion of TPH1 218A/C polymorphism with treatment 61. Verhagen M, van der Meij A, van Deurzen PA, et al.: response and intolerance to SSRIs in Japanese pa- Meta-analysis of the BDNF Val66Met polymorphism tients with major depression. Neuropsychobiology in major depressive disorder: effects of gender and 2007; 56: 167-71. ethnicity. Mol Psychiatry 2010; 15: 260-71. 71. Wang HC, Yeh TL, Chang HH, et al.: TPH1 is associ- 62. Cooper JR, Melcer I: The enzymic oxidation of tryp- ated with major depressive disorder but not with tophan to 5-hydroxytryptophan in the biosynthesis of SSRI/SNRI response in Taiwanese patients. serotonin. J Pharmacol Eexper Ther 1961; 132: Psychopharmacology 2011; 213: 773-9. • 90 • Pharmacogenetics of Antidepressants

72. Walther DJ, Bader M: A unique central tryptophan 175-9. hydroxylase isoform. Biochem Pharmacol 2003; 66: 77. Yin L, Zhang Y, Zhang X, Yu T, He G, Sun X: TPH, 1673-80. SLC6A2, SLC6A3, DRD2 and DRD4 polymor- 73. Zill P, Baghai T, Zwanzger P, et al.: SNP and haplo- phisms and neuroendocrine factors predict SSRIs type analysis of a novel tryptophan hydroxylase iso- treatment outcome in the Chinese population with form (TPH2) gene provide evidence for association major depression. Pharmacopsychiatry 2015; 48: with major depression. Mol Psychiatry 2004; 9: 95-103. 1030-6. 78. Uher R, Perroud N, Ng MY, et al.: Genome-wide 74. Van Den Bogaert A, Sleegers K, De Zutter S, et al.: pharmacogenetics of antidepressant response in the Association of brain-specifi c tryptophan hydroxy- GENDEP project. Am J Psychiatry 2010; 167: lase, TPH2, with unipolar and bipolar disorder in a 555-64. Northern Swedish, isolated population. Arch Gen 79. Garriock HA, Kraft JB, Shyn SI, et al.: A genome- Psychiatry 2006; 63: 1103-10. wide association study of citalopram response in ma- 75. Gao J, Pan Z, Jiao Z, et al.: TPH2 gene polymor- jor depressive disorder. Biol Psychiatry 2010; 67: phisms and major depression–a meta-analysis. PloS 133-8. One 2012; 7: e36721. 80. Ising M, Lucae S, Binder EB, et al.: A genomewide 76. Gizatullin R, Zaboli G, Jönsson EG, Åsberg M, association study points to multiple loci that predict Leopardi R: The tryptophan hydroxylase (TPH) 2 antidepressant drug treatment outcome in depression. gene unlike TPH-1 exhibits no association with Arch Gen Psychiatry 2009; 66: 966-75. stress-induced depression. J Affect Disord 2008; 107: