Pharmacogenetics of bipolar disorder

Pharmaco genetics o f Bipo lar Diso rder Hader A. Mansour, MD , MSc, Martin Alda, MD , FRCP( C) , and Vishwajit L. Nimgaonkar, MD , PhD Address W estern Psychiatric Institute and Clinic, 3811 O ’H ara Street, Room 443, Pittsburgh, PA 15213, USA. E-mail: nimga@ pitt.edu Current Psychiatr y Reports 2002, 4:117–123 Current Science Inc. ISSN 1523-3782 Copyright © 2002 by Current Science Inc. To review the pharmacogenetics of bipolar disorders, the authors searched databases for genetic association and linkage studies involving response to long-term prophylactic lithium treatment, as well as treatment with antidepressants or clozapine. Significant ethnic variations in the metabolism and efficacy of antidepressants, as well as clozapine, have been reported by several groups. Systematic studies suggest that that genetic factors affect the response to prophylactic lithium treatment. N umerous associations between the three traits of interest and candidate gene polymorphisms have been proposed. Among these, an association between the serotonin transporter gene and response to serotonin reuptake inhibitors appears robust. Considerable interest has also focused on serotonergic gene polymorphisms and response to clozapine. Response to pharmacotherapy in bipolar disorders may be mediated by genetic factors, but the role played by heritability is unknown. Intro ductio n Individual variatio ns in the respo nse to m edicatio ns, as well as the adverse effects o f such drugs are influenced by numero us facto rs. They include co mpliance, bo dy weight, age, gender, general health and nutritio nal status. Variability b etween ethnic gro ups is also well kno wn [1•]. Fo r exam ple, prim aquine-induced hem o lytic anem ia, due to gluco se-6-pho sphate dehydro genase ( G-6-PD) deficiency is relatively co m m o n am o ng black individuals, as well as certain Mediterranean and So utheast Asian po pulatio ns [2]. Individual differences in iso niazid-induced peripheral neuritis and hepatitis are related to ethnic differences in a po lym o rphism go verning hepatic acetylatio n [3]. Given such ethnic variatio n, it is lo gical to ask if ind ivid ual genetic differences also play a ro le. Pharmaco genetics is the field o f enq uiry dealing with variab ility o f respo nses to m edicatio ns that is asso ciated with genetic variatio n. The term pharmacogenomics, which has beco me mo re po pular, refers to the search fo r genetic variatio ns that are asso ciated with efficacy. It highlights the geno m ic scale o f such searches, with an accent o n pharmaco dynamic, rather than pharmaco kinetic effects. Be c au se n u m e ro u s f ac to rs o b vi o u sl y i n f l u e n c e respo nse to drugs, it is no t o nly impo rtant to demo nstrate a gen etic in fluen ce, b ut also to ask h o w m uch o f th e variab ility asso ciated with the trait can b e attrib uted to genetic variatio n. The term heritability is used to deno te the latter. In classic hum an genetics, evid ence fo r genetic influences, as well as estimates o f heritability and plausible m o d es o f inheritance are garnered fro m fam ily b ased studies. The subsequent gene mapping effo rts are also usually based o n family based linkage analyses. Because pharm aco genetics by definitio n invo lves respo nse to a drug, traditio nal family based analyses are difficult, if no t impo ssible. Therefo re, researchers o ften supplant such effo rts by investigating genetic variants even befo re heritability has b een estab lished . The m o st p o p ular ap p ro ach, called “asso ciatio n analysis,” invo lves case-co ntro l co m pariso ns o f selected genetic po lym o rphism s. If the cho ice o f the p o lym o rp h ism s is b ased o n im p uted m ech an ism s o f actio n o f drugs, such studies are also called “candidate gene asso ciatio n studies.” Two gro ups o f traits are usually investigated— estim atio ns o f therapeutic drug respo nse, and adverse effects. Tho ugh ad verse affects ap p ear intuitively to b e m o re related to variable drug metabo lism, these two sets o f traits are intimately related [4,5]. Evidently, pro per definitio n o f respo nse is critical to pharm aco genetic studies. Tho ugh arbitrary criteria such as 50% im pro vem ent o n a specific scale are co m m o n in clinical trials, such definitio ns m ay no t be the mo st suitable fo r genetic research, as they may no t b e heritab le. Furtherm o re, traits relevant in genetic research are tho se representing stable characteristics o f an individual. Therefo re, the treatm ent respo nse sho uld b e in tra-in d ivid ually rep ro d ucib le. Mo reo ver, th eir very arbitrariness may make estimatio n difficult, especially fo r behavio ral traits. Extreme pheno type, such as patients with co mplete respo nse ( o r remissio n) are mo re tractable fro m this po int o f view, but m ay have less po wer fo r statistical an alyses. In eith er even t, b y stud yin g th e treatm en t re sp o n se ge n e ti c al l y i t i s i m p l i c i tl y assu m e d th at subgro ups asso ciated with different geno types may exist. Several asso ciatio ns b etween clinical resp o nse and genetic variab ility have b een d em o nstrated [ 6 ] . Such investigatio ns co ntinue, thanks to advances in the human geno me pro ject. Pharmaco genetic studies in psychiatry are 118 Genetic Diso rders also increasingly po pular. Their im po rtance canno t b e underestim ated, given the large num b ers o f individuals receiving psycho tro pic drugs [7]. In this review, the autho rs will fo cus o n three po pular areas o f research relevant to b ipo lar diso rder, nam ely pro phylactic lithium therapy, an ti d e p re ssan t tre atm e n t, an d tre atm e n t w i th th e antip sycho tic d rug clo zap ine. Fo r the p urp o ses o f this review, the autho rs have retrieved and screened publicatio ns fro m Medline using the key wo rds pharmaco genetic, genetic, m ania, m anic, b ipo lar diso rder, and treatm ent. O nly papers published in English were included. Pharmaco genetics o f Pro phylactic Treatment: Lithium regatio n suggests the lo catio n o f the liab ility gene if the chro m o so m al lo catio n o f the genetic m arker is kno wn. A full geno me scan invo lving 31 families o f lithium-respo nsive pro b ands suggested several regio ns with lo d sco res abo ve 1.8 fo r the pheno type o f recurrent affective diso rders ( b ipo lar o r unipo lar) . The highest two -po int lo d sco re o bserved was 3.43 o n 15q14 and the seco nd highest lo d sco re was 2.7 o n 7q 11.2. Because o nly a fractio n o f the family members had been treated with lithium, the po wer o f th e stud y to d etec t lin kage fo r th e p h en o typ e o f respo nsiveness to lithium was lim ited. Nevertheless, fo r this pheno type the lo cus o n 7q11.2 gave a lo d sco re o f 1.53 with an em pirical significance o f 0.003 as determ ined by simulatio n [24]. Family studies Asso ciatio n studies Respo nsiveness to lithium is perhaps the o nly psychiatric pharmaco genetic trait to be investigated intensively using system atic fam ily based analyses. An asso ciatio n between fam ily histo ry o f bipo lar illness and satisfacto ry respo nse to lithium has lo ng been suggested [8–10]. Mendlewicz et al. [11,12] studied the relatio nship b etween successful lithium treatm ent and the presence o f affective illness in the fam ilies o f b ipo lar patients thro ugh a do ub le b lind study o f lithium pro phylaxis. They fo und that 66% o f the successfully treated lithium cases had at least o ne firstdegree relative with bipo lar illness, and 21% o f the lithium failures had a first-degree relative with bipo lar illness. They did no t find a relatio nship b etween respo nse to lithium and fam ily histo ry o f unipo lar illness. Furtherm o re, the respo nse to lithium appears to be a familial trait. In a study o f 24 relatives o f pro bands who respo nded unequivo cally to l i th i u m , 1 6 ( 6 7 % ) sh o w ed a c l ear- c u t resp o n se co mpared with o nly nine o ut o f 30 ( 30% ) bipo lar patients attending an o utpatient clinic [13]. Two rep o rts h ave sub seq uen tly argued again st an asso ciatio n o f family histo ry and lithium respo nse [14,15]. Ho wever, it is unclear to what extent their results co ntradict th e earlier fin d in gs an d to w h at exten t th ey reflec t m etho d o lo gical d ifferences, esp ecially with resp ect to definitio n o f lithium respo nse [16]. Several stud ies suggest co n co rd an ce fo r lith ium respo nse amo ng parent-o ffspring pairs [17–20]. Familiality o f lithium treatm ent respo nse in children o f b ipo lar pro b ands have b een indirectly suppo rted in a study by Duffy et al. [21] who fo und sim ilarities between affected parents and children with respect to the episo dicity o f their clinical co urse. This is a hallm ark o f lithium -respo nsive fo rm o f BD. Such stud ies len d cred en ce to earlier segregatio n analysis, suggesting an auto so m al recessive inheritance [22,23]. Because the segregatio n analysis suppo rted an auto so mal liability gene o f significant effect, geno me wide linkage analyses were initiated. Such studies investigate the co -inheritance o f selected genetic markers with the trait o f interest in selected families. Statistically significant co -seg- The respo nse to lithium evaluated in the prio r studies may represent a subtype o f the illness o r may be independent o f the illness. These two views are also reflected in different types o f asso ciatio n studies. A num ber o f studies investigated differences between respo nders and no n-respo nders, while o thers used the treatment respo nse as an additio nal criterio n to increase ho m o geneity o f their sam ples. The l atter stu d i es i m p l i c i tl y assu m e th at th e i n c reased p heno typ ic ho m o geneity rep resents also an increased genetic ho mo geneity. O n e o f th e auth o rs o f th is p ap er h as rep o rted a significant asso ciatio n b etween a po lym o rphism at the pho spho lipase C γ1 and respo nsiveness to lithium amo ng bipo lar patients recruited fro m selected centers in Euro pe and Canada [25]. Asso ciatio ns with additio nal candidate genes were no t detected [26–28•,29]. Ho wever, o thers did no t detect a significant asso ciatio n using the pho spho lipase C γ1 marker in a smaller Euro pean sample [30]. O ther candidate genes regulating the pho spho ino sito l cycle have also been investigated. Steen et al. [ 31] did no t detect any variatio n in the co ding sequence o f the ino sito l m o no p ho sp hatase gene ( IM PA1 ) . Sub seq uently, they c h arac teriz ed th e gen o m ic stru c tu re o f IM PA 1 an d described several po lymo rphisms [32]. Ho wever, they did n o t d etect any sign ifican t d ifferen ces am o n g b ip o lar p atien ts an d co n tro l sub jects in th ree sam p les fro m No rway, Israel, and Canada [33]. Interestingly, there is a ho mo lo gue o f IMPA1 o n the sho rt arm o f chro mo so me 18 in the regio n that might be linked to bipo lar diso rder [34]. In a series o f studies, the sam e gro up also exam ined the gene fo r ino sito l po lypho sphate 1-pho sphatase ( INPP1) . The allelic distributio ns o f the gene did no t differ between patients and co ntro ls. Ho wever, there was a difference between respo nders and no nrespo nders to lithium in the No rwegian sam p le, b ut no t am o ng the p atients fro m Israel [35]. Serretti et al. [ 3 6 ] investigated p o lym o rp hism s o f several candidate genes in a sam ple o f patients treated w i th l i th i u m an d su b d i vi d e d i n to re sp o n d e rs an d no nrespo nders, b ut fo und no significant evidence o f an Pharmaco genetics o f Bipo lar Diso rder • Mansour et al. asso ciatio n with pro phylactic respo nse to lithium . Their sam p le in c lud ed b etween 5 5 an d 2 01 sub jec ts w ith bipo lar and unipo lar m ajo r affective diso rders in individual stud ies. Th e can d id ate gen es in clud ed sero to n in recep to r 2 A, 2 C, an d 1 A, d o p am in e D 2 ( D RD 2 ) , D 3 ( D RD 3 ) , D 4 ( D RD 4 ) , and GABA recep to r α -1 sub unit ( GABRA1 ) genes [37,38]. Recently, the sam e gro up fo und an asso ciatio n b etween p ro p hylactic lithium resp o nse an d th e sero to n in tran sp o rter ( SLC6 A4 ) . A b i-allelic po lym o rphism in the 5’ untranslated regio n, deno ted 5H TTLPR was investigated. Individuals ho m o zygo us fo r the sho rt allele ( ss) had po o rer respo nse. These results are interesting, b ecause the H TTPLR p o lym o rp hism m ay influence the transcriptio nal activity o f the gene: the “ l” allele is asso ciated with greater expressio n o f the transpo rter in vitro [39]. Ho wever, this asso ciatio n m ay reflect a difference in pre-lithium freq uency o f episo des, since there was no difference b etween gro ups in the episo de freq uency during lithium treatm ent [40]. Interestingly, D el Zo m po , et al. [41] studied the sam e po lym o rphism and fo und a trend to wards higher freq uency o f the lo ng ( l) allele am o ng lithium no n-resp o nd ers co m p ared to co ntro l subjects. Ano ther study repo rted that 63% bipo lar patients with a histo ry o f antidepressant-induced m ania had the ‘s’ allele co m pared with 29% in bipo lar subjects who had b een exp o sed to antid ep ressants b ut d id no t develo p m ania [42]. Since these repo rts are inco nclusive, further research is necessary. Pharmaco genetics o f Antidepressants Fam i l i al c o rre l ati o n i n th e c l i n i c al re sp o n se to antid ep ressants has no t b een investigated extensively, tho ugh trainees are enjo ined to inquire abo ut treatm ent respo nse in affected relatives when selecting antidepressants. A recent study repo rted o n data fro m 45 pairs o f relatives with unipo lar and bipo lar depressio n who were treated with fluvo xam ine [ 4 3 ] . The p ro b and s had all resp o nd ed satisfacto rily to fluvo xam ine. Am o ng their first-degree relatives, 30 ( 67% ) also respo nded favo rably to fluvo xam in e. Th e sam e gro up co n d ucted co m p lex segregatio n analysis am o ng 171 fam ilies o f b ipo lar and un ip o lar p ro b an d s resp o n sive to fluvo xam in e. Th ey suggested a m ajo r-gene effect in a sub set o f 68 fam ilies o f fam ilies o f b ip o lar p ro b and s, b ut no t in the entire sam ple [40]. Pharm aco genetic research has fo cused o n variants o f drug metabo lizing enzymes. The cyto chro me P450 ( CYP) iso zym es, CYP2D6 and CYP2C19, are respo nsible fo r the m etab o lism o f m any psycho tro pic drugs, with CYP2D 6 playing a m ajo r ro le fo r antipsycho tic and antidepressant drugs [1]. The gene enco ding CYP2D6 has m o re than 50 allelic variants, so m e with im po rtant functio nal effects. Po o r m etabo lizers can be fo und in appro xim ately 7% o f white individuals, and ultra-rapid metabo lizers are fo und in 1% to 10% o f whites [44,45] 119 Clinically impo rtant info rmatio n is available abo ut the pharmaco kinetics o f tricyclic antidepressants ( TCA) [46•]. CYP2D 6 po lym o rphism s are asso ciated with variatio ns TCA m etab o lism , and can result in unpredictab le do serespo nse relatio nship. This is impo rtant, because TCAs display a narro w therapeutic range and co nsiderable to xicity is asso ciated with elevated co ncentratio ns [47]. Pre-therapeutic geno typing seem s, therefo re, to b e a reaso nab le strategy o nce co st effectiveness based o n impro ved clinical o utco me has been demo nstrated [48]. Several p ub lished stud ies have rep o rted o n ethnic d ifferen c es in th e p h arm ac o kin etic s o f TC As. So m e repo rted that plasm a clo m ipram ine co ncentratio ns and d rug-related ad verse effects were significantly higher amo ng Asians ( Pakistani and Indian) co mpared with white British investigato rs [4 9 ,50]. O thers rep o rted that the m ean plasm a clearance o f desipram ine was significantly h i gh e r am o n g w h i te s th an th e C h i n e se e ve n af te r co rrecting fo r bo dy weight [51]. There was no significant difference in half-life o r plasm a pro tein binding between the two gro up s. Elsewhere, it has b een suggested that Asians have greater areas under the curve ( AUC) fo r bo th no rtrip tyline and its m ain m etab o lite co m p ared with whites [52]. Because Asians also have lo wer clearance rates fo r no rtriptyline, it has b een suggested that Asians have relatively slo wer hepatic hydro xylatio n fo r co m pared to whites. These findings may explain why Asians need lo wer do ses o f antidepressants than whites [53,54]. Less info rmatio n is available abo ut selective sero to nin reuptake inhibito rs ( SSRIs) [55]. Many SSRIs are metabo liz ed b y th e c yto c h ro m e P4 5 0 system , p artic u larly CYP2D 6. Unlike TCAs, SSRIs have a flat do se–respo nse curve, and, thus, have a wide therapeutic index. Data fro m fixed do se studies suggest that there is no clear co rrelatio n between serum co ncentratio ns and therapeutic effectiveness [55]. Based o n this assessm ent, no benefit fro m preth erap eutic gen o typ in g o f m etab o lizin g p o lym o rp h enzymes can be expected [46•]. The presumed majo r pharmaco lo gic effect o f TCAs may relate to their ability to blo ck presynaptic neuro nal uptake o f the neuro transm itters no repinephrine and sero to nin [47]. Selective sero to nin reup take inhib ito rs are m o re specific and po tent inhibito rs o f sero to nin reuptake [56]. These data have pro vided the im petus fo r candidate gene asso ciatio n studies, but pharmaco dynamic variability has been less extensively studied than pharmaco kinetics. Marco s et al. [ 57 ] fo und Hispanic patients required less than half o f the do ses o f TCAs, and had m o re side effects th an w h ite p atien ts. N o p h arm aco kin etic d ata were co llected; therefo re, it is difficult to kno w whether the o bserved variability was due to pharm aco kinetic o r pharm aco dynam ic facto rs. In a later study, Gaviria et al. [58] repo rted that there were no pharmaco kinetic differences in no rtriptyline m etab o lism b etween Hispanic and white po pulatio ns, suggesting pharm aco dynam ic differences as the so urces o f the ethnic differences [1•]. 120 Genetic Diso rders Several candidate gene asso ciatio n studies have been rep o rted recently [ 5 9 – 61 ] . The sero to nin transp o rter ( SLAC 6 A4 , alias “ 5 - H TT ” , lo calized to ch ro m o so m e 17q11.1 to q12) has attracted the mo st attentio n thus far. In ad d itio n to the H TTPLR p o lym o rp hism allud ed to previo usly, ano ther co mmo nly studied marker is a variable num ber o f tandem repeats ( VNTR) po lym o rphism in the seco nd intro n o f the gene. This m arker is no t kno wn to affect the gene functio n. Asso ciatio n analyses targeting liability fo r affective diso rders have yielded inco nsistent results [62–67]. The 5-HTT gene was recently studied in relatio n to the treatment respo nse to fluvo xamine [68]. In a sample o f 56 subjects, tho se with at least o ne co py o f the l allele were m o re likely to respo nd, co m pared with 15 “ ss” ho m o zygo us cases. Ho wever, this asso ciatio n co uld no t be detected am o n g 4 6 o th er p atien ts w h o rec eived p in d o lo l in ad d itio n to fluvo xam in e. Th e auth o rs suggested th at pindo lo l may have co mpensated fo r the altered transcriptio nal activity o f the gene amo ng. Asso ciatio ns with respo nse to o ther SSRIs have also b een repo rted, nam ely paro xetine [69], fluo xetine and paro xetine [70]. These studies have suggested a significant asso ciatio n o f the respo nse and presence o f the l allele; the latter stud y is the o nly o ne to d ate suggesting a b etter respo nse amo ng ss ho mo zygo us subjects. Co nsistent with the m ajo rity o f findings, Po llo ck et al. [71] fo und that amo ng elderly patients with majo r depressio n 11 patients sho wed a faster respo nse to paro xetine. The asso ciatio n appeared specific to paro xetine, as there was no allelic o r geno typic difference with respect to no rtriptyline respo nse. Recently, Arias et al. [ 7 2 ] fo und a sim ilar asso ciatio n b etween 5 -H TTLPR and citalo pram , ano ther SSRI. In a sample o f 102 patients with majo r depressio n, they fo und th at rem issio n was less likely in sub jects w ith th e ss geno type. Thus, co nsistent asso ciatio ns with therapeutic respo nse have been detected at SLC6A4. In ad d itio n to treatm en t resp o n se stud ies, o th er pheno types have also been tested with respect to SLC6A4 . Two neuro endo crine studies repo rted a stro nger pro lactin respo nse to either clo mipramine [73] o r fenfluramine [74] amo ng tho se with ll geno type. Pharmaco genetics o f Clo zapine Mo st o f the pharm aco genetic studies invo lving clo zapine have been co nducted amo ng patients with schizo phrenia, as it is used prim arily fo r the treatm ent o f this diso rder. Clo zapine is used increasingly fo r acute and lo ng-term treatment o f patients with psycho tic bipo lar diso rder who have no t respo nded to co nventio nal pharm aco therapy [75]. Therefo re, the pharm aco genetic studies in schizo p h ren ia m ay b e ap p licab le to b ip o lar d iso rd er also . Altho ugh it has m any advantages, clo zapine has so m e serio us side effects, eg, agranulo cyto sis [76]. The clinical respo nse to clo zapine is variable; the effective therapeutic do se o f clo zapine varies fro m 50 to 900 m g per day [77– 80]. So m e studies suggest variab le plasm a levels am o ng patients o n stable clo zapine do ses [81,82]. It has been suggested that the variability may be co rrelated with genetic facto rs [83•]. Cyto chro m e P450 1 A2 ( CYP1A2) is the m ain enzym e respo nsible fo r clo zapine m etab o lism [ 8 4 – 8 6 ] . CYP1 A2 p o lym o rp h ism s m ay m ed iate th is variab ility [ 8 7 ,8 8 ] . In turn , in d ivid ual variab ility in clo zap ine p harm aco kinetics m ay lead to differences in respo nse [89]. There may be ethnic differences in the pharmaco kinetics and pharm aco dynam ics o f clo zapine. Matsuda et al. [ 9 0 ] an d h ave d em o n strated th at Ko rean -Am eric an patients had lo wer clo zapine co ncentratio ns than whites. Co mpared with white patients, Ko rean-American patients experience m arked im pro vem ent at significantly lo wer clo zap ine d o ses and p lasm a levels and have a higher incidence o f anticho linergic as well as o ther side effects [90]. In co ntrast, Chinese patients have 30% to 50% higher co ncentratio ns than whites [91]. The variability in respo nse to c lo z ap in e m ay b e d u e to p o lym o rp h ism s o f th e do pamine D4 recepto r ( D RD 4 ) , the majo r binding sites o f clo zapine [92]. The autho rs are no t aware o f cro ss-ethnic co mpariso ns with respect to D RD 4 . Ethnic differences in adverse respo nses to clo zapine were suggested b y th e o b servatio n o f an asso ciatio n between Jewish ethnicity and the predispo sitio n to clo zapine-induced agranulo cyto sis. The human lympho cyte antigens ( HLA) -B3 8 , D R4 , and D Q w3 are asso ciated with clo zapine-induced agranulo cyto sis. No tab ly, these antigens are mo re prevalent in the Jewish po pulatio n ( 10% to 12% ) co m pared with o ther white ethnic gro ups ( 0.4% to 0.8% ) [93]. Pub lished studies ab o ut the ethnic variatio ns in the extrap yram id al sid e effects ( EPS) o f clo z ap in e h ave d em o n strated co n flictin g results. So m e in vestigato rs rep o rted th at EPS were m o re freq uen t am o n g Asian patients co mpared with white patients, yet o thers o bserved no significant differences [94–97]. Pharm aco genetic predictio ns o f clo zapine respo nse have fo cussed o n candidate genes that enco de sero to nergic and do paminergic recepto rs, but the results are co ntradicto ry [ 8 3 •] . H o w e ve r, m e ta- an al ysi s d e m o n strate d significant asso ciatio ns with 2 p o lym o rp hism s o f the sero to n in 2 A gen e ( H T2 A ) [ 9 8 ] . Th ese wo rkers also investigated 19 po lym o rphism s fro m 10 genes. Lo gistic regressio n analysis suggested six po lym o rphism s at the HT2A , HT2C , and SLC6A4 lo ci had a po sitive predictive value o f 0 .7 6 fo r satisfacto ry resp o nse. The results are p l au si b l e as al l th re e ge n e s m e d i ate se ro to n e rgi c neuro transm issio n and thus m ay be instrum ental fo r the therapeutic benefits o f clo zapine [99]. Pharmaco genetics o f Bipo lar Diso rder • Mansour et al. Co nclusio ns Several studies suggest significant ethnic differences in the m etab o lism and efficacy o f antid ep ressants, as well as clo zapine. The ethnic differences may reflect genetic variatio n. This po ssibility is suppo rted by several case-co ntro l asso ciatio n studies, tho ugh a clear picture is yet to emerge. Mo re co nsistent evidence is available fo r genetic asso ciatio ns with lithium pro phylaxis. Rapid, o ngo ing advances in geno m ics have facilitated extensive and o ngo ing pharm aco geno m ic studies. The p ro sp ects fo r tailo rin g in d ivid ual th erap y b ased o n individual genetic variatio n are exciting, b ut it is wo rth reiteratin g th at a m ultifacto rial o r p o lygen ic m o d el explains therapeutic variability best. Therefo re, the co ntrib utio n o f any single po lym o rphism is likely to b e sm all and the chances o f detecting such asso ciatio ns are lo w [100]. Co nsequently, the risks co ntributed by individual genetic po lymo rphisms are mo st likely to be meaningful if th ey are an alyz ed an d u sed in th e c o n text o f o th er functio nally related genetic po lym o rphism s [99]. Such studies will also b e m eaningful if genes o f m ajo r effect exist, as suggested by o ngo ing studies o f lithium respo nse. References and Reco mmended Reading Papers o f particular interest, published recently, have been highlighted as: • O f impo rtance •• O f majo r impo rtance 1.• Po o lsup N, Li Wan Po A, Knight TL: Pharmaco genetics and psycho pharmaco therapy. J Clin Pharm Ther 2000, 25:197–220. This co mprehensive article highlights ethnic differences in the pharmaco lo gy and pharmaco genetics o f antipsycho tic drugs and the antidepressants. 2. Lin KM, Po land RE, Wan YJ, et al. : The evo lving science o f 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. pharmaco genetics: clinical and ethnic perspectives. Psychopharmacol Bull 1996, 32:205–217. 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