1. Late life depression

2. Pharmacogenetics of late life

depression

3. Conclusions

4. Expert opinion

Review

Pharmacogenetic considerationsfor late life depression therapyPothitos M Pitychoutis, Nikolaos Kokras, Despina Sanoudou,Christina Dalla & Zeta Papadopoulou-Daifoti††National & Kapodistrian University of Athens, Medical School, Department of Pharmacology,

Athens, Greece

Introduction: Geriatric depression is a heterogeneous disorder with a complex

genetic background. Current first-line treatment of depression is associated with

a lower therapeutic outcome in aged depressed patients, when compared to

younger subjects. Research which has explored this inadequate response has

highlighted several factors which have come into play with the pharmacogenetics

of antidepressants in the elderly being a particular area of interest.

Areas covered: The authors perform a critical review of the English language

articles from PubMed using search terms such as late-life/geriatric depression,

antidepressants, pharmacogenetics, pharmacogenomics, pharmacokinetic,

genetic, genotype, remission, therapy, treatment and polymorphism.

Expert opinion: The emerging clinical and pharmacogenetic data are slowly

unveiling the importance of the genome -- age interaction in antidepressant

response. This data introduces a critical new parameter in personalized medi-

cine. A profound analysis of the age factor in the pharmacogenetics of antide-

pressant response is imperative, in order to elucidate the clinical significance of

these findings and thereby improve patient treatment in the elderly.

Keywords: 5-HTT gene-linked polymorphic region, antidepressant drug, brain-derived

neurotrophic factor, citalopram, cytochrome P450, dopamine transporter 1, elderly, geriatric

depression, remission, serotonin transporter, stressful life episodes, treatment

Expert Opin. Drug Metab. Toxicol. [Early Online]

1. Late life depression

Depressive disorders affect > 18 million people in Europe each year [1] and theirtreatment still remains far from optimal [2]. As population ages, the prevalence ofdepression in late life is expected to rise, thus posing new challenges for the mentalhealth systems in the Western world. In fact, as noted by Kessler et al. in an earlierUS study, in 1994, at least 8 -- 25% of the older adults in the general populationmay experience depression [3]. Interestingly, a recent systematic review on the preva-lence of late life depression reported that although the incidence of depression in theelderly is no different from younger age groups, the prevalence is considerably higher,suggesting that late life depression is characterized primarily by chronicity [4].

Aging per se is the natural course of life, and successful aging has been the focus ofseveral investigators over the last years. There is now enough evidence showing thatseveral modifiable factors during younger age, such as alcohol abuse and tobaccosmoking, can significantly interfere with successful aging and deteriorate qualityof life in aged populations [5]. Depression, on the other hand, is one of the key fac-tors that fall outside the control of the individual, yet comprise a significant cause ofimpaired quality of life in geriatric populations. Furthermore, depression in theelderly can be as fatal as in younger patients, given that it may increase both suicideand non-suicide mortality [6,7], whereas there is evidence that suicide attempts in latelife are frequently more severe and with a fatal outcome [8].

10.1517/17425255.2013.794786 © 2013 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 1All rights reserved: reproduction in whole or in part not permitted

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Differences in the presentation of depression betweenyounger and older adults have been systematically studied,yet there is still ongoing debate on whether such differencesare qualitative or quantitative [9]. There is consensus thatdepressed aged patients are less likely to have family historyof depression and are more likely to score low in themini--mental state examination, suggesting greater cognitiveimpairment [10,11]. Although elderly depressed patients mayhave fewer premorbid personality disturbances and be lesslikely to suffer or complain about cognitive--affective symp-toms, including dysphoria, worthlessness and guilt [12], noparticular and distinctive symptom profile with substantialusefulness in clinical settings has emerged as characteristic oflate life depression [10]. Furthermore, the intensity and/orthe reporting of depressive symptoms in the elderly are sus-pected to be covert and not properly meeting diagnostic crite-ria. This effect has led to the development of several termsattempting to describe the variability of depressive phenome-nology in late life, such as “subsyndromal” or “non-major”depression [9].On the other hand, there are many variables which are

implicated in the etiology of late life depression, includingfactors related to psychosocial adversity, increased medicalcomorbidity, neurological abnormalities and genetic vulnera-bility [13,14]. The multiple interactions of such factors in givingrise to depressive symptoms often characterize the clinical pre-sentation of late life depression, as well. For instance, patientswith a vascular subtype of depressive illness have beenreported to display decreased negative cognitions, more

psychomotor retardation, increased apathy, dysexecutive fea-tures on neurocognitive evaluation and to present a poorerresponse to treatment [15,16].

In this context, it has been proposed that patients with firstonset of a depressive episode in later life include a large sub-group of patients with acquired organic pathology [12]. Indeed,late life depression can be differentiated from depression inyounger patients, given that it possesses a unique pathophysiol-ogy comprising of several neuroanatomical findings recentlyreviewed by Disabato and Sheline [17]. As noted by Alexopoulosand Bruce [18] late life depression can be mediated by the inter-action of stressful life events (SLE) with age-related abnormali-ties in brain structures responsible for emotional regulation inpredisposed individuals. In particular, abnormalities in fronto-limbic structures give rise to executive dysfunction [19], whichis also a known prognostic factor for poor treatment responsein late life [20]. In fact, executive dysfunction is currently thefocus of several investigators, given that cognitive impairmentis particularly evident in depressed aged patients who score sig-nificantly worse in neuropsychological tests than their youngercounterparts [21].

2. Pharmacogenetics of late life depression

Late life depression can be seen as a heterogeneous syndromewith regard to clinical presentation, course of illness andresponse to treatment according to the identified underlyingetiopathology. However, despite its significant impact onquality of life, depression remains underdiagnosed in agedpatients and even fewer of them receive proper treatment [22].Furthermore, there is substantial evidence showing that first-line treatment of depression produces inadequate responsein a far greater percentage of elderly depressed patients incomparison to younger counterparts [20,23,24]. In exploringthis inadequate response to first-line treatments, several fac-tors have come into play with pharmacogenetics of late lifedepression being an area of particular interest.

Pharmacogenetics investigates how genes influence respon-siveness to drugs, both in terms of efficacy and adverse effects.The ultimate goal of this interdisciplinary scientific field is toprovide tailor-made pharmacotherapies based on the geneticmakeup of the individual. The advent of elegant genetic/genomic techniques has set the basis for personalized medi-cine in neuropsychiatric disorders, such as major depression.During the past years, it became apparent that polymor-phisms in several genes regulating pharmacokinetics andpharmacodynamics may be implicated in both the course ofthe depressive episode and in the outcome of antidepressanttreatment [25]. In the current review, a literature search wasperformed among the English language articles of thePubMed database focusing on search terms such as late lifeand geriatric depression, antidepressants, pharmacogenetics,pharmacogenomics, pharmacokinetic, cytochrome P450(CYP), genetic, genotype, remission, therapy, treatment andpolymorphism, in various combinations. Furthermore,

Article highlights.

. Late life depression can be seen as a heterogeneousdiagnostic category, according to the identifiedunderlying etiopathology, with regard to clinicalpresentation, course of illness and responseto treatment.

. Substantial evidence shows that first-line treatment ofdepression produces inadequate response in a far largerpercentage of elderly depressed patients in comparisonto younger counterparts.

. The emerging clinical and pharmacogenetic data areslowly unveiling the importance of the genome -- ageinteraction in antidepressant response, introducing acritical new parameter in personalized medicine.

. Pharmacogenetic research, so far, has identified severalpharmacodynamics- (i.e., 5-HTTLPR, DAT1 and NET) andpharmacokinetics-related genetic targets (i.e.,CYP2D6 and MDR1), as well as genes pertaining toother neurobiological systems (i.e., BDNF and AGTR1)that have been reported to regulate antidepressantresponse in the elderly.

. Overall, despite the promising advances in this field,pharmacogenetics-driven, personalized antidepressantpharmacotherapies in geriatric patients are still far frombeing introduced into the clinic.

This box summarizes key points contained in the article.

P. M. Pitychoutis et al.

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reference lists were screened for relevant articles that may havebeen of potential interest.

As far as elderly depressed patients are concerned, currentlyavailable evidence implicates a number of genetic loci in the mod-ulation of antidepressant drug response. Research so far haslargely focused on pharmacodynamics- and pharmacokinetics-related genetic targets, as well as in genes pertaining to otherneurobiological systems that have been reported to regulateantidepressant response in aged patients.

2.1 Monoamine transporters2.1.1 Serotonin transporterNumerous pharmacogenetic studies regarding responsivenessto antidepressants have focused on the genetic variations ofthe serotonin (5-HT) transporter gene solute carrier, family6, member (SLC6A4; 5-HTT) which is located on chromo-some 17q12 in humans [26]. Of particular interest is thefunctional polymorphism on the promoter of the 5-HTTgene, known as 5-HTT gene-linked polymorphic region(5-HTTLPR) that consists of 16 imperfect 22 base-pairrepeats. The polymorphic nature of this site involves thepresence/absence of two of these repeats. Thus, their absenceproduces a short allele (s), whereas their presence produces a44 base-pair long allele (l). The functional implication ofthis bi-allelic scheme is that carriers of the l-allele are character-ized by enhanced expression rate of the 5-HTT, with theopposite being the case for s-allele carriers. Indeed, at a cellularlevel, cells with the s-allele may have 50% less 5-HTT expres-sion than cells that are homozygous for the l-allele [27]. Con-sidering that the 5-HTT accounts for a direct protein targetfor most antidepressant drugs, it has been postulated thatl-allele carriers may benefit more from antidepressant treat-ment. The latter may possibly be attributed to a generalizedresponsiveness of the serotonergic system owing to theenhanced expression/activity of 5-HTT [28].

Interestingly, genetic variation within the SLC6A4 locusmay contribute to interindividual differences in response toselective 5-HT reuptake inhibitors (SSRIs) in elderly subjectswith major depression. In their landmark paper, Pollock et al.reported that geriatric depressed patients homozygous for thel-allele appear to respond more rapidly (i.e., as early as week2) to paroxetine treatment, as compared to s-allele carriers.Moreover, the fact that the onset of therapeutic response tonortriptyline was not influenced by the 5-HTTLPR polymor-phism led the authors to hypothesize that elderly patients withincreased 5-HT reuptake are more likely to exhibit a moreacute response to SSRIs [29]. Importantly, their findings werereplicated in a follow-up study [30], as well as in a sertraline-based study where subjects homozygous for the l-allele of5-HTTLPR also showed a favorable response at weeks 1 and2 posttreatment [31]. However, it should be mentioned thatseveral studies documented no association between the l-alleleof the 5-HTTLPR and therapeutic response to antidepressantdrugs [32-34].

In white populations, depressed patients carrying at leastone l-allele of the 5-HTTLPR polymorphism (i.e., sl and ll)generally show a better, more accelerated response to SSRIsas compared to s-allele homozygotes (ss) [26,35,36]. However,results are more conflicting in Japanese and Korean patients,underpinning the important role of ethnicity-related differen-ces in the pharmacogenetics of antidepressants. For instance,in contrast to studies conducted in European cohorts, a studyof geriatric depression in an elderly Korean cohort concludedthat patients homozygous for the s-allele presented enhancedresponse to treatment with either fluoxetine or sertraline, ascompared to l-allele carriers [37]. Of note, in the same study,response to nortriptyline was also associated with the5-HTTLPR polymorphism with greater response rates beingobserved in ss homozygotes.

Another polymorphism influencing 5-HTT expression,described as a 17-bp variable number of tandem repeats(VNTR) polymorphism, was identified by Ogilvie et al.within intron 2 (STin2) [38]. As with the 5-HTTLPR varia-tion, the STin2 VNTR consists of 9 -- 12 repeats of a16/17 bp unit; the shorter allele (i.e., nine copies) has beenassociated with enhanced protein expression of 5-HTT ascompared to the longer copies of the VNTR [39,40].A battery of evidence suggested this polymorphism as a riskfactor for major depression and suicidal behavior in Europeanpatients, while a number of authors have reported an effectof STin2 on antidepressant response [35]. However, thegeriatric Korean study of Kim et al. yielded the oppositeassociation, as was the case for 5-HTTLPR; the l-alleles(10 -- 12 repeats) were associated with greater response ratesthan the s-allele [37].

As noted, elderly subjects bearing the s-allele appear to pres-ent a slower response to SSRIs, during the initial weeks oftreatment [29-31]. On this, a very intriguing study exploredthe concentration -- response association for paroxetine in geriat-ric depression and suggested that this relationship is governedby a dynamic regulatory influence of the “s and l” 5-HTTLPRalleles [30]. In particular, the authors reported that from as earlyas the second week of paroxetine treatment, drug levels weresignificantly correlated with improvement in depression scalesin s-allele carriers but not in ll homozygotes [30]. The latterassociation supported the notion that elderly patients carryingthe s-allele may actually require higher SSRI concentrations inorder to present accelerated response and take advantage of thefull benefits of drug treatment [41].

SSRIs are thought to act through the inhibition of the5-HTT, so a promoter variant that affects the expression ofthis protein target may theoretically equally affect efficacyand putative adverse drug reactions (ADRs). Indeed, the5-HTTLPR polymorphism has been associated with the dif-ferent manifestation of ADRs between the different geno-types. For instance, agitation and insomnia were reported tobe more prevalent in fluoxetine-treated patients homozygousfor the s-allele [42]. Importantly, in another study thatextended these findings to the geriatric population, the

Pharmacogenetic considerations for late-life depression therapy

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5-HTTLPR polymorphism was associated with the probabil-ity of discontinuing paroxetine and mirtazapine due toADRs [43]. In this study, patients with the sl genotype showeda significantly greater risk of discontinuation due to ADRs ascompared to ll homozygotes, while homozygosity for thes-allele conferred a greater severity of ADRs, as compared topatients with the ll genotype. ADRs associated with discontin-uation in paroxetine-treated patients with the ss genotypeincluded gastrointestinal complaints, fatigue, agitation, sweat-ing and dizziness. On the other hand, among mirtazapine-treated patients, the l-allele conferred greater risk of discontin-uation of therapy due to ADRs. Adverse events associatedwith discontinuation among mirtazapine-treated patientswith the ll genotype included drowsiness, dizziness andanxiety. Based on these findings it was suggested that the5-HTTLPR polymorphism may serve as a marker for risk ofdiscontinuation of medication in geriatric patients [43].Age-related alterations that compromise the integrity of

frontolimbic connectivity may contribute to non-remissionof geriatric depression [12]. Indeed, imaging studies haveshown that depression in the elderly is manifested with whitematter abnormalities in frontolimbic pathways that are char-acterized by both macromolecular and microstructural altera-tions [44]. In a recent study, Alexopoulos et al. reported thatelderly depressed carriers of the s-allele treated with a fixeddose of escitalopram (10 mg/day for 12 weeks) have moreextensive microstructural white matter abnormalities in fron-tolimbic and other regions and are less likely to achieveremission of depression than ll homozygotes [45]. Importantly,this study suggested a negative impact of the s-allele of5-HTTLPR on frontolimbic networks that may subsequentlyworsen treatment outcome in late life depression, but furtherresearch is needed to confirm these findings.As noted, SLEs comprise a well-recognized risk factor for

the precipitation of depressive symptomatology [46,47]. How-ever, the association between negative stressful episodes, thecourse of the disease and treatment response remains elusive.On this, a preliminary study reported that the s-allele of the5-HTTLPR polymorphism may interact with stressors preced-ing the onset of the illness to predict worse treatment outcomewith fluvoxamine [48], but a more recent study failed to yieldstatistically significant stress -- genotype associations [49]. As faras geriatric patients are concerned, in a recent flexible-dose study conducted in elderly depressed patients treatedwith various antidepressants, the greater number of negativeSLEs at baseline predicted worse outcomes for ll homozygotes,but slightly better outcomes for the s-allele carriers at12 months [50]. These findings require further validation, butit could be speculated that indices of negative SLEs and per-ceived stress severity may serve as important predictors of thecourse of geriatric depression in “vulnerable” s-allele carriers.

2.1.2 Catecholamine transportersThe norepinephrine (NE) transporter (NET) in humans isencoded by the SLC6A2 gene and functions by transporting

the neurotransmitter NE from the synapse back to cytosol.Several groups have explored the putative relationshipbetween NET genetic polymorphisms and vulnerability tomajor depression without observing a major influence ofthis gene. However, a number of functional NET variantshave been reported to affect antidepressant response [35]. Asfar as elderly patients are concerned, in their Korean studyKim et al. [37] showed a positive association between theG/G genotype of the G1287A polymorphism in exon 9 ofthe NET gene (that appears to have no functional consequen-ces [51]) and favorable response to nortriptyline, although noeffect on SSRI (fluoxetine and sertraline) responsewas detected.

Besides the important role of central serotonergic and nor-adrenergic circuits, dopamine (DA) has also been stronglyimplicated in depression and antidepressant response. Forinstance, both dopamine transporter 1 (DAT1) activity andextracellular striatal DA levels have been reported to be regu-lated by SSRI treatment [52,53]. Indeed, an earlier naturalisticcohort study reported that the 9-repeat allele of the DAT140 bp VNTR polymorphism was associated with significantlypoorer response compared to the 10-repeat allele [54]. Eventhough some studies support that the DAT1 9-repeat alleleis associated with reduced expression of DAT which in turnresults in increased synaptic DA levels, as compared to the10-repeat allele, other studies yielded the exact oppositeresults or even concluded that this variation has no functionalsignificance [55]. As far as elderly depressed patients are con-cerned, Lavretsky et al. reported in their pilot study that theDAT VNTR 10/10 genotype may be associated with anendophenotype of late life depression with executive dysfunc-tion that preferentially responds to augmentation of SSRIwith methylphenidate which in turn results in significantimprovement of mood and cognitive symptoms [56]. Thus,the relationship between DAT polymorphisms and antide-pressant response remains elusive [35].

2.2 Brain-derived neurotrophic factorThe brain-derived neurotrophic factor (BDNF) gene encodesa neurotrophin that is highly expressed in the central nervoussystem, especially in the hippocampus where it plays a role inthe proliferation, differentiation and the maintenance of neu-ronal integrity throughout lifespan [57]. According to the neu-rotrophin hypothesis of depression, a reduction of BDNFexpression is involved in the pathophysiology of majordepression, whereas the use of antidepressants leads to anupregulation of BDNF in the hippocampus of depressed indi-viduals [58]. A functional single-nucleotide polymorphism(SNP) (G196A) in the BDNF gene that results in the substi-tution of Val to Met at codon 66 (Val66Met) is a commongenetic variation with variable frequency in different popula-tions which has been associated with anxiety and majordepression [59,60]. Notably, the Met66 allele has been associ-ated with abnormal intracellular trafficking and secretion ofBDNF [61]. In general, findings regarding the implication of

P. M. Pitychoutis et al.

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this polymorphism in antidepressant response are controver-sial with some studies reporting a better outcome for eitherthe Val/Val or the heterozygous phenotypes [35]. In a recentstudy, it was reported that geriatric depressed patients carryingthe Met66 allele were more likely to achieve remission thanVal66 homozygotes following 3 months of treatment with afixed dose of escitalopram [62]. Around the same time, it wasreported that elderly depressed patients carrying the Met66allele are almost twice as likely to achieve remission at6 months (but not at 3 months), as compared to Val66homozygous subjects [63]. Despite these interesting findings,additional clinical trials with larger sample sizes should beconducted in order to replicate these data [64].

2.3 Other genetic variantsPharmacogenetics has significantly contributed to the character-ization of functional polymorphisms in key drug-metabolismgenes [26]. In this context, the CYP and the multidrug resistance1 (MDR1) gene families have been meticulously studied.Research on the CYP2D6 enzyme (debrisoquine/sparteinehydroxylase) has gained ground over the other CYP iso-morphs, as it catalyzes the metabolism of numerous widelyprescribed antidepressants (e.g., fluoxetine, paroxetine and clo-mipramine) [65,66]. In a thorough pharmacokinetic analysis,Feng et al. reported that female and male elderly depressedpatients with different CYP2D6 genotypes have different elim-ination rates and may need to be dosed differently based on themetabolizer status [67]. Notably, in a cohort of 246 elderlydepressed patients treated with paroxetine or mirtazapine,microarray profiling of relevant CYP2D6 genotypes did notreveal any meaningful associations between discontinuationrates due to ADRs or the severity of ADRs [68]. Nevertheless,these negative findings could also be attributed to thepronounced involvement of other CYP enzymes such asCYP3A4 in the metabolism of these antidepressants, whichmay dilute the effect of altered CYP2D6 activity onplasma levels.

The ATP-binding cassette, subfamily B, member 1 trans-porter (ABCB1; MDR1), encodes P-glycoprotein, an ATP-dependent efflux pump. MDR1 is a major component ofthe blood--brain barrier that contributes to the eliminationof several antidepressant drugs (e.g., paroxetine and fluoxe-tine). In a recent study Sarginson et al. reported that twoMDR1 polymorphisms (i.e., two intronic SNPs, namelyrs2032583 and rs2235040) may predict treatment responseto citalopram in a cohort of elderly depressed patients [69].However, it should be noted that studies investigating theputative effect of relevant polymorphisms on antidepressantresponse have yielded contradictory results, renderingthe clinical applicability of MDR1 pharmacogeneticsquestionable [26,35].

According to numerous reports, older adults suffering fromlate life depression are more likely to have vascular risk factorsincluding history of cerebrovascular disease [70]. Upon this,Kondo et al. found an intriguing association between a genetic

marker of vascular disease, namely the A1166C, a non-functional SNP at the 5¢ site of the 3¢ untranslated region(UTR) of angiotensin II receptor, vascular type 1 (AGTR1)gene, and treatment outcome, with geriatric patients carryingthe CC genotype presenting poorer treatment outcome [71].Moreover, variations in the FK506 binding protein 5 genethat encodes a glucocorticoid receptor-regulating co-chaper-one of heat shock protein 90 have been associated with antide-pressant response in adult patients suffering from depressivedisorders [72]. However, Sarginson et al. failed to replicatethis finding in a cohort of elderly depressed patients treatedwith paroxetine and mirtazapine [73].

3. Conclusions

Late life depression may be viewed as a heterogeneous syn-drome in terms of clinical presentation, course of illness andresponse to treatment. Of note, a battery of evidence showsthat first-line treatment of depression is associated with poorerresponse rates in elderly depressed patients, as compared toyounger subjects. Focused pharmacogenetic screening hasexposed numerous variations in genetic loci that appear toinfluence the efficacy and tolerability of antidepressant drugsin the elderly. Research so far has largely focused on pharma-codynamics- (i.e., 5-HTTLPR, DAT1 and NET) andpharmacokinetics-related genetic targets (i.e., CYP2D6 andMDR1), as well as in genes pertaining to other neurobiologi-cal systems (i.e., BDNF and AGTR1) that have been reportedto regulate antidepressant response in adult depressedpatients [26,74]. Even though results appear promising, a pro-found analysis of the age factor in the pharmacogenetics ofantidepressant response is considered imperative in order forthe clinical significance of these findings to be elucidated.

4. Expert opinion

There is continuing interest in identifying genetic markersthat might predict response to antidepressant drugs, as morethan one-third of all patients do not present a satisfactoryresponse to the first-line antidepressant pharmacotherapy.Several studies in the field support the notion that allelic var-iations may partly account for the variability in therapeuticoutcomes and ADRs observed in the clinic. Indeed, discover-ing predictors of the response to antidepressant pharmaco-therapy is a major goal of molecular psychiatry. However,despite a decade of intensive research on the pharmacoge-netics of antidepressants, the gap from basic research to clini-cal practice has yet to be bridged [36].

Geriatric depression is a complex, heterogeneous disorderwith an elusive genetic background [14]. Indeed, the evidencesupporting a strong association between specific geneticmarkers and antidepressant response in elderly depressedpatients is still scarce (Table 1). To date, polymorphisms in5-HTT and BDNF genes have received most attention. Euro-pean patients carrying the s-allele tend to present a delayed

Pharmacogenetic considerations for late-life depression therapy

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Table

1.Pharm

aco

geneticstudiesthathaverevealedinfluencesofrelevantpolymorphismsin

geriatric

depressedpatients.

Gene

Polymorphism

Drug

Cohort

Resu

ltRefs.

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Paroxetine(20--30mg/day)

upto

12weeks

51elderlypatients

(meanage:72.0

±7.9

years)

Depressedpatients

homozygousfor

thel-allele

respondedmore

rapidly

(i.e.,asearlyasweek2)to

paroxetine,

ascomparedto

s-allele

carriers

[29]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Sertraline(50--100mg)vs

placebofor8weeks

106elderlydepressed

patients

(meanage:69.7

years)

Homozygosity

forthel-allele

was

associatedwithafavorable

response

atweeks1and2posttreatm

ent

[31]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Paroxetine(20--40mg/day)

vsmirtazapine(15--45mg/day)

for8weeks

124vs

122depressed

patients

(approximate

mean

age72.0

±5.9

years)

Paroxetine-treateds-allele

carriers

experiencedmore

severe

ADRs,

achievedlowerfinaldaily

dosesand

hadhigherdiscontinuationrates.

Incontrast,in

mirtazapine-treated

patients

discontinuationswere

most

frequentamongthose

withthe

llgenotype

[43]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Paroxetine*

110depressedpatients

(60years

orolder)*

Thel-allele

was

associatedwithantidepressant

response

at2weeks.Paroxetine

concentrationwassignificantly

correlatedwithim

provementin

depressionscoresatweek2withthe

s-allele,butnotthellgenotype

[30]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Escitalopram

10mg/day(12weeks)

27depressedpatients

vs27elderlycontrols

(60years

orolder)

Thes-allele

carriers

have

more

extensive

microstructuralwhitematter

abnorm

alitiesin

frontolim

bic

andother

regionsandare

less

likely

toachieve

remissionofdepressionthanll

homozygotes

[45]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

Variousantidepressants

(flexible-dosingfor6and12months)

216elderlydepressedpatients

(remittedvs

non-remitted;approximate

meanage:69years)

Thegreaternumberofnegative

SLEs

atbaselinepredictedworseoutcomes

forllhomozygotes,butslightlybetter

outcomesforthes-allele

carriers

at

12months

[50]

5-HTT(SLC

6A4)

5-HTTLPR‘long/short’

polymorphism

(promoter)

andStin2VNTR(intron2)

Fluoxetine30mg/dayorsertraline

75mg/day(6

weeks)

119elderlyKoreandepressedpatients

(approximate

mean

age:55--57years)

Incontrast

tostudiesin

whitepatients,

thefavorable

allele

forSSRIresponse

wasthes-allele

[37]

NET

G1287A

(exon9)

Nortriptyline55mg/day(6

weeks)

89elderlyKoreandepressedpatients

(approximate

mean

age:55--57years)

Positive

associationbetw

eentheGG

genotypeandfavorable

response

tonortriptyline

[37]

*Readers

are

referredto

theactualresearchstudy,

formore

inform

ationin

studydesign.

5-HTT:Serotonin

transporter;AGTR1:AngiotensinIIreceptor,vasculartype1;BDNF:

Brain-derivedneurotrophic

factor;CYP:CytochromeP450;DAT:Dopaminetransporter;MDR1:Multidrugresistance

gene1;

NET:Norepinephrinetransporter.

P. M. Pitychoutis et al.

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Table

1.Pharm

aco

geneticstudiesthathaverevealedinfluencesofrelevantpolymorphismsin

geriatric

depressedpatients

(continued).

Gene

Polymorphism

Drug

Cohort

Resu

ltRefs.

DAT1

40bpVNTR(3¢-U

TR)

Citalopram/m

ethylphenidate

vscitalopram/placebo

15elderlypatients

(mean

age:71.4

years)

Patients

withthe10/10genotype

respondedpreferentially

tomethylphenidate

addedto

citalopram

withagreaterreductionin

depressionseverity

overtime

[56]

AGTR1

A1166C

(3¢U

TR)

Variousantidepressants

(upto

18months)

236elderlypatients

(approximate

meanage:70years)

Patients

carryingtheCC

genotype

presentedpoorertreatm

entoutcome

[71]

BDNF

G196A

(Val66Met)

Escitalopram

10mg/day(12weeks)

32depressedpatients

(approximate

meanage:70years)

BDNF v

al/valsubjectshadlower

remissionrates(40%

)thanBDNF m

et

carriers

(64.7%

)

[62]

BDNF

G196A

(Val66Met)

Variousantidepressants

(for3and6months)*

229elderlydepressedpatients

(60years

orolder)

Carriers

oftheMet66allele

are

alm

ost

twiceaslikely

toachieve

remissionat

6months(butnotat3months),as

comparedto

Val66homozygous

subjects

[63]

MDR1(ABCB1,

p-glycoprotein)

rs2032583(intron22)

andrs2235040

(intronboundary

exon21)

Paroxetinevs

mirtazapine(8

weeks)*

124vs

122depressedpatients

(65years

orolder)

These

polymorphismspredictedtime

ofremissionin

paroxetine-treatedbut

notin

mirtazapine-treatedelderly

depressedpatients

[73]

CYP2D6

CYP2D6alleles*

Paroxetine10--40mg/day*

171elderlypatients

(mean

age:77years)

Female

andmale

subjectswith

differentCYP2D6polymorphismshave

differentelim

inationratesandmay

needto

bedoseddifferentlybasedon

metabolizergenotype

[67]

*Readers

are

referredto

theactualresearchstudy,

formore

inform

ationin

studydesign.

5-HTT:Serotonin

transporter;AGTR1:AngiotensinIIreceptor,vasculartype1;BDNF:

Brain-derivedneurotrophic

factor;CYP:CytochromeP450;DAT:Dopaminetransporter;MDR1:Multidrugresistance

gene1;

NET:Norepinephrinetransporter.

Pharmacogenetic considerations for late-life depression therapy

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response to SSRIs [29-31]. This pattern is by no means universalbut rather ethnicity-dependent as the opposite associationseems to be the case for patients of Asian ethnicity [37]. The5-HTTLPR may also influence treatment response to paroxe-tine in both a direct (i.e., genotype -- concentration interaction)and an indirect fashion (i.e., by influencing discontinuationthrough ADRs) in geriatric depressed patients [41]. Of note,these findings underpin the need for conducting pharmacoki-netic analyses in parallel with pharmacogenetic screen-ing [41,75]. Notably, the CYP450 genotyping test is beingimplemented in the clinic for the determination of the differ-ent metabolizer types, in an increasing number of health insti-tutions [26]. Despite initial skepticism, the elucidation of themetabolizer status of the patient may, indeed, result in amore rationalized dose-escalation for refractory treatment-resistant depressive episode, as is often the case in the geriatricpopulation. Furthermore, this matter is of utmost importancein geriatric patients, as they often present alterations in phar-macokinetic parameters due to aging. On the other hand,elderly depressed patients are most likely treated with othernon-psychotropic drugs which in turn may interact with theconcomitantly prescribed antidepressants [76]. Such potentialand multiple interactions in pharmacokinetics may signifi-cantly impact the dose--response relationship. Thus, it is pre-dicted that drug -- genotype interactions upon insufficient acuteresponse to a given antidepressant could dictate personalizeddose escalations and combinations of antidepressants or med-ication switch. Indeed, a previous study elegantly showed thatvariations in steady-state fluoxetine and norfluoxetine concen-trations were at least partly explained by genetic variations inCYP2D6 and CYP2C9 [77]. Thus, as was previously sug-gested, dose reductions as much as 50% should be performedin patients treated with tricyclic antidepressants who are clas-sified as poor metabolizers with regard to CYP2D6 andCYP2C9, although differences were generally smaller forSSRIs such as fluoxetine [78]. Inversely, ADRs may be pre-vented in cases where particular drug-genotype interactionssuggest a high probability of altered pharmacokinetics in vul-nerable geriatric depressed patients. In this context, geneticfactors influencing antidepressant pharmacokinetics mightbe of particular relevance in elderly depressed patients in com-parison to younger patients, whereas genetic polymorphismsaffecting pharmacodynamics of antidepressants are still ofunclear importance in young and elderly depressed patients.Of note, a battery of clinical and experimental evidence

supports a critical role of sex in the modulation of pharmaco-genetics, pharmacodynamics and pharmacokinetics of antide-pressant drugs (reviewed in Refs [74,79]). On this, Feng et al.suggested that elderly male and female depressed patientscarrying different CYP2D6 genotypes may need to be dosed

sex-dependently in view of different elimination rates andmetabolizer stati [67]. In this regard, focused research on therole of sex in the pharmacogenetics of geriatric depressionmay ultimately expose a novel sex -- genetic interplay thatmay influence antidepressant response in the elderly.

Around the time that Gerretsen and Pollock published theirelegant review, only five studies had been published on the roleof the pharmacogenetics of 5-HTTLPR polymorphism in latelife depression [41]. Since then, hypothesis-driven research hasexposed novel genetic loci that may predict antidepressantresponse in the elderly (e.g., BDNF, MDR1, DAT1 andAGTR1), but still results are considered limited. Of note,the functional Val66Met polymorphism in the BDNF genehas been shown to affect antidepressant response in geriatricdepressed patients, with the carriers of the Met66 allele beingmore likely to achieve remission, as compared to Val66 homo-zygous subjects. Overall, these promising findings could meritfrom further validation and should be extended to includeadditional antidepressant drug classes and age groups andalso take into account putative sex differences.

The emerging clinical and pharmacogenetic data are slowlyunveiling the importance of the genome -- age interaction inantidepressant response, introducing a critical new parameterin personalized medicine. However, despite the promisingadvances in this field, pharmacogenetics-driven, personalizedantidepressant pharmacotherapies in geriatric patients are stillfar from being introduced into the clinic. Although it is stillearly for firm conclusions, the currently available evidenceimplicates a number of genetic variants in the modulation ofantidepressant drug response in elderly subjects. Undoubt-edly, further research is expected to expose novel genetic var-iations, either in linkage disequilibrium with polymorphismsalready known to affect treatment outcomes in the elderly orin unrelated, distinct parts of the human genome. Given therelatively limited number of geriatric-based clinical trials andantidepressants used, the clinical significance of these findingsneeds to be elucidated. Thus, these genotype -- response associ-ations could merit from further replication in large multicen-ter trials based on standardized study designs that in parallelmonitor drug levels and ADRs.

Declaration of interest

PM Pitychoutis and D Sanoudou have received funding fromthe European Community’s Framework Programme (FP7/2007 -- 2013) under grant agreement no 278611. N Kokras,D Sanoudou, C Dalla and Z Papadopoulou-Daifoti havereceived funding from the National Action “Cooperation”of the Greek Ministry of Development under grant agreementno 09SYN-21-1003.

P. M. Pitychoutis et al.

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AffiliationPothitos M Pitychoutis*1,2 PhD,

Nikolaos Kokras1,3 MD PhD,

Despina Sanoudou1 PhD,

Christina Dalla1 PhD &

Zeta Papadopoulou-Daifoti†1 PhD†,*Authors for correspondence1National & Kapodistrian University of Athens,

Medical School, Department of Pharmacology,

75 Mikras Asias Street, Goudi,

Athens, 115 27, Greece

Tel: +30 210 7462702; +30 210 7462579;

Fax: +30 210 746 2554;

E-mail: zdaifoti@med.uoa.gr;

ppitychout@med.uoa.gr2Biomedical Research Foundation of the

Academy of Athens (BRFAA),

Athens, Greece3National & Kapodistrian University of Athens,

Eginition Hospital, Medical School,

First Department of Psychiatry,

Athens, Greece

Pharmacogenetic considerations for late-life depression therapy

Expert Opin. Drug Metab. Toxicol. [Early Online] 11

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