Ci a ion: Ga cía-González, X.; Cubo, E.;
Simón-Vicen e, L.; Ma iscal, N.; Alca az,
R.; Aguado, L.; Ri adeney a-Posadas, J.;
Sanz-Solas, A.; Saiz-Rod íguez, M.
Pha macogene ics in he T ea men o
Hun ing on’s Disease: Re iew and
Fu u e Pe spec i es. J. Pe s. Med.
2023,13, 385. h ps://doi.o g/
10.3390/jpm13030385
Academic Edi o : Ma ea
Zajc Pe ano i´c
Recei ed: 25 Janua y 2023
Re ised: 20 Feb ua y 2023
Accep ed: 21 Feb ua y 2023
Published: 22 Feb ua y 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
Jou nal o
Pe sonalized
Medicine
Re iew
Pha macogene ics in he T ea men o Hun ing on’s Disease:
Re iew and Fu u e Pe spec i es
Xand a Ga cía-González 1, Es he Cubo 2,3, Lucía Simón-Vicen e 3, Na i idad Ma iscal 2, Raquel Alca az 4,
Lau a Aguado 2, Jéssica Ri adeney a-Posadas 4, An onio Sanz-Solas 4and Mi iam Saiz-Rod íguez 3,4,*
1Pha macy Depa men , Ins i u o de In es igación Sani a ia G ego io Ma añón (IiSGM),
Hospi al Gene al Uni e si a io G ego io Ma añón, 28007 Mad id, Spain
2Neu ology Depa men , Hospi al Uni e si a io de Bu gos, 09006 Bu gos, Spain
3Depa men o Heal h Sciences, Uni e si y o Bu gos, 09001 Bu gos, Spain
4Resea ch Uni , Fundación Bu gos po la In es igación de la Salud (FBIS),
Hospi al Uni e si a io de Bu gos, 09006 Bu gos, Spain
*Co espondence: [email p o ec ed]
Abs ac :
Hun ing on’s disease (HD) is an au osomal dominan p og essi e b ain diso de , caused
by a pa hological expansion o a CAG epea ha encodes he hun ing in gene. This gene ic neu ode-
gene a i e a e disease is cha ac e ized by cogni i e, mo o , and neu opsychia ic mani es a ions.
The aim o he ea men is symp oma ic and add esses he hype kine ic diso de s (cho ea, dys-
onia, myoclonus, ics, e c.) and he beha iou al and cogni i e dis u bances (dep ession, anxie y,
psychosis, e c.) associa ed wi h he disease. HD is s ill a complex condi ion in need o inno a i e
and e icien ea men . The long- e m goal o pha macogene ic s udies is o use geno ype da a o
p edic he e ec i e ea men esponse o a speci ic d ug and, in u n, p e en po en ial undesi able
e ec s o i s adminis a ion. Cho ea, dep ession, and psycho ic symp oms ha e a subs an ial impac
on HD pa ien s’ quali y o li e and could be be e con olled wi h he help o pha macogene ic
knowledge. We aimed o ca y ou a e iew o he a ailable publica ions and e idence ela ed o
he pha macogene ics o HD, wi h he objec i e o compiling all in o ma ion ha may be use ul in
op imizing d ug adminis a ion. The impac o pha macogene ic in o ma ion on he esponse o
an idep essan s and an ipsycho ics is well documen ed in psychia ic pa ien s, bu his app oach has
no been in es iga ed in HD pa ien s. Fu u e esea ch should add ess se e al issues o ensu e ha
pha macogene ic clinical use is app op ia ely suppo ed, easible, and applicable.
Keywo ds: Hun ing on; pha macogene ics; an icho eic; an idep essan ; an ipsycho ic
1. In oduc ion
Ra e neu odegene a i e diseases a e a al, wi h no a ailable he apy o cu e o slow
down hei p og ession. O e he las decades, he e has been a g owing in e es in esea ch
on a e diseases, o en suppo ed by egula o y agencies. Pa ien s and heal h p o essionals
showed di e en esea ch p io i ies o a e neu ological diseases. In e es ingly, pa ien
ep esen a i es indica ed ha he apies a e o he u mos impo ance since hei li es
a e o en hea ily impac ed, and hei main goal is o elie e he bu den o disease [
1
].
Among a e diseases, Hun ing on’s disease (HD) is o special in e es gi en he easy access
o diagnosis in de eloped coun ies. HD is an au osomal dominan p og essi e b ain
diso de , caused by a pa hological expansion o a CAG epea (
≥
36 epea s) ha encodes
he hun ing in gene (HTT). This gene ic neu odegene a i e disease is cha ac e ized by
cogni i e, mo o , and neu opsychia ic mani es a ions. The wo ldwide p e alence o HD
is 2.7 pe 100,000 [
2
]. E e y a emp o p e en o slow HD p og ession in pa ien s and
mu a ion ca ie s has ailed so a [3].
Clinical mani es a ions o HD a e associa ed wi h he loss o neu ons, especially in
he co ex and s ia um, caused by he expansion o he hun ing in p o ein. This a ec s
J. Pe s. Med. 2023,13, 385. h ps://doi.o g/10.3390/jpm13030385 h ps://www.mdpi.com/jou nal/jpm
J. Pe s. Med. 2023,13, 385 2 o 18
neu o ansmission media ed by dopamine and glu ama e, which is why hese neu o ans-
mi e s a e cu en ly he main a ge o a ailable pha maco he apy [
4
]. The aim o he
ea men is symp oma ic and add esses he hype kine ic diso de s (cho ea, dys onia, my-
oclonus, ics, e c.) and he beha iou al and cogni i e dis u bances (dep ession, anxie y,
psychosis, e c.) associa ed wi h he disease.
Te abenazine and deu e abenazine (cen al monoamine deple o s) a e indica ed o
he ea men o cho ea, whe eas neu olep ics a e commonly used o he ea men o
cho ea and psychosis ela ed o HD. In addi ion, since HD is a mul isymp oma ic disease,
pa ien s o en ecei e o he concomi an medica ion o ea symp oms such as dep ession,
i i abili y, apa hy, o anxie y.
Va ia ions in esponse o d ugs may be pha macodynamic o pha macokine ic and,
he e o e, a ec he e icacy and oxici y o d ugs. Response a es o medica ions, used o
ea a wide ange o diso de s, ypically ange om 50% o 75%, meaning ha up o hal o
pa ien s see no bene i [
5
]. In addi ion, many indi iduals su e om ad e se d ug eac ions
(ADRs). Nea ly 8.4% o hospi al admissions in Eu ope a e ela ed o ADRs, and abou 10%
o pa ien s su e an ADR du ing hospi aliza ion [
6
,
7
]. In he USA, i is es ima ed ha se e e
d ug oxici ies cause o e 100,000 dea hs and cos USD 30–100 billion annually [
8
]. In e -
indi idual a iabili y in d ug esponse a ec s no only pa ien well-being, bu also poses
eno mous clinical and inancial bu dens. I is well known ha an idopamine gic d ugs
imp o e cho ea bu , on he o he hand, can induce signi ican mo bidi y and mo ali y,
including dep ession wi h suicidal ou comes, obesi y, diabe es, me abolic synd ome, and
ca dio oxici y in HD [
9
]. Acco ding o p eclinical and clinical s udies, he side e ec s
o an icholine gic d ugs can be a ibu ed o he d ugs’ mul iple binding o dopamine,
his amine, 5-hyd oxy yp iamine, his amine ace ylcholine, ad ene gic, NMDA, and GABAa
ecep o s. The e icacy and ADR p o iles o an icho eic d ugs a e he e ogeneous wi h la ge
in e indi idual a iabili y. As a esul , ea men selec ion emain a la gely ial-and-e o
p ocess in HD. In his ega d, he e is a g owing in e es on pha macogene ics, because i
could p o ide impo an in o ma ion abou gene ic a ian s in he an icho eic me abolizing
enzymes and ecep o s, and, he e o e, help clinicians implemen pe sonalized medicine.
The aim o his s udy is o ca y ou a e iew o he a ailable publica ions and e idence
ela ed o he pha macogene ics o HD, wi h he objec i e o compiling all in o ma ion ha
may be use ul in op imizing d ug he apy in hese pa ien s.
2. Ma e ials and Me hods
This sys ema ic e iew was conduc ed acco ding o he p e e ed epo ing i ems o
sys ema ic e iews and me a-analyses (PRISMA) s a emen s [
10
]. The li e a u e sea ch
included he ollowing da abases: MEDLINE, Pha mGKB [
11
], EU Clinical T ials Regis e
and ClinicalT ials.go . The sea ch s a egy included simila keywo ds in all da abases:
Hun ing on, Hun ing on’s disease, polymo phism (o SNP, o single nucleo ide poly-
mo phism o pha macogene ics o pha macogenomics); and he d ugs included in he
In e na ional Guidelines o he T ea men o Hun ing on’s Disease [
12
]: monoamine
anspo e ype 2 (VMAT2) inhibi o s ( e abenazine, deu e abenazine), i s -gene a ion
an ipsycho ic d ugs (halope idol), second-gene a ion an ipsycho ic d ugs (a ipip azole,
olanzapine, clozapine, ispe idone), selec i e se o onin eup ake inhibi o s (ci alop am,
esci alop am, luoxe ine, pa oxe ine, se aline), and benzodiazepines (diazepam, e izolam,
quazepam, desme hylclobazam, alp azolam, midazolam, clonazepam, lo azepam). Two
independen e iewe s (XGG and MSR) indi idually sc eened all he i les and abs ac s
and e alua ed each a icle. Disag eemen s we e esol ed by consensus and in conco dance
wi h a hi d e iewe (EC), when necessa y. S udies ha ul illed he ollowing c i e ia
we e included: (1) s udies wi h pha macogene ic bioma ke s analysed in diagnosed HD
pa ien s’ coho s, in which any o he ollowing we e p esc ibed: e abenazine, deu e a-
benazine, halope idol, chlo p omazine, pluphenazine, a ipip azole, olanzapine, que iap-
ine, ispe idone, ci alop am, esci alop am, luoxe ine, pa oxe ine, se aline, ami ip y-
line, desip amine, doxepin, imip amine, no ip yline, imip amine, diazepam, e izolam,
J. Pe s. Med. 2023,13, 385 3 o 18
quazepam, desme hylclobazam, alp azolam, midazolam, clonazepam, lo azepam, and
(2) s udies epo ing e icacy and ou come a iables. The Eu opean Medicines Agency
(EMA) and U.S. Food and D ug Adminis a ion (FDA) d ug labels we e e iewed in
sea ch o any ecommenda ions based on pa ien geno ype. Addi ionally, he mos ecen
guidelines and publica ions by he Clinical Pha macogene ics Implemen a ion Conso ium
(CPIC) and Du ch Pha macogene ics Wo king G oup (DPWG) we e also e iewed o any
d ug-gene ecommenda ions.
3. Pha macogene ics o he D ugs Used in he Managemen o Cho ea in
Hun ing on’s Disease
The pha macologic ea men o pa ien s su e ing om cho ea is indica ed only in
hose cases in which his symp om in e e es wi h he pa ien ’s unc ionali y [
4
]. Con olling
his symp om can educe he isk o alls o choking and imp o e he pa ien
´
s speech and
es , bu he medica ions used can induce pa kinsonism, dep ession and suicidal hough s.
Fo his eason, he decision o s a ea men mus always be based on a comp ehensi e
isk–bene i analysis. This a icle will e iew he pha macogene ic da a o he d ugs used
acco ding o he ea men algo i hm o cho ea in HD (Figu e 1) [13].
3.1. Monoamine T anspo e Type 2 (VMAT2) Inhibi o s (Te abenazine and Deu e abenazine)
Vesicula monoamine anspo e ype 2 (VMAT2) inhibi o s a e usually conside ed
he d ugs o choice o he managemen o cho ea, excep o pa ien s wi h dep ession, due
o he isk o wo sening dep ession and suicidali y.
Te abenazine is he o iginally comme cialized molecule, and in 2017 he FDA ap-
p o ed Deu e abenazine (Aus edo
®
), which is an iso opic isome o e abenazine. By
inco po a ing deu e ium ins ead o hyd ogen in six posi ions, he molecule shows slowe
me abolism, which allows o ewe daily adminis a ions [
14
]. Deu e abenazine is cu -
en ly no comme cialized in Eu ope and o he coun ies.
D owsiness, seda ion, ex apy amidal symp oms, dep ession, aka hisia, and pa kin-
sonism a e common side e ec s o VMAT2 inhibi o s. The e is also an inc eased isk o
suicidali y, QT p olonga ion, and neu olep ic malignan synd ome [15,16].
Bo h e abenazine and deu e abenazine a e apidly ans o med by ca bonyl educ-
ase o hei espec i e nondeu e a ed and deu e a ed me aboli es,
α
-dihyd o e abenazine
(
α
-HTBZ) and
β
-dihyd o e abenazine (
β
-HTBZ), ha bind selec i ely o VMAT2, hus
inhibi ing monoamine anspo o he in e io o p esynap ic neu onal esicles, e ec i ely
deple ing dopamine and o he monoamines in he cen al ne ous sys em.
α
-HTBZ and
β
-HTBZ a e mainly me abolized by cy och ome P450 (CYP) 2D6, wi h
mino con ibu ions om CYP1A2 and CYP3A4/5 [17].
CYP2D6 is an enzyme ha pa icipa es in he me abolism o a ound a qua e o he
d ugs used in he apeu ics [
18
]. The CYP2D6 gene is highly polymo phic wi h gene ic a i-
an s ha ha e subs an ial unc ional consequences, including educed (e.g.,*9,*10,*17,*41)
and non- unc ional alleles (e.g., *3,*4,*5,*6), gene dele ions, and duplica ions [
19
]. Based on
hei capaci y o me abolize CYP2D6 subs a es, pa ien s can be ca ego ized as ul a apid
me abolize s (UM), no mal me abolize s (NM), in e media e me abolize s (IM), and poo
me abolize s (PM) [
20
]. Pa ien me abolic abili y can also be a ec ed by he concomi an
adminis a ion o s ong enzyme inhibi o s, such as pa oxe ine, luoxe ine, quinidine, o
bup opion [21].
Pa ien s wi h impai ed CYP2D6 me abolism ha e highe plasma concen a ions o i s
subs a es due o accumula ion, and his can lead o a ia ions in esponse and/o a highe
isk o d ug-induced ad e se e en s.
The ecommended ini ial dose o e abenazine is 25 mg h ee imes a day, and i can be
inc eased e e y 3 o 4 days, a a a e o 25 mg/day, up o a maximum o 200 mg/day, o i he
ole ance limi is eached due o undesi able e ec s. CYP2D6 geno yping is equi ed by he
FDA and he Swiss Agency o The apeu ic P oduc s (Swissmedic). Bo h d ug labels s a e
ha pa ien s equi ing doses abo e 50 mg pe day o e abenazine should be geno yped
J. Pe s. Med. 2023,13, 385 4 o 18
due o he inc eased isk o ad e se e en s in pa ien s wi h impai ed me abolism. The US
d ug label also s a es ha pa ien s wi h a CYP2D6 PM pheno ype should no exceed a o al
daily dose o 50 mg, wi h a maximum o 25 mg adminis e ed pe dose. The ecommended
dose o CYP2D6 IM and NM is 100 mg, wi h a maximum single dose o 37.5 mg.
J. Pe s. Med. 2022, 12, x FOR PEER REVIEW 4 o 20
Figu e 1. T ea men algo i hm o cho ea in HD, adap ed om Suchowe sky e al.’s Hun ing on Dis-
ease: Managemen [13].
Figu e 1.
T ea men algo i hm o cho ea in HD, adap ed om Suchowe sky e al.’s Hun ing on
Disease: Managemen [13].
J. Pe s. Med. 2023,13, 385 5 o 18
The Eu opean Summa y o P oduc Cha ac e is ics only s a es ha e abenazine
me aboli es a e subs a es o CYP2D6 and ha Dosing, he e o e, may be in luenced by he
pa ien
´
s CYP2D6 me abolic s a us and he concomi an adminis a ion o CYP2D6 po en
inhibi o s [22].
Only one s udy has e alua ed he clinical implica ions o CYP2D6 pha macogene ic
p o iling in pa ien s ea ed wi h e abenazine [
23
]. CYP2D6 geno yping was pe o med
in 127 pa ien s ea ed wi h e abenazine, and he du a ion o i a ion o a s able dose,
o al daily dose, esponse a ing sco es, and ad e se e en s we e e ospec i ely analysed.
Ti a ion ime was signi ican ly longe in UM han in NM, IM and PM (8 weeks s. 3.3, 4.4,
and 3 espec i ely p< 0.01) and a e age s able daily doses we e highe . When compa ed o
NM, IM had a wo se clinical esponse (p= 0.013). No s a is ically signi ican di e ences in
he incidence o ad e se e en s we e de ec ed acco ding o me abolic s a us. These indings
led he au ho s o doub he ad ice on CYP2D6 geno yping ha is cu en ly p o ided.
Deu e abenazine is indica ed o he ea men o cho ea associa ed wi h Hun ing on’s
disease and a di e dyskinesia in he US. The ecommended s a ing dose is 6 mg once
daily, and i can be up- i a ed a weekly in e als by 6 mg pe day, up o a maximum
ecommended daily dosage o 48 mg (24 mg wice daily). The FDA d ug label s a es ha
in pa ien s ca ying he CYP2D6 PM pheno ype o in pa ien s ecei ing s ong CYP2D6
inhibi o s (e.g., quinidine, an idep essan s such as pa oxe ine, luoxe ine, and bup opion),
he o al daily dosage o deu e abenazine should no exceed 36 mg (maximum single dose
o 18 mg).
No clinical consensus guidelines a e cu en ly a ailable o geno yping o CYP2D6
and dose adjus men o e abenazine and deu e abenazine.
3.2. Second-Gene a ion An ipsycho ic D ugs (A ipip azole, Olanzapine, and Rispe idone)
An ipsycho ics a e used o he ea men o cho ea in hose pa ien s o whom VMAT2
inhibi o s a e con aindica ed (e.g., dep ession) o when hey ail o con ol symp oms and
can also help wi h HD psychia ic symp oms [
24
–
27
]. Second gene a ion an ipsycho ics ac
by blocking se o onin ecep o s, especially 5-HT2A, as well as D2 dopamine ecep o s, and
a e usually p e e ed o i s -gene a ion d ugs, which a e discussed in he nex pa ag aph,
because o hei lowe isk o ex apy amidal e ec s.
CYP2D6 is he main enzyme in ol ed in he me abolism o a ipip azole and ispe i-
done, al hough o he CYP450 enzymes, such as CYP3A4, also play a ole [
28
,
29
]. A ailable
e idence and cu en pha macogene ic ecommenda ions o hese d ugs a e mainly e-
la ed o CYP2D6 me abolize s a us, al hough s udies ha e been ca ied ou in psychia ic
popula ions and no speci ically in HD pa ien s.
Al hough he e is subs an ial e idence linking a ipip azole and i s ac i e me aboli e,
dehyd oa ipip azole, o he CYP2D6 pheno ype, no di ec impac on clinical ou comes has
been es ablished [
30
–
33
]. Hence, dosing ecommenda ions a e based mainly on a ailable
pha macokine ic s udies.
Bo h he Ame ican and Eu opean d ug agencies conside ha dose adjus men s a e
necessa y o CYP2D6 PMs aking a ipip azole. A 50% dose educ ion is ecommended
o he o al p esen a ions, and he s a ing and main enance dose o he in amuscula
p olonged elease injec able should be 300 mg (ins ead o 400 mg) in known CYP2D6 PM,
and his should be u he educed o 200 mg i s ong CYP3A4 inhibi o s a e concomi an ly
used [
34
,
35
]. The DPWG also ecommends educing he maximum dose o a ipip azole
o 68–75% o pa ien s ca ying CYP2D6 PM pheno ypes [
36
]. The DPWG sugges s ha
geno yping pa ien s be o e s a ing a ipip azole may be help ul in p e en ing ad e se
ou comes. Geno yping can be conside ed on an indi idual pa ien basis. Howe e , he
DPWG ad ises ollowing he gene-d ug guideline i he geno ype is a ailable [
36
]. Va i-
an s in DRD2,ANKK1 and DAOA genes ha e been associa ed wi h a ipip azole e icacy
in schizoph enic pa ien s [
37
–
40
]. Howe e , he e idence is s ill insu icien o p o ide
speci ic ecommenda ions.

J. Pe s. Med. 2023,13, 385 6 o 18
S ong e idence (le el 1A) links he CYP2D6 geno ype, and ispe idone clea ance and
plasma concen a ions [
41
,
42
]. As in he case o a ipip azole, dose adjus men ecommen-
da ions a e mainly based on his es ablished pha macokine ic ela ionship [36].
In hei 2020 guideline upda e, he DPWG ca ego ized CYP2D6 geno yping as po en-
ially bene icial be o e he ini ia ion o ispe idone ea men , o he p e en ion o side
e ec s and o d ug e ec i eness [
43
]. When geno ype is a ailable, i is ecommended o
educe he dose o CYP2D6 PM and use an al e na i e d ug, o o i a e he dose acco ding
o he maximum dose o he ac i e me aboli e o CYP2D6 UM [43].
Va ian s in se e al pha macogenes, including ABCB1, AKT1, CCL2 and COMT, ha e
been associa ed wi h he ispe idone esponse, bu no s ong ela ionship has been es ab-
lished ye [44–47].
Glucu onida ion is he main me abolic pa hway o olanzapine, bu CYP1A2, CYP2D6
and CYP3A4 also play a ole [
48
]. No ecommenda ions on d ug labels and/o pha maco-
gene ic guidelines a e a ailable o olanzapine. Howe e , pa ien s using lu oxamine o
o he CYP1A2 inhibi o s should be gi en olanzapine a a educed s a ing dose, conside ing
CYP1A2 is highly in ol ed in i s me abolism. A ecen sys ema ic e iew showed ha
mul iple s udies ound s ong e idence linking DRD2 Taq1A ( s1800497) *A1, LEP-2548
( s7799039) G and CYP1A2*1F alleles o a ia ions in he e icacy and sa e y o olanzap-
ine. Wi h a easonable deg ee o e idence, DRD2-141 ( s1799732) Ins, A-241G ( s1799978)
G, DRD3 Se 9Gly ( s6280) Gly, HTR2A s7997012 A, ABCB1 C3435T ( s1045642) T and
G2677T/A ( s2032582) T and UGT1A4*3 alleles we e ela ed o sa e y, e icacy, and/o
pha macokine ic a iabili y [
49
]. Mo eo e , ca ie s o UGT1A4 142T > G we e shown o
ha e a dec ease in daily dose-co ec ed plasma concen a ions o 25% in schizoph enic
pa ien s [50].
Rela ing o ad e se e en s, polymo phisms in DRD2 ha e been associa ed wi h
an ipsycho ic- ela ed hype p olac inemia o weigh gain [
51
,
52
]. Cannabinoid ecep o 1
(CNR1) and lep in gene (LEP) may also be associa ed wi h weigh gain in schizoph enia pa-
ien s ea ed wi h i s and second gene a ion an ipsycho ics [
53
,
54
]. The s udy pe o med
by Kolle e al. desc ibed ha sho - e m ea men wi h a ipip azole and olanzapine had a
signi ican in luence on me abolic pa ame e s, such as p olac in le els, highe C-pep ide,
glucose and insulin le els, among o he s, and ha hese we e ela ed o polymo phisms
in DRD3, CYP3A, COMT, UGT1A1, APOC3 and HTR2A [55]. Once mo e, he e is a lack o
s udies pe o med on HD pa ien s.
3.3. Fi s -Gene a ion An ipsycho ic D ugs (Halope idol)
Fi s -gene a ion an ipsycho ics a e elega ed o hose cases o se e e cho ea un espon-
si e o VMAT inhibi o s and second-gene a ion an ipsycho ics, due o hei highe po ency.
Howe e , hey ha e a highe isk o side e ec s, such as seda ion, dys onia, pa kinsonism,
hypo ension, o aka hisia.
Halope idol is p obably he mos commonly used op ion, in doses om 0.5 mg o
10 mg pe day [
56
]. I is mainly gluco onized (50–60%) by UGT2B7, UGT1A9, and UGT1A4,
bu a ound 25% o he adminis e ed dose unde goes educ ion by CYP3A4 (main enzyme)
and CYP2D6 [
57
,
58
]. Despi e i s seconda y ole, se e al s udies ha e p o en he ela ionship
be ween CYP2D6 me abolize s a us and halope idol plasma le els [59–61].
Fo his eason, he DPWG ecommends using 60% o he s anda d dose o halope idol
o CYP2D6 PM and 1.5 imes he s anda d dose o CYP2D6 UM, o selec ing an al e na i e
d ug [62].
3.4. O he D ugs Used in he Managemen o Cho ea
Benzodiazepines, such as clonazepam and lo azepam, may be used in he sho
e m o dec ease se e e episodes o cho ea, bu hei use is no ecommended in he
long e m. The polymo phic CYP2C19 and CYP3A4/5 enzymes p ima ily o pa ially
me abolize a numbe o benzodiazepines. CYP2C19 polymo phism has been shown o
a ec he pha macokine ics o diazepam, e izolam, quazepam, and desme hylclobazam [
63
].
J. Pe s. Med. 2023,13, 385 7 o 18
Diazepam is me abolized by CYP2C19 and CYP3A4. A dose educ ion o 50% and 20–30%
may be adequa e o CYP2C19 PM and IM, espec i ely [
64
]. On he con a y, UM may
bene i om a dose inc ease o 25–50% [
64
]. The me abolism o clobazam in ol es CYP2C19
and CYP3A4. The d ug label o clobazam includes dosage modi ica ions based on he
pheno ype o CYP2C19: PMs should s a wi h a dose o 5 mg/day and i a e he dose
g adually based on weigh , wi h a maximum dose o hal he ecommended dose [
64
].
Signi ican CYP3A4 me abolism occu s wi h midazolam, clonazepam, alp azolam and
iazolam. The e a e no published guidelines a his ime since li le esea ch has been
done on he po en ial e ec s o he CYP3A4 pheno ype on exposu e and sa e y [
64
]. The e
is e idence ha e izolam and desme hylclobazam oxici y o side e ec s a e caused by
CYP2C19 de iciency [63].
O he d ugs es ed o he managemen o cho ea in HD include cannabinoids (cannabid-
iol, nabilone), aman adine and an icon ulsan s, such as le e i ace am o opi ama e, bu
a ailable e idence is s ill e y limi ed [13].
4. Pha macogene ics o he D ugs Used in he Managemen o Dep ession, I i abili y,
Apa hy, Anxie y and Psychosis in Hun ing on’s Disease
Acco ding o es ima es, be ween 33 and 76% o HD pa ien s will expe ience a psycho-
logical p oblem a some poin in hei li e imes. These diso de s can de elop a a ious
s ages o he disease cou se and de e io a e o e ime as he disease wo sens [
65
,
66
]. Ad-
di ionally, i is expec ed ha an as ounding 98% o HD pa ien s wi h mo o symp oms
will expe ience a leas one psychological symp om o dis u bance [
67
]. Impo an ly, p e-
symp oma ic HD gene ca ie s ha e a highe p e alence o dep ession, which can appea
up o en yea s be o e mo o symp oms [
68
]. In addi ion o ha ing a signi ican nega i e
in luence on he pa ien ’s quali y o li e and au onomy, psychia ic symp oms may also
ha e a majo de imen al impac on amily membe s and o he ca egi e s, and can lead o
unc ional impai men [
69
]. These psychological aspec s, a he han he mobili y diso de ,
a e hough o be he mos de as a ing o HD pa ien s, and equen ly lead o hospi aliza-
ion and a e he bes p edic o s o he equi emen o esiden ial ca e [
70
]. The e o e, he
managemen o psychia ic symp oms, such as dep ession, anxie y, and psychosis, is o
g ea ele ance o HD pa ien s.
One o he mos p e alen psychia ic symp oms in HD is dep ession, which causes
a de imen al e ec on he quali y o li e. As a esul , i is impo an o be p oac i e in
ecognizing and ea ing dep ession h oughou each phase o he disease.
Ea ly de ec ion o mood changes may be possible wi h psycho he apy and cogni i e
beha iou al he apy. I g ade B dep ession occu s in HD pa ien s [
71
], an an idep essan
may be ecommended [
12
]. A selec i e se o onin eup ake inhibi o (SSRI) o a se o onin
no ad enaline eup ake inhibi o (SNRI) is ad ised. In he e en ha sleep is dis u bed,
mianse in o mi azapine a e o he al e na i es [12].
CPIC guidelines o SSRI include impo an in o ma ion o CYP2D6 and CYP2C19
geno ypes and dosing o ci alop am, esci alop am, lu oxamine, pa oxe ine and se a-
line [
72
]. Table 1summa izes he dosing ecommenda ions o pa oxe ine and lu oxam-
ine based on CYP2D6 pheno ype, and ci alop am, esci alop am and se aline based on
CYP2C19 pheno ype [
72
]. Acco ding o ou knowledge, he e is no cu en s udy ha e al-
ua es he esponse o SSRI an idep essan s in HD pa ien s, based on hei pha macogene ic
ea u es. Fu he esea ch is wa an ed.
When he use o a SNRI is p e e ed, enla axine, des enla axine o duloxe ine can be
used. No clinical guideline ecommends including pha macogene ic in o ma ion o guide
hei ea men ; howe e , some impo an in o ma ion should be aken in o accoun .
Humans highly me abolize enla axine, exc e ing be ween 1 and 10% o he adminis-
e ed dose o he unmodi ied d ug in he u ine [
73
]. The main pa hway o enla axine’s
i s pass me abolism is deme hyla ion o O-desme hyl enla axine [
74
]. CYP2D6 is he
p ima y enzyme in ol ed in O-desme hyl enla axine p oduc ion [
75
]. Des enla axine
succina e, a sal o O-desme hyl enla axine, is an app o ed d ug ha is also comme cial-
J. Pe s. Med. 2023,13, 385 8 o 18
ized. Addi ionally, CYP3A4 and CYP2C19 ca alyse he N-deme hyla ion o enla axine
o N-desme hyl enla axine, which is ypically a mino me abolic ou e [
76
]. CYP2D6
me abolize pheno ype has been demons a ed o ha e a clea impac on he pha macoki-
ne ics o enla axine, and s udies ha e ound a co ela ion be ween he CYP2D6 geno ype
and he me abolic a io o enla axine o O-desme hyl enla axine [
77
–
79
]. The DPWG
guideline ecommends selec ing an al e na i e o enla axine o educing he dose and
moni o ing he pa ien ’s plasma me aboli e le el o pa ien s wi h CYP2D6 PM and IM
pheno ypes [
36
,
80
]. Fo CYP2D6 UM, he ecommenda ion is o inc ease he dose o 150%
o selec an al e na i e o enla axine [36,80].
Table 1.
Dosing ecommenda ions o pa oxe ine, lu oxamine, ci alop am, esci alop am and se a-
line based on CYP2D6 o CYP2C19 pheno ype.
Pheno ype * Pa oxe ine Flu oxamine Ci alop am Esci alop am Se aline
UM
Conside al e na i e
d ug no
p edominan ly
me abolized by
CYP2D6.
No ecommenda ion.
Conside an
al e na i e d ug no
p edominan ly
me abolized by
CYP2C19.
Conside an
al e na i e d ug no
p edominan ly
me abolized by
CYP2C19.
I pa ien does no espond o
ecommended s a ing dose,
conside al e na i e d ug no
p edominan ly me abolized
by CYP2C19.
NM
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended s a ing dose.
IM
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended
s a ing dose.
Ini ia e he apy wi h
ecommended s a ing dose.
PM
Conside al e na i e
d ug no
p edominan ly
me abolized by
CYP2D6 o conside
a 50% educ ion o
ecommended
s a ing dose.
Conside al e na i e
d ug no
p edominan ly
me abolized by
CYP2D6 o conside
a 25–50% educ ion
o ecommended
s a ing dose.
Conside al e na i e
d ug no
p edominan ly
me abolized by
CYP2C19 o conside
a 50% educ ion o
ecommended
s a ing dose.
Conside al e na i e
d ug no
p edominan ly
me abolized by
CYP2C19 o conside
a 50% educ ion o
ecommended
s a ing dose.
Conside al e na i e d ug no
p edominan ly me abolized
by CYP2C19 o conside a
50% educ ion o
ecommended s a ing dose.
CYP2D6 * CYP2C19 *
* e e s o he pheno ype o ei he CYP2D6 o CYP2C19. Abb e ia ions: CYP2C19: cy och ome P450 amily 2
sub amily C membe 19; CYP2D6: cy och ome P450 amily 2 sub amily D membe 6; UM, ul a apid me abolize ;
NM: no mal me abolize ; IM: in e media e me abolize ; PM: poo me abolize . Adap ed om: Hicks e al. [72].
The e is a need o u he esea ch on he combined e ec o CYP2D6 and CYP2C19
on enla axine me abolism, since i has only been examined in s udies wi h small sample
sizes [
79
,
81
]. When e alua ing pha macogenomic da a o enla axine dose modi ica ions,
bo h CYP2D6 and CYP2C19 geno ypes should be aken in o accoun . This is due o
allelic a ian s in bo h CYP2D6 and CYP2C19 ha a ec he o e all concen a ion o he
ac i e subs ances enla axine and O-desme hyl enla axine [
79
]. Mo eo e , since CYP2C19
PM and UM pheno ypes a e p esen in mos popula ions, i is easonable o expec ha
hese may ha e an impac on enla axine me abolism, pa icula ly in CYP2D6 PM and IM
subjec s, in which he o ma ion o O-desme hyl enla axine is diminished [
74
]. In candida e
gene associa ion esea ch, he ABCB1 gene, which codes o he anspo e P-glycop o ein,
was ound o be ela ed o a ia ions in he clinical e icacy o P-glycop o ein subs a e
an idep essan s, like enla axine [82].
Only a ew candida e gene s udies in es iga e he in luence o a ian s in pha ma-
codynamic genes such as ca echol-O-me hyl ans e ase (COMT), se o onin ecep o 2A
(HTR2A), b ain-de i ed neu o ophic ac o (BDNF), and dopamine anspo e (SLC6A4),
on he a iabili y o ea men ou comes. No signi ican indings we e desc ibed o he
COMT and BDNF genes, bu an in luence o he HTR2A and SLC6A4 genes was obse ed.
Subjec s ca ying he G allele o he HTR2A s7997012 single nucleo ide polymo phism ex-
pe ience supe io ea men ou comes o e ime [
83
]. Mo eo e , he dopamine anspo e
SLC6A4 a iable numbe o andem epea s polymo phism in luenced he apid esponse o
an idep essan he apy (SSRI, icyclics, mi azapine and enla axine) [
84
]. Un o una ely,
J. Pe s. Med. 2023,13, 385 9 o 18
a cumula i e e ec o he a ia ions was no in es iga ed because each sepa a e s udy only
examined one gene. No ably, none o hese s udies we e conduc ed on HD pa ien s.
Al hough CYP1A2 and CYP2D6 a e men ioned on he FDA label as being in ol ed
in duloxe ine’s me abolism, he e is no pa icula ad ice based on hese speci ic enzymes’
me abolic pheno ype [
85
]. S ong CYP2D6 inhibi o s may change he concen a ions
o duloxe ine, acco ding o he FDA label, which also ad ises agains using hem [
85
].
Di e ences in CYP1A2 exp ession o ac i i y le els may accoun o highe duloxe ine
plasma concen a ions in non-smoke s and in women [
86
]. Fu he esea ch is wa an ed o
be e es ablish he in luence o CYP1A2 polymo phisms on enzyme ac i i y, and, he e o e,
duloxe ine e icacy in HD pa ien s.
Mi azapine is ex ensi ely me abolized in he li e by he isoenzymes CYP1A2,
CYP2D6 and CYP3A4 [
87
]. I is help ul o hose wi h dep ession who also ha e symp oms
o anxie y and sleep dis u bances [
87
]. An impac o CYP2D6 geno ype on s eady-s a e
se um concen a ions o he enan iome s o mi azapine and i s me aboli es was ound
in he s udy by Lind e al. [
88
]. Howe e , he small p opo ion o CYP2D6 UM and PM
ound p ecludes us om d awing i m conclusions. A s udy pe o med in 45 pa ien s wi h
majo dep essi e episodes ound ha in non-smoke s, he plasma le els o mi azapine
and i s me aboli es depended on he CYP2D6 geno ype [
89
]. The e o e, he in luence o
he CYP2D6 geno ype appea s o be hidden by he ele a ed CYP1A2 ac i i y obse ed in
smoke s [89].
An ex emely ypical HD symp om is i i abili y. Impa ience and a p opensi y o
become upse a he sligh es p o oca ion a e he de ining ai s o his changeable diso de .
Impulsi i y a ou s o e low and lack o con ol, which can esul in hos ile conduc
owa d onesel o o he s and, in excep ional cases, c iminal ac ion [
12
]. This symp om
may be b ough on by he pa ien ’s annoyance o e he signi ican loss o his abili ies,
di icul ies in exp essing himsel , neu ological/psychological i edness b ough on by
he la e , and he pa ien ’s eelings o us a ion [
12
]. Po en ial en i onmen al ac o s
unde lying he pa ien ’s annoyance and i i abili y should be in es iga ed be o e beginning
pha maceu ical ea men [
12
]. SSRIs a e i s -line ea men s o i i abili y, bu in o de o
be success ul, hey may need o be aken a o close o he maximum dosage [
12
]. When
sleep dis u bances a e p esen , combined he apy wi h mi azapine may be bene icial o
i i able pa ien s who do no espond well o an SSRI alone [
12
]. A neu olep ic is ad ised
as he i s line o ea men o pa ien s who exhibi agg essi e conduc [
12
]. SSRIs and
mi azapine pha macogene ics ha e al eady been discussed. Rega ding neu olep ics, one
o he mos widely used is halope idol, which has he apy ecommenda ions based on
CYP2D6 geno ype, as discussed abo e.
Le y and Cze necki’s de ini ion o apa hy as “a quan i a i e loss in goal-di ec ed
beha iou ” [
90
], s a es ha i shows up clinically as a decline in in e es , spon anei y,
mo i a ion, and d i e. I is he mos p e alen psychological and beha iou al symp om
o HD, pa icula ly in he middle and la e s ages, and i signi ican ly educes daily li ing
ac i i ies. Apa hy and i i a ion a e wo sides o he same cogni i e and psychological
symp om [
91
]. Apa hy may in ensi y wi h dep ession, and a SSRI is hen ad isable.
Mo eo e , i is ecommended o p e en unnecessa y p esc ip ions o seda i es o o limi
hei dosage, as hey may cause apa hy. In his ega d, pha macogene ic in o ma ion migh
be use ul o guide he ea men .
In HD, anxie y—de ined as he uneasy sensa ion o app ehension o wo y abou
some hing ha has happened o migh ha e happened—is p e alen . In addi ion o being
co ela ed wi h amily, social, and economic p oblems, as well as he bu den o he pa ien ’s
disease, anxie y is linked o he o he symp oms (mo o and cogni i e), as he pa ien
is ne ous due o he loss o impo an unc ions [
12
]. Anxie y is linked o i i a ion,
diminished quali y o li e, pain, sickness belie s, coping, and dep ession. SRI o SNRI a e
i s -line ea men s o anxie y, especially when i coexis s wi h dep ession. Anxioly ics
ha a e p esc ibed on demand may be ad an ageous, bu ca e mus be aken because
o he po en ial o alls o exace ba ion o exis ing condi ions. When o he he apies o
J. Pe s. Med. 2023,13, 385 16 o 18
32.
an de Weide, K.; an de Weide, J. The In luence o he CYP3A4*22 Polymo phism and CYP2D6 Polymo phisms on Se um
Concen a ions o A ipip azole, Halope idol, Pimozide, and Rispe idone in Psychia ic Pa ien s. J. Clin. Psychopha macol.
2015
,
35, 228–236. [C ossRe ]
33.
Lisbe h, P.; Vincen , H.; K is o , M.; Be na d, S.; Manuel, M.; Hugo, N. Geno ype and Co-Medica ion Dependen CYP2D6
Me abolic Ac i i y: E ec s on Se um Concen a ions o A ipip azole, Halope idol, Rispe idone, Palipe idone and Zuclopen hixol.
Eu . J. Clin. Pha macol. 2016,72, 175–184. [C ossRe ]
34.
U.S. Food & D ug Adminis a ion (FDA). D ugs FDA: FDA-App o ed D ugs. A ailable online: h ps://www.accessda a. da.
go /sc ip s/cde /da /index.c m?e en =o e iew.p ocess& a applno=021436 (accessed on 11 Janua y 2023).
35.
Eu opean Medicines Agency (EMA). Abili y Main ena. A ailable online: h ps://www.ema.eu opa.eu/en/medicines/human/
epa /abili y-main ena (accessed on 11 Janua y 2023).
36.
Swen, J.J.; Nijenhuis, M.; de Boe , A.; G andia, L.; Mai land- an de Zee, A.H.; Mulde , H.; Rongen, G.A.P.J.M.;
an Schaik, R.H.N.
;
Schalekamp, T.; Touw, D.J.; e al. Pha macogene ics: F om Bench o By e—An Upda e o Guidelines. Clin. Pha macol. The .
2011
,
89, 662–673. [C ossRe ]
37.
Shen, Y.-C.; Chen, S.-F.; Chen, C.-H.; Lin, C.C.H.; Chen, S.-J.; Chen, Y.-J.; Luu, S.-U. E ec s o DRD2/ANKK1 Gene Va ia ions and
Clinical Fac o s on A ipip azole E icacy in Schizoph enic Pa ien s. J. Psychia . Res. 2009,43, 600–606. [C ossRe ]
38.
Kwon, J.S.; Kim, E.; Kang, D.-H.; Choi, J.S.; Yu, K.-S.; Jang, I.-J.; Shin, S.-G. APLUS s udy g oup Taq1A Polymo phism in
he Dopamine D2 Recep o Gene as a P edic o o Clinical Response o A ipip azole. Eu . Neu opsychopha macol. J. Eu . Coll.
Neu opsychopha macol. 2008,18, 897–907. [C ossRe ]
39.
Kim, E.; Kwon, J.S.; Shin, Y.-W.; Lee, J.S.; Kang, W.J.; Jo, H.J.; Lee, J.-M.; Yu, K.-S.; Kang, D.-H.; Cho, J.-Y.; e al. Taq1A
Polymo phism in he Dopamine D2 Recep o Gene P edic s B ain Me abolic Response o A ipip azole in Heal hy Male Volun ee s.
Pha macogene . Genom. 2008,18, 91–97. [C ossRe ]
40.
Pae, C.-U.; Chiesa, A.; Se e i, A. In luence o DAOA Gene Va ian s on An ipsycho ic Response a e Swi ch o A ipip azole.
Psychia y Res. 2010,178, 430–432. [C ossRe ]
41.
Choong, E.; Pola i, A.; Kamdem, R.H.; Ge asoni, N.; Spisla, C.; Jaquenoud Si o , E.; Bickel, G.G.; Bondol i, G.; Conus, P.;
Eap, C.B.
Pha macogene ic S udy on Rispe idone Long-Ac ing Injec ion: In luence o Cy och ome P450 2D6 and P egnane X Recep o on
Rispe idone Exposu e and D ug-Induced Side-E ec s. J. Clin. Psychopha macol. 2013,33, 289–298. [C ossRe ]
42.
Wang, L.; Yu, L.; Zhang, A.-P.; Fang, C.; Du, J.; Gu, N.-F.; Qin, S.-Y.; Feng, G.-Y.; Li, X.-W.; Xing, Q.-H.; e al. Se um P olac in
Le els, Plasma Rispe idone Le els, Polymo phism o Cy och ome P450 2D6 and Clinical Response in Pa ien s wi h Schizoph enia.
J. Psychopha macol. Ox . Engl. 2007,21, 837–842. [C ossRe ]
43.
Du ch Pha macogene ics Wo king G oup (DPWG) Risk Analysis Documen o Rispe idone and CYP2D6. A ailable online:
h ps://www.g-s andaa d.nl/ isicoanalyse/b0001536.pd (accessed on 11 Janua y 2023).
44.
Co eia, C.T.; Almeida, J.P.; San os, P.E.; Sequei a, A.F.; Ma ques, C.E.; Miguel, T.S.; Ab eu, R.L.; Oli ei a, G.G.; Vicen e, A.M.
Pha macogene ics o Rispe idone The apy in Au ism: Associa ion Analysis o Eigh Candida e Genes wi h D ug E icacy and
Ad e se D ug Reac ions. Pha m. J. 2010,10, 418–430. [C ossRe ]
45.
Ikeda, M.; Yamanouchi, Y.; Kinoshi a, Y.; Ki ajima, T.; Yoshimu a, R.; Hashimo o, S.; O’Dono an, M.C.; Nakamu a, J.;
Ozaki, N.
;
Iwa a, N. Va ian s o Dopamine and Se o onin Candida e Genes as P edic o s o Response o Rispe idone T ea men in Fi s -
Episode Schizoph enia. Pha macogenomics 2008,9, 1437–1443. [C ossRe ]
46.
Xiong, Y.; Wei, Z.; Huo, R.; Wu, X.; Shen, L.; Li, Y.; Gong, X.; Wu, Z.; Feng, G.; Li, W.; e al. A Pha macogene ic S udy o
Rispe idone on Chemokine (C-C Mo i ) Ligand 2 (CCL2) in Chinese Han Schizoph enia Pa ien s. P og. Neu opsychopha macol.
Biol. Psychia y 2014,51, 153–158. [C ossRe ]
47.
Zhao, Q.-Z.; Liu, B.-C.; Zhang, J.; Wang, L.; Li, X.-W.; Wang, Y.; Ji, J.; Yang, F.-P.; Wan, C.-L.; Xu, Y.-F.; e al. Associa ion be ween a
COMT Polymo phism and Clinical Response o Rispe idone T ea men : A Pha macogene ic S udy. Psychia . Gene .
2012
,22,
298–299. [C ossRe ]
48.
U ichuk, L.; P io , T.I.; Du sun, S.; Bake , G. Me abolism o A ypical An ipsycho ics: In ol emen o Cy och ome P450 Enzymes
and Rele ance o D ug-D ug In e ac ions. Cu . D ug Me ab. 2008,9, 410–418. [C ossRe ]
49.
Zubiau , P.; So ia-Chaca egui, P.; Villapalos-Ga cía, G.; Go dillo-Pe domo, J.J.; Abad-San os, F. The Pha macogene ics o
T ea men wi h Olanzapine. Pha macogenomics 2021,22, 939–958. [C ossRe ] [PubMed]
50.
Gho bi, R.; Mannheime , B.; Aklillu, E.; Suda, A.; Be ilsson, L.; Eliasson, E.; Osby, U. Ca ie s o he UGT1A4 142T>G Gene
Va ian A e P edisposed o Reduced Olanzapine Exposu e–an Impac Simila o Male Gende o Smoking in Schizoph enic
Pa ien s. Eu . J. Clin. Pha macol. 2010,66, 465–474. [C ossRe ]
51.
Young, R.M.; Law o d, B.R.; Ba nes, M.; Bu on, S.C.; Ri chie, T.; Wa d, W.K.; Noble, E.P. P olac in Le els in An ipsycho ic
T ea men o Pa ien s wi h Schizoph enia Ca ying he DRD2*A1 Allele. B . J. Psychia y J. Men . Sci.
2004
,185, 147–151.
[C ossRe ]
52.
Hong, C.-J.; Liou, Y.-J.; Bai, Y.M.; Chen, T.-T.; Wang, Y.-C.; Tsai, S.-J. Dopamine Recep o D2 Gene Is Associa ed wi h Weigh
Gain in Schizoph enic Pa ien s unde Long-Te m A ypical An ipsycho ic T ea men . Pha macogene . Genom.
2010
,20, 359–366.
[C ossRe ]
53.
Tiwa i, A.K.; Zai, C.C.; Likhodi, O.; Liske , A.; Singh, D.; Souza, R.P.; Ba a, P.; Zaidi, S.H.E.; Chen, S.; Liu, F.; e al. A
Common Polymo phism in he Cannabinoid Recep o 1 (CNR1) Gene Is Associa ed wi h An ipsycho ic-Induced Weigh Gain in
Schizoph enia. Neu opsychopha macol. O . Publ. Am. Coll. Neu opsychopha macol. 2010,35, 1315–1324. [C ossRe ] [PubMed]

J. Pe s. Med. 2023,13, 385 17 o 18
54.
Cala ge, C.A.; Elling od, V.L.; Zimme man, B.; Acion, L.; Si i z, W.I.; Schlech e, J.A. Lep in Gene -2548G/A Va ian s P edic
Rispe idone-Associa ed Weigh Gain in Child en and Adolescen s. Psychia . Gene . 2009,19, 320–327. [C ossRe ]
55.
Kolle , D.; Almena a, S.; Mejía, G.; Saiz-Rod íguez, M.; Zubiau , P.; Román, M.; Ochoa, D.; Na a es-Gómez, M.; San os-Molina, E.;
Pin os-Sánchez, E.; e al. Me abolic E ec s o A ipip azole and Olanzapine Mul iple-Dose T ea men in a Randomised C osso e
Clinical T ial in Heal hy Volun ee s: Associa ion wi h Pha macogene ics. Ad . The . 2021,38, 1035–1054. [C ossRe ]
56.
Wheelock, V. The Mo o Diso de . In A Physician’s Guide o he Managemen o Hun ing on’s Disease, 3 d ed.; Nance, M.,
Paulsen, J.S.
,
Rosenbla , A., Wheelock, V., Eds.; Hun ing on’s Disease Socie y o Ame ica: New Yo k, NY, USA, 2011.
57.
Ka o, Y.; Nakajima, M.; Oda, S.; Fukami, T.; Yokoi, T. Human UDP-Glucu onosyl ans e ase Iso o ms In ol ed in Halope idol
Glucu onida ion and Quan i a i e Es ima ion o Thei Con ibu ion. D ug Me ab. Dispos. Biol. Fa e Chem.
2012
,40, 240–248.
[C ossRe ]
58. Kudo, S.; Ishizaki, T. Pha macokine ics o Halope idol: An Upda e. Clin. Pha macokine . 1999,37, 435–456. [C ossRe ]
59.
Mu ay, M. Role o CYP Pha macogene ics and D ug-D ug In e ac ions in he E icacy and Sa e y o A ypical and O he
An ipsycho ic Agen s. J. Pha m. Pha macol. 2006,58, 871–885. [C ossRe ]
60.
Oha a, K.; Tanabu, S.; Yoshida, K.; Ishibashi, K.; Ikemo o, K.; Shibuya, H. E ec s o Smoking and Cy och ome P450 2D6*10 Allele
on he Plasma Halope idol Concen a ion/Dose Ra io. P og. Neu opsychopha macol. Biol. Psychia y
2003
,27, 945–949. [C ossRe ]
61.
Someya, T.; Shimoda, K.; Suzuki, Y.; Sa o, S.; Kawashima, Y.; Hi okane, G.; Mo i a, S.; Yokono, A.; Takahashi, S. E ec o CYP2D6
Geno ypes on he Me abolism o Halope idol in a Japanese Psychia ic Popula ion. Neu opsychopha macol. O . Publ. Am. Coll.
Neu opsychopha macol. 2003,28, 1501–1505. [C ossRe ]
62.
Du ch Pha macogene ics Wo king G oup (DPWG) Risk Assessmen . A ailable online: h ps://api.pha mgkb.o g/ 1/download/
ile/a achmen /dpwg_may_2021.pd (accessed on 11 Janua y 2023).
63.
Fukasawa, T.; Suzuki, A.; O ani, K. E ec s o Gene ic Polymo phism o Cy och ome P450 Enzymes on he Pha macokine ics o
Benzodiazepines. J. Clin. Pha m. The . 2007,32, 333–341. [C ossRe ]
64.
Zubiau , P.; Abad-San os, F. Use o Pha macogene ics o Benzodiazepine P esc ip ion: S a e o he A and Expec a ions.
Pha macogenomics 2022,23, 949–952. [C ossRe ]
65.
Epping, E.A.; Kim, J.-I.; C au u d, D.; B ashe s-K ug, T.M.; Ande son, K.E.; McCuske , E.; Lu he , J.; Long, J.D.; Paulsen, J.S.
PREDICT-HD In es iga o s and Coo dina o s o he Hun ing on S udy G oup Longi udinal Psychia ic Symp oms in P od omal
Hun ing on’s Disease: A Decade o Da a. Am. J. Psychia y 2016,173, 184–192. [C ossRe ]
66.
Paoli, R.; Bo u i, A.; Ciammola, A.; Silani, V.; P unas, C.; Lucchia i, C.; Zugno, E.; Cale i, E. Neu opsychia ic Bu den in
Hun ing on’s Disease. B ain Sci. 2017,7, 67. [C ossRe ]
67. Paulsen, J.S. Neu opsychia ic Aspec s o Hun ing on’s Disease. J. Neu ol. Neu osu g. Psychia y 2001,71, 310–314. [C ossRe ]
68.
Du , K.; Paulsen, J.S.; Beglinge , L.J.; Langbehn, D.R.; S ou , J.C. Psychia ic Symp oms in Hun ing on’s Disease be o e Diagnosis:
The P edic -HD S udy. Biol. Psychia y 2007,62, 1341–1346. [C ossRe ]
69.
Goh, A.M.; Wibawa, P.; Loi, S.M.; Wal e ang, M.; Velakoulis, D.; Looi, J.C. Hun ing on’s Disease: Neu opsychia ic Mani es a ions
o Hun ing on’s Disease. Aus alas. Psychia y 2018,26, 366–375. [C ossRe ]
70.
Loi, S.M.; Wal e ang, M.; Velakoulis, D.; Looi, J.C. Hun ing on’s Disease: Managing Neu opsychia ic Symp oms in Hun ing on’s
Disease. Aus alas. Psychia y 2018,26, 376–380. [C ossRe ]
71.
Beglinge , L.J.; Adams, W.H.; Langbehn, D.; Fiedo owicz, J.G.; Jo ge, R.; Biglan, K.; Ca iness, J.; Olson, B.; Robinson, R.G.;
Kiebu z, K.; e al. Resul s o he Ci alop am o Enhance Cogni ion in Hun ing on Disease T ial: Ci alop am in HD. Mo . Diso d.
2014,29, 401–405. [C ossRe ]
72.
Hicks, J.K.; Bishop, J.R.; Sangkuhl, K.; Mülle , D.J.; Ji, Y.; Leckband, S.G.; Leede , J.S.; G aham, R.L.; Chiulli, D.L.; LLe ena, A.; e al.
Clinical Pha macogene ics Implemen a ion Conso ium (CPIC) Guideline o CYP2D6 and CYP2C19 Geno ypes and Dosing o
Selec i e Se o onin Reup ake Inhibi o s. Clin. Pha macol. The . 2015,98, 127–134. [C ossRe ]
73.
Klame us, K.J.; Maloney, K.; Rudolph, R.L.; Sisenwine, S.F.; Jusko, W.J.; Chiang, S.T. In oduc ion o a Composi e Pa ame e o he
Pha macokine ics o Venla axine and I s Ac i e O-Desme hyl Me aboli e. J. Clin. Pha macol. 1992,32, 716–724. [C ossRe ]
74.
Sangkuhl, K.; S ingl, J.C.; Tu peinen, M.; Al man, R.B.; Klein, T.E. Pha mGKB Summa y: Venla axine Pa hway. Pha macogene .
Genom. 2014,24, 62–72. [C ossRe ]
75.
O on, S.V.; Ball, S.E.; Cheung, S.W.; Inaba, T.; Rudolph, R.L.; Selle s, E.M. Venla axine Oxida ion in Vi o Is Ca alysed by CYP2D6.
B . J. Clin. Pha macol. 1996,41, 149–156. [C ossRe ]
76.
Fogelman, S.M.; Schmide , J.; Venka ak ishnan, K.; on Mol ke, L.L.; Ha ma z, J.S.; Shade , R.I.; G eenbla , D.J. O- and N-
Deme hyla ion o Venla axine in Vi o by Human Li e Mic osomes and by Mic osomes om CDNA-T ans ec ed Cells: E ec
o Me abolic Inhibi o s and SSRI An idep essan s. Neu opsychopha macol. O . Publ. Am. Coll. Neu opsychopha macol.
1999
,20,
480–490. [C ossRe ]
77.
Lobello, K.W.; P esko n, S.H.; Guico-Pabia, C.J.; Jiang, Q.; Paul, J.; Nichols, A.I.; Pa one a, A.; Ninan, P.T. Cy och ome P450 2D6
Pheno ype P edic s An idep essan E icacy o Venla axine: A Seconda y Analysis o 4 S udies in Majo Dep essi e Diso de .
J. Clin. Psychia y 2010,71, 1482–1487. [C ossRe ]
78.
Nichols, A.I.; Foch , K.; Jiang, Q.; P esko n, S.H.; Kane, C.P. Pha macokine ics o Venla axine Ex ended Release 75 Mg and
Des enla axine 50 Mg in Heal hy CYP2D6 Ex ensi e and Poo Me abolize s: A Randomized, Open-Label, Two-Pe iod, Pa allel-
G oup, C osso e S udy. Clin. D ug In es ig. 2011,31, 155–167. [C ossRe ]
J. Pe s. Med. 2023,13, 385 18 o 18
79.
McAlpine, D.E.; Bie nacka, J.M.; M azek, D.A.; O’Kane, D.J.; S e ens, S.R.; Langman, L.J.; Cou son, V.L.; Bhagia, J.; Moye , T.P.
E ec o Cy och ome P450 Enzyme Polymo phisms on Pha macokine ics o Venla axine. The . D ug Moni .
2011
,33, 14–20.
[C ossRe ]
80.
Du ch Pha macogene ics Wo king G oup. Anno a ion o DPWG Guideline o Venla axine and CYP2D6. A ailable online:
h ps://www.pha mgkb.o g/chemical/pa451866/guidelineanno a ion/pa166104968 (accessed on 24 Janua y 2023).
81.
Fukuda, T.; Nishida, Y.; Zhou, Q.; Yamamo o, I.; Kondo, S.; Azuma, J. The Impac o he CYP2D6 and CYP2C19 Geno ypes on
Venla axine Pha macokine ics in a Japanese Popula ion. Eu . J. Clin. Pha macol. 2000,56, 175–180. [C ossRe ]
82.
Uh , M.; Ton sch, A.; Namendo , C.; Ripke, S.; Lucae, S.; Ising, M.; Dose, T.; Ebinge , M.; Rosenhagen, M.; Kohli, M.; e al.
Polymo phisms in he D ug T anspo e Gene ABCB1 P edic An idep essan T ea men Response in Dep ession. Neu on
2008
,
57, 203–209. [C ossRe ]
83.
Loho , F.W.; Aquino, T.D.; Na asimhan, S.; Mul ani, P.K.; E emad, B.; Rickels, K. Se o onin Recep o 2A (HTR2A) Gene
Polymo phism P edic s T ea men Response o Venla axine XR in Gene alized Anxie y Diso de . Pha m. J.
2013
,13, 21–26.
[C ossRe ]
84.
Ki chheine , J.; Nickchen, K.; Sasse, J.; Baue , M.; Roo s, I.; B ockmölle , J. A 40-Basepai VNTR Polymo phism in he Dopamine
T anspo e (DAT1) Gene and he Rapid Response o An idep essan T ea men . Pha m. J. 2007,7, 48–55. [C ossRe ]
85.
U.S. Food and D ug Adminis a ion (FDA) Label In o ma ion o Duloxe ine. A ailable online: h ps://www.accessda a. da.
go /d ugsa da_docs/label/2010/022516lbl.pd (accessed on 16 Janua y 2023).
86.
Knadle , M.P.; Lobo, E.; Chappell, J.; Be gs om, R. Duloxe ine: Clinical Pha macokine ics and D ug In e ac ions. Clin. Pha ma-
cokine . 2011,50, 281–294. [C ossRe ]
87.
An ila, S.A.K.; Leinonen, E.V.J. A Re iew o he Pha macological and Clinical P o ile o Mi azapine. CNS D ug Re .
2006
,7,
249–264. [C ossRe ]
88.
Lind, A.-B.; Reis, M.; Beng sson, F.; Jonzie -Pe ey, M.; Powell Golay, K.; Ahlne , J.; Baumann, P.; Dahl, M.-L. S eady-S a e Concen-
a ions o Mi azapine, N-Desme hylmi azapine, 8-Hyd oxymi azapine and Thei Enan iome s in Rela ion o Cy och ome
P450 2D6 Geno ype, Age and Smoking Beha iou . Clin. Pha macokine . 2009,48, 63–70. [C ossRe ]
89.
Si o , E.J.; Ha enbe g, S.; Vandel, P.; Lima, C.A.M.; Pe enoud, P.; Kemme ling, K.; Zullino, D.F.; Hille e , H.; C e ol, S.;
Jonzie -Pe ey, M.; e al.
Mul icen e S udy on he Clinical E ec i eness, Pha macokine ics, and Pha macogene ics o Mi azapine
in Dep ession. J. Clin. Psychopha macol. 2012,32, 622–629. [C ossRe ]
90. Le y, R.; Cze necki, V. Apa hy and he Basal Ganglia. J. Neu ol. 2006,253, ii54– ii61. [C ossRe ]
91.
Bouwens, J.A.; an Duijn, E.; an de Mas , R.C.; Roos, R.A.C.; Gil ay, E.J. I i abili y in a P ospec i e Coho o Hun ing on’s
Disease Mu a ion Ca ie s. J. Neu opsychia y Clin. Neu osci. 2015,27, 206–212. [C ossRe ]
92.
U.S. Food & D ug Adminis a ion (FDA) Label In o ma ion o Clozapine. A ailable online: h ps://www.accessda a. da.go /
d ugsa da_docs/label/2010/019758s062lbl.pd (accessed on 17 Janua y 2023).
93.
Saiz-Rod íguez, M.; Gil-Polo, C.; Diez-Fai en, M.; Ma inez-Ho a, S.-I.; Samped o San alo, F.; Collazo, C.; Cal o, S.;
Alonso-Ga cía, E.
; Riñones-Mena, E.; Aguado, L.; e al. Polymo phisms in he Oxy ocin Recep o and Thei Associa ion wi h
Apa hy and Impai ed Social Cogni ion in Hun ing on’s Disease. J. Neu ol. Neu osu g. Psychia y 2022,93, A50. [C ossRe ]
94.
Wesson, M.; Boileau, N.R.; Pe lmu e , J.S.; Paulsen, J.S.; Ba on, S.K.; McCo mack, M.K.; Ca lozzi, N.E. Suicidal Idea ion
Assessmen in Indi iduals wi h P emani es and Mani es Hun ing on Disease. J. Hun ing . Dis. 2018,7, 239–249. [C ossRe ]
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