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P H A R M A C O G E N E T I C S A N D A N T I P S Y C H O T I C S I N T H E L I G H T O F P E R S O N A L I Z E D
P H A R M A C O T H E R A P Y
A l m a M i h a l j e v i - P e l e a1 , M a r i n a `a g u d 1 , N a d a B o ~i n a 2 , M a j a }i v k o v i 3 a n d N i k o l i n a J o v a n o v i 1
1 S c h o o l o f M e d i c i n e , U n i v e r s i t y o f Z a g r e b , C l i n i c a l H o s p i t a l C e n t r e Z a g r e b , D e p a r t m e n t f o r p s y c h i a t r y , K i ap a t i e v a 1 2 , 1 0 0 0 0 Z a g r e b , C r o a t i a
2 S c h o o l o f M e d i c i n e , U n i v e r s i t y o f Z a g r e b , C l i n i c a l H o s p i t a l C e n t r e Z a g r e b , C l i n i c a l I n s t i t u t e o f L a b o r a t o r y d i a g n o s t i c , K i ap a t i e v a 1 2 , 1 0 0 0 0 Z a g r e b , C r o a t i a
3 N e u r o p s y c h a i t r i c H o s p i t a l D r I v a n B a r b o t , P o p o v a
a , C r o a t i a
C o r r e s p o n d e n c e :
A l m a M i h a l j e v i - P e l e a
S c h o o l o f M e d i c i n e , U n i v e r s i t y o f Z a g r e b , C l i n i c a l H o s p i t a l C e n t r e Z a g r e b
K i ap a t i e v a 1 2 , 1 0 0 0 0 Z a g r e b , C r o a t i a
E - m a i l : a p e l e s @ m e f . h r
S U M M A R Y
T h e c o n c e p t o f p e r s o n a l i z e d d r u g t h e r a p y o n t h e basis of genetic investigations has become a
major issue in psychopharmacology. Pharmacogenetic studies have focused on polymorphisms in liver cytochrome P450 isoenzymes that metabolize many antidepressant and antipsychotic medications. The most significant results are the association between drug metabolic polymorphisms of cytochrome P450 with variations in drug metabolic rates and side effects. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. The contribution of kinetic factors to the clinical outcome of antipsychotic treatment has a strong evidence base. Genetic tests for the pretreatment prediction of antipsychotic response have obvious implications for the selection and improvement of antipsychotic treatment. The pretreatment determination of individuals drug metabolic rates by CYP genotyping is the leading field. This review sum m a r i z e s t h e p r e s e n t k n o w l e d g e o f a s s o c i a t i o n s b e t w e e n c y t o c h r o m e P 4 5 0 i s o e n z y m e s a n d t h e e f f i c a c y a n d s i d e e f f e c t s o f a n t i p s y c h o t i c s .
K e y w o r d s : p h a r a m a c o g e n e t i c s , a n t i p s y c h o t i c s , p o l y m o r p h i s m s , i s o e n z y m e s P 4 5 0
S A }E T A K
F a r m a k o t e r a p i j a p r i l a g o e n a s v a k o m p o j e d i n o m b o l e s n i k u , d a n a s j e u s r e d i at u z a n i m a n j a p s i h o f a r m a k o l o g i j e . F a r m a k o g e n e t s k e s t u d i j e f o k u s i r a n e s u n a i s t r a ~i v a n j e p o l i m o r f i z a m a e n z i m a c i t o k r o m a P 4 5 0 , k o j i m e t a b o l i z i r a j u v e i n u a n t i d e p r e s i v a i a n t i p s i h o t i k a . N a j z n a
a j n i j i r e z u l t a t i i s t r a ~i v a n j a p o l i m o r f i z a m a e n z i m a c i t o k o r m a P 4 5 0 , d o b i v e n i s u u s t u p n j u m e t a b o l i z i r a n j a l i j e k o v a i p o j a v n o s t i n u s p o j a v a . N a d a l j e , p o l i m o r f i z m i d o p a m i n s k i h i s e r o t o n i n s k i h r e c e p t o r a u b r z a n o s e p o v e z u j u s t e r a p i j s k i m o d g o v o r o m , r e f l e k t i r a j u i p r i t o m s p e c i f i
n i p o t e n c i j a l a n t i p s i h o t i k a z a p o j e d i n e r e c e p t o r e . Z a k i n e t s k e
i m b e n i c e p r e m a t o m e p o s t o j e n e o s p o r n i d o k a z i o n j i h o v o j v a ~n o s t i u a n t i p s i h o t i
n o m l i j e
e n j u . S u k l a d n o t o m e u v o e n j e p r e d i k c i j s k i h t e s t o v a u a n t i p s i h o t i
n o l i j e
e n j e , z a s i g u r n o e p o b o l j aa t i l i j e
e n j e a n t i p s i h o t i c i m a . V o d e i p r e d v i a j u i t e s t o v i s v a k a k o s u t e s t o v i p o l i m o r f i z a m a e n z i m a c i t o k r o m a P 4 5 0 . O v a j p r e g l e d d o n o s i s a d a an j a s a z n a n j a o p o v e z a n o s t i i z o e n z i m a c i t o k r o m a P 4 5 0 s u
i n k o v i t o au i p o j a v n o s t i n u s p o j a v a p r i l i j e
e n j u a n t i p s i h o t i c i m a .
INTRODUCTION
Antipsychotic drugs achieve a certain degree of clinical improvement in the treatment of psychosis in about 50% of schizophrenic patients (Miyamoto et al, 2005. ). Delay in finding an adequate treatment for psychosis has a detrimental effect on prognosis and chances of recovery. The nature of drug response is highly complex, involving clinical, genetic and environmental factors.
Because of these factors there are much interindividual variabilities in the treatment with antipsychotics. Genetic determination of patients metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions (Arranz and de leone, 2007.). The summary of this findings relevant for schizophrenia will be presented in this review.
Clinical and environmental factors
Response to for example the clozapine, may be influenced by clinical and demographic factors. Male gender and early age of onset predict poor response, whereas presence of EPS with previous treatments and paranoid symptoms predict good response to treatment with clozapine (Lieberman et al, 1996.). Environmental factors such as cigarette smoking and diet can induce or inhibit metabolic pathways, which affects plasma levels of antipsychotic metabolites.
Therefore, the knowledge of patients eating and smoking habits can be used as an indicator
for the adjustment of therapeutic doses (Nebert et Dieter, 2000.). Despite the fact that clinical and environmental factors, have small to moderate influence, together with genetic determinants of response, they should be considered when selecting treatments.
Pharmacokinetic factors
Genetic variants in Phase I and II enzymes are known to reduce or increase antipsychotic activity. Phase I oxidation reactions are involved in the metabolism of antipsychotic drugs. CYP enzymes show large interindividual differences in activities due to genetic variants constituting multialelic systems. These can be distinguished as poor (PM), intermediate (IM), extensive (EM) or ultra fast metabolizers (UM) (Bondy and Spellmann, 2007.). Mutant alleles differ from normal alleles by point mutations, gene deletions or gene duplications. The poor metabolizers have inactive allelic variant, intermediate metabolizers have at least one copy of an active gene and ultra fast metabolizers contain duplicated or amplified gene copies. Due to concentrations of drug could be increased or decreased. ( M i h a l j e v i - P e l e a e t a l , 2 0 0 8 . ) . T h e r e a r e a l s o c o n s i d e r a b l e d i f f e r e n c e s i n a l l e l e a n d g e n o t y p e f r e q u e n c y a c r o s s e t h n i c g r o u p s .
C Y P 2 C 1 9 m a y b e c l i n i c a l l y r e l e v a n t f o r t h e m e t a b o l i s m o f a n t i d e p r e s s a n t s b u t h a s s m a l l s i g n i f i c a n c e f o r a n t i p s y c h o t i c t r e a t m e n t . CYP2D6 is the main metabolic pathway of many
antidepressants and a number of classical antipsychotics (Bertilsson et al, 2002. ). The gene coding for this enzyme is highly variable. Kirchheiner et al. have demonstrated that the metabolism of the haloperidol is severely reduced in PMs, and a reduced therapeutic dose should be used (Kirchheiner et al, 2004.). At the other hand, CYP2D6 did not predict response to risperidone, but predicted metabolic ratios and side effects (de Leone et al, 2005.). No association was found between CYP2D6 PM variants and clozapine response (Arranz et al, 1995.). However, the incidence of tardive dyskinesia is higher in patient with inactive CYP2D6-alleles (Kapitany et al, 1998.). CYP 1A2 is the main metabolic pathway of the antipsychotics clozapine and olanzapine and several polymorphisms have been reported in the CYP1A2 (Eirmann et al, 1997.; Ring et al ,1996., Murayama et al, 2004.). In addition, CYP1A2 polymorphisms did not significantly influence individuals clozapine metabolic capacity (Kootstra-Ros et al, 2005.). Smoking seriously affects the activity of CYP1A2. Smoking may result in reduced clozapine plasma levels, and an adjustment of therapeutic dose is recommended. The most common polymorphisms involved in antipsychotic phase I metabolism are presented in table 1.
Table 1. The most important polymorphisms in CYP450 enzymes
CYP 450SubstrateInhibitorInducerPolymorphism1A2Clozapine
Olanzapine
Duloxetine
Mirtazapine
Propranolol
Teophiline
Caffeine
Clomipramine
Estr a d i o l F l u v o x a m i n e
C i m e t i d i n e
C i p r o f l o x a c i n e
O r a l c o n t r a c e p t i v e s
E s t r o g e n e s
S e v e r e r e s p i r a t o r y t r a c t i n f e c t i o n s C i g a r e t t e s m o k e B r u s s e l s p r o u t s
O m e p r a z o l e C Y P 1 A 2 * 1 C - ! i n d u c i b i l i t y i n s m o k e r s , C Y P 1 A 2 * 1 F - ! i n d u c i b i l i t y i n s m o k e r s 2 C 9 P h e n i t o i n e
F l u v a s t a t i n e
I b u p r o f e n
D i c l o p h e n a k
T o l b u t a m i d e
W a r f a r i n e
V a l p r o i c a c i d F l u v o x a m i n e
F l u o x e t i n e ( m o d e r a t e i n h i b i t o r )
F l u c o n a z o l e P r e d n i s o n e
R i f a m p i c i n e C Y P 2 C 9 * 2 , * 3 - ! a c t i v i t y , e v e n u p t o 9 0 % , p o l y m o r p h i s m i n 3 5 % C a u c a s i a n s 2 C 1 9 A m i t r y p t i l i n e
D i a z e p a m
M o c l o b e m i d e
O m e p r a z o l e
P a n t o p r a z o l e
C l o m i p r a m i n e
C i t a l o p r a m F l u v o x a m i n e
F l u o x e t i n e C a r b a m a z e p i n e
R i f a m p i c i n e 3 - 5 % C a u c a s i a n s h a v e n o e n z y m e e c p r e s s i o n
( C Y P 2 C 1 9 * 2 a l e l l e ) 2 D 6 R i s p e r i d o n e
H a l o p e r i d o l
F l u p h e n a z i n e
S e r t i n d o l e
A r i p i p r a z o l
Z u c l o p e n t i x o l
C o d e i n e
T r a m a d o l
- b l o c k e r s
S o m e a n t i a r r h y t h m i c s
( f l e c a i n i d e )
O l a n z a p i n e ( m i n o r p a t h w a y ) F l u o x e t i n e
P a r o x e t i n e
F l u v o x a m i n e a n d s e r t r a l i n e a r e w e a k i n h i b i t o r s N o t i n d u c i b l e 5 - 1 0 % C a u c a s i a n s h a v e n o e n z y m e e c p r e s s i o n
( m o s t l y C Y P 2 D 6 * 4 a l e l l e ) 3 A 4 Z i p r a s i d o n e
Q u e t i a p i n e
S e r t i n d o l e
(minor pathway)
Aripiprazole
Calcium antagonists
Statins
Macrolide antibiotics
Alprazolam
Carbamazepine
Cinidine
Cyclosporine
Tacrolimus
Tamoxifen
Protease HIV-1inhibitors
TestosteroneFluvoxamine
ClarythromycineCarbamazepine
Glucocorticoides
Hyperphorine
Phenobarbitale
RifampicineLimited data for existing polymorphismsDe Leon et al, 2005; Zanger et al, 2008; Brouwers et al, 2009
Although there are several variants of the CYP3A4 enzyme, involved in the metabolism of most antipsychotics, no significant associations of these variants with antipsychotic variability have been reported. There are also no significant response associations with the polymorphic CYP3A5, CYP2C9 and CYP2C19.
At the end, phase II enzymes, which are responsible for the inactivation of drug metabolites via conjugation have not been extensively investigated. This is,however, an important area for future research.
CONCLUSION
The aim of pharamacogenetics is to help clinicians to choose the best treatment for each individual patient. Genotyping CYP2D6 is proposed to improve drug dosing in the individual patient: Individualizing dose escalation schemes have been developed both for antidepressants and antipsychotics, which are based on the distinction of PM, UM and others. Depending on the impact of the CYP2D6-enzyme activity on the metabolism of a specific drug, dosage recommendations propose to prescribe 3070% dose reduction on PM and 135180% dose elevation in UM patients (Maier and Zobel, 2008.).
LITERATURE:
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Lieberman JA, Koreen AR, Chakos M, Sheitman B, Woerner M, Alvir JM et al. Factors influencing treatment response and outcome of first-episode schizophrenia: implications for underst a n d i n g t h e p a t h o p h y s i o l o g y o f s c h i z o p h r e n i a . J C l i n P s y c h i a t r y 1 9 9 6 ; 5 7 ( S u p p l 9 ) : 5 9 .
B o n d y B a n d S p e l l m a n n I . : P h a r a m a c o g e n e t i c s o f a n t i p s y c h o t i c s : U s e f u l f o r t h e C l i n i c i a n ? C u r r O p i n P s y c h i a t r y . 2 0 0 7 ; 2 0 ( 1 ) ; 1 2 6 - 1 3 0
M i h a l j e v i c - P e l e s A , `a g u d M , B o ~i n a N , }i v k o v i M . P h a r m a c o g e n e t i c s a n d a n t i d e p r e s s a n t t r e a t m e n t i n i n t e g r a t i v e p s y c h i a t r y p e r s p e c t i v e . P s y c h i a t r i a D a n u b i n a , 2 0 0 8 ; V o l . 2 0 , N o . 3 , p p 3 5 5 3 5 5
N e b e r t D W , D i e t e r M Z . T h e e v o l u t i o n o f d r u g m e t a b o l i s m . P h a r m a c o l o g y 2 0 0 0 ; 6 1 : 1 2 4 1 3 5 .
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l B a ytz 6 26 :6 P6 [6 i6 r6 6 6 6 6 6 6 6 6 6 7 7 7 E7 $$If a$gdwr 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 D7 E7 F7 [7 m7 7 7 7 8 9 '9 A9 O9 9 9 9 9 9 9 : øvv hwr h mHsH hwr hWU mHsH hwr hki mHsH hwr h mHsH hwr h)*l mHsH hwr h65 mHsH hwr hwr mHsH hwr hz mHsH hwr hf hwr h" nH tH hwr hwr hwr hz hwr h" hwr hz nH tH +E7 F7 7 7 8 9 9 J B 6 6 6 6 $7$ 8$ H$ a$gdwr $a$gdwr kd $$If l r -
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& F
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: : : !: R: S: `: : : : : : ; ; "; B; r; s; ; ; < K= > > @ @ @ 4A 6A A B p p p q q q ^r s ɾttti hwr hc mHsH hwr h-f mHsH Uhwr hS> mHsH hwr h^ 6]mHsH hwr hFU hwr h^ hwr hE| mHsH hwr h= mHsH hwr h ] mHsH hwr ht0 mHsH hwr h mHsH hwr hWU mHsH hwr hQfK mHsH hwr hk mHsH', Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53: 111122.
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