The pharmacogenetics of symptom response to antipsychotic drugs.

Abstract

Antipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as well as by the substantial variability in response between patients. Pharmacogenetic studies have sought to identify the genetic factors that underlie the individual variability in response to treatment, with a past emphasis on dopamine and serotonin receptors as candidate genes. Few studies have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment between these syndromes. Where this has been done most findings are consistent with the conclusion that dopamine receptor polymorphisms relate to positive symptom response, while negative symptom improvement is influenced by polymorphisms of genes involved in 5-HT neurotransmission. A wide range of polymorphisms in other candidate genes have been investigated, with some positive findings in those genes associated with glutamatergic transmission and/or risk factors for schizophrenia. However, there remains a lack of good replicated findings; furthermore there is little evidence to support drug-specific genetic associations with treatment response. While most past studies focused on single candidate genes, technology now permits genome-wide association studies with response to antipsychotics. Although not without major limitations, these "hypothesis-free" approaches are beginning to identify further important risk factors for treatment response. Again there is little consistency between various studies, although some of the polymorphisms identified are in genes involved in neurodevelopment, which is increasingly being recognized as important in the pathophysiology of schizophrenia.

Full text

Page 1

INTRODUCTION-CONCEPTS AND
APPROACHES
Severe mental illness represents a huge burden to society,
reflecting the limited efficacy of current treatment for schizo-
phrenia, bipolar disorder and major depressive disorder. The
antipsychotic drugs, developed for the treatment of schizo-
phrenia, are increasingly used for the treatment of mania in
bipolar disorder, in which the evidence indicates they are the
most effective therapy.1 They may also be used in treating a
variety of behavioural problems associated with disorders
from childhood to the elderly; in total well over 1% of the ad-
ult population now receive antipsychotic drug treatment. Wh-
Print ISSN 1738-3684 / On-line ISSN 1976-3026
OPEN ACCESS
http://dx.doi.org/10.4306/pi.2012.9.1.1
Copyright © 2012 Korean Neuropsychiatric Association 1
ile some people with schizophrenia respond well to antipsy-
chotic drug treatment, a similar proportion (approximately one
third) show little amelioration of their symptoms, while the
remainder present varying degrees of symptom improve-
ment. Treatment adherence is a frequently underestimated
factor that contributes to this substantial variability and which
can be influenced by the emergence of adverse drug effects, al-
though patients taking their medication as prescribed can still
show profound differences in response. There is little under-
standing of the underlying reasons for these individual differ-
ences, although accumulating evidence over the past 15 years
indicates that genetic factors contribute substantially to the
extent of symptom improvement following drug treatment.
Studies of siblings and twins have provided some evidence
in support of genetics influencing the response to antipsycho-
tic drugs. Thus symptom improvement following clozapine2
and olanzapine3 has shown strong concordance in monozy-
gotic twin pairs. Identifying the genetic factors responsible
for individual variability in the effects of drug treatment is the
aim of pharmacogenetics. The pharmacogenetics of antipsy-
chotic drugs has received substantial research effort over the
REVIEW ARTICLE
The Pharmacogenetics of Symptom Response
to Antipsychotic Drugs
Gavin P Reynolds
Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB U.K.
Antipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as
well as by the substantial variability in response between patients. Pharmacogenetic studies have sought to identify the genetic factors that
underlie the individual variability in response to treatment, with a past emphasis on dopamine and serotonin receptors as candidate genes.
Few studies have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment
between these syndromes. Where this has been done most findings are consistent with the conclusion that dopamine receptor polymor-
phisms relate to positive symptom response, while negative symptom improvement is influenced by polymorphisms of genes involved in
5-HT neurotransmission. A wide range of polymorphisms in other candidate genes have been investigated, with some positive findings in
those genes associated with glutamatergic transmission and/or risk factors for schizophrenia. However, there remains a lack of good rep-
licated findings; furthermore there is little evidence to support drug-specific genetic associations with treatment response. While most
past studies focused on single candidate genes, technology now permits genome-wide association studies with response to antipsychotics.
Although not without major limitations, these “hypothesis-free” approaches are beginning to identify further important risk factors for
treatment response. Again there is little consistency between various studies, although some of the polymorphisms identified are in genes
involved in neurodevelopment, which is increasingly being recognized as important in the pathophysiology of schizophrenia.

Psychiatry Investig 2012;9:1-7
Key Wordsaa Polymorphisms, Genes, Schizophrenia, Negative symptoms, Positive symptoms.
Received: December 4, 2011 Revised: December 12, 2011
Accepted: December 12, 2011 Available online: January 9, 2012
 Correspondence: Gavin P Reynolds
Biomedical Research Centre, Sheffield Hallam University, Howard Street,
Sheffield S1 1WB U.K.
Tel: +44 7740 651500
E-mail: gavin.reynolds@hotmail.com
cc This is an Open Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (http://creativecommons.org/licenses/by-
nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduc-
tion in any medium, provided the original work is properly cited.

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2 Psychiatry Investig 2012;9:1-7
Pharmacogenetics of Antipsychotic Response
past decade, driven by an awareness of the varied and often
limited effectiveness of these drugs both in controlling symp-
toms of schizophrenia and in inducing adverse effects.
This review will address progress in the pharmacogenetics
of antipsychotic response, an important target for study given
the high proportion of patients in whom antipsychotic treat-
ment is less that optimally effective. The inadequate response
to treatment is more apparent in subgroups of symptoms; wh-
ile antipsychotic drugs are often effective at controlling the
positive psychotic symptoms, they are less able to ameliorate
the negative and cognitive features of schizophrenia. These in-
clude social withdrawal, blunted mood, lack of self care and de-
ficits in executive function and working memory which, along
with depressed mood, are the symptoms that are most prob-
lematic in integrating the patient into society.
By far the great majority of pharmacogenetic studies of an-
tipsychotic drug response have been performed in the context
of schizophrenia, and the current review will be limited to
this topic. It will not be a comprehensive listing of all pharma-
cogenetic results relating to individual differences in symptom
response, but the major genes of interest will be mentioned,
particularly where they have given rise to further pharmaco-
genetic study. Thus the review will aim to illustrate the current
status of the field, with examples as well as reference to more
specific review articles, primarily focusing on pharmacody-
namic rather than pharmacokinetic influences on drug action.
Pharmacokinetic effects, such as genetic variation resulting
in differences in activity in drug metabolising enzymes, can of
course affect antipsychotic drug treatment by influencing plas-
ma concentrations and availability to the brain, or by affecting
the synthesis of active metabolites. These effects may to some
extent be compensated for by titration to an effective dose.
Such pharmacokinetic factors represent one level of pharma-
cogenetic influence; three further pharmacodynamic levels of
pharmacogenetic associations can be identified depending on
the nature of the gene-drug interaction.4 These influences in-
clude a) genes known or thought to be directly involved in
the mechanisms of drug action, such as the dopamine D2 re-
ceptor, b) genes that may indirectly modify the primary drug
mechanism, such as those involved in second messenger func-
tion or in interacting neurotransmitter systems and c) genes
that are involved in disease pathology, such as dysbindin, or dise-
ase modification, such as catechol-O-methyltransferase (CO-
MT), and which may therefore determine how responsive the
disease may be to pharmacotherapy.
The starting point for pharmacogenetic investigation of tr-
eatment response, the phenotype, has in the past investigated
variability in the DNA of one or a small number of “candidate”
genes for study. Choice of candidate genes is hypothesis-driv-
en, whereby genes are usually selected on the basis of their cod-
ing for a protein that is known to be, or is potentially, involved
in pharmacokinetic or pharmacodynamic aspects of drug ac-
tion. Identification of sites of common DNA variation in these
genes, primarily single nucleotide polymorphisms (“SNPs”)
or insertion/deletion sequences, provide the factors for associ-
ation of genotype with phenotype.
Technological advance has resulted in the opportunity to in-
vestigate many (perhaps 1 million) SNPs across the whole ge-
nome and offer great power in identifying novel genetic as-
sociations unconstrained by prior hypotheses which, for the
candidate gene approach, are inevitably founded on a limited
understanding of the underlying mechanisms. These hypothe-
sis-free genome-wide association studies (GWAS) are not with-
out limitations; typically they select SNPs on the basis of po-
sition in the genome sequence, rather than as having known,
or potential, functionality that may be chosen in candidate
gene studies. They also have problems associated with the dif-
ficulties of data handling (where over 109 individual results
may be accumulated) and consequent statistical analysis and
interpretation.
CANDIDATE GENE STUDIES-FOCUS ON
DOPAMINE AND SEROTONIN
RECEPTORS
It is generally considered that the primary antipsychotic me-
chanism involves antagonist action at dopamine D2 recep-
tors in the brain. Thus polymorphisms in this gene (DRD2)
have been widely investigated in respect of symptom resp-
onse, as have the related D2-like receptor genes DRD3 and
DRD4. Similarly, the 5-HT2A receptor is a major drug target
proposed to differentiate the atypical antipsychotics from the
older drugs.
The often inadequate effect of antipsychotic drugs on neg-
ative symptoms and cognitive deficits of schizophrenia, com-
pared to the response of positive symptoms, has been em-
phasised above. However, the pharmacological mechanisms
that might underlie antipsychotic drug effects on negative and
cognitive symptoms are far from clear. It has been suggested
that drug action at 5-HT2A receptors is also responsible for
some improved efficacy of the atypical antipsychotics on ne-
gative symptoms, although the supporting evidence for this
clinical effect is very limited,5 as is our understanding of the
underlying mechanism. Nevertheless, there is some indication
that 5-HT systems are involved in models of cognitive dys-
function in schizophrenia6,7 as well as in symptom ameliora-
tion by newer antipsychotic drugs,7 providing candidature in
pharmacogenetic studies for HTR2A and other serotonergic
genes such as HTR1A, HTR2C, HTR6 and HTT.
The first reports assessing genetic associations with antipsy-

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GP Reynolds
www.psychiatryinvestigation.org 3
chotic treatment response inevitably concentrated on the most
obvious candidate genes with some replicated, if not totally
consistent, findings of polymorphisms in three receptors: do-
pamine D2, dopamine D3 and serotonin 5-HT2A, being asso-
ciated with response to treatment (reviewed in 8, 9). The associ-
ation of the D2 receptor gene with response has been confirm-
ed more recently in a systematic review,10 while overall associ-
ation of the D3 gene remains weak and inconsistent (e.g. 11,
12). Other dopaminergic factors have been investigated in
relation to drug response. The dopamine transporter (DAT)
gene has shown both positive (with clozapine) and negative
(with risperidone) association results,13,14 but there are no con-
vincing findings indicating an influence of SNPs in the dopa-
mine D1 or D4 receptors on treatment response.
A review of association studies with SNPs in the 5-HT2A
receptor gene concluded that results indicate some weak as-
sociation with antipsychotic response as well as with psycho-
sis itself.15 Some further supporting data for the association
with drug response has emerged from several more recent
small studies including one employing the methodologically
more rigorous transmission disequilibrium test.16 Neverthe-
less the effect is a small one and not consistently obtained. The
same is true for genes for other markers of serotonergic func-
tion. The serotonin transporter (HTT), with what is perhaps
the most studied polymorphism in psychiatry, the insertion/
deletion (ins/del) sequence in the promoter region,17 is asso-
ciated with antipsychotic response in some (e.g. 18, 19) but
not all20 studies. A SNP in the 5-HT1A receptor gene has also
been shown to have effects on the response to antipsychotic tr-
eatment.21-23 These HTT and HTR1A genes both code for pro-
teins that control presynaptic activity of the serotonin neuron;
the major SNPs investigated in each case appear to directly in-
fluence gene expression. Thus promoter sequence HTT SNPs
including the ins/del polymorphism of HTT and the SNP
found in the insertion sequence,24 influence HTT expression
and activity, while the -1019C/G promoter SNP in HTR1A af-
fects a transcription factor binding site, again influencing ex-
pression levels and their control of the 5-HT1A receptor, as
well as being associated with suicide and diagnosis of depres-
sion.25
DIFFERENTIATING EFFECTS ON
POSITIVE AND NEGATIVE SYNDROMES
In developing the opportunities for genetic testing, it seems
more valuable to differentiate groups of symptoms in terms of
their response to treatment. As mentioned above, the negative
features of the disease respond poorly to antipsychotic drugs
and it is these, rather than the positive symptoms, that are more
important in determining functional recovery in patients. A
minority of outcome studies have assessed separately the re-
sponses of positive and negative symptoms to drug treatment,
despite the established differences in the effects of antipsycho-
tics on these symptom clusters. However, where this has been
done, it appears that the majority of genes associated with
positive symptom response are of dopamine receptors, while
effects on negative symptoms are more associated with sero-
toninergic genes, in particular the 5-HT1A and 5-HT2A re-
ceptors.4 Updating these initial observations, more recent re-
sults confirm the general association of genetic polymorphisms
in dopamine systems with changes in positive symptoms, and
serotonin with negative symptoms, with notably few anoma-
lies. Thus the previous finding of the association of negative
symptom response has been confirmed for the HTR1A pro-
moter SNP21,23 and identified for the HTT gene.26 An associa-
tion with positive symptom response has been again confirm-
ed for the ser9gly functional DRD3 SNP27 and intriguingly
newly identified for the norepinephrine transporter gene.28
These results demonstrate relatively strong consistency, in
spite of the substantial differences between samples in terms
of treatment history (drug-naïve or previously-treated) and
ethnicity.
These findings may seem surprising on first sight, given the
variety of different genes involved. However this multiplicity
of genetic factors points to common mechanistic pathways; for
example, changes in the expression and activity of both 5-HT1A
receptors and the 5-HT transporter are likely to affect seroto-
nergic activity at the synapse, consequences of which may be
mediated by post-synaptic receptors such as 5-HT2A. A si-
milar but unconfirmed observation has been seen for another
5-HT receptor gene, HTR3E29; notably the results for COMT
indicate association solely with negative symptom improve-
ment (discussed below). Nevertheless the results strongly sug-
gest that the catecholamine and serotonin neurotransmitter
systems are implicated separately in drug response of the two
syndromes, while the exact mechanisms of their involvement
remain elusive. Certainly there is evidence that selective se-
rotonin uptake inhibitors may be useful in the relief of nega-
tive symptoms in some patients.30
There are some other genetic associations with drug-in-
duced changes in the more problematic negative and cognitive
symptoms in schizophrenia. These include the val/met CO-
MT polymorphism,31-33 which has a strong effect on enzyme
activity and thereby influences dopamine (and norepinephrine)
concentrations in the cortex where this enzyme, rather than
neuronal transport, is primarily responsible for synaptic re-
moval of catecholamine neurotransmitters. The glutamate
metabotropic receptor-3 gene, a further risk factor for schizo-
phrenia, has been reported as having SNPs associated with re-
sponse,32 particularly of negative symptoms,34 although a fol-

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4 Psychiatry Investig 2012;9:1-7
Pharmacogenetics of Antipsychotic Response
lowing study showed an association not with negative symp-
tom response but with treatment-refractory schizophrenia.35
Dysbindin1, another gene with an established association with
schizophrenia and implicated in neuronal and synaptic de-
velopment as well as dopamine receptor function, also shows
association with treatment response in refractory schizo-
phrenia.36
Few other pharmacogenetic studies have specifically ad-
dressed positive symptom improvement, although many ge-
netic associations with undifferentiated measures of symp-
tom response may primarily reflect the generally greater im-
provement in positive symptoms. The latest and strongest sin-
gle gene risk factor for schizophrenia, ZNF804A, is also re-
ported to be associated with positive symptom response.37
In one study where a 5-HT1A gene SNP explained much of
the variance in negative symptom response in first-episode pa-
tients,22 there was also an association with depressive symp-
tom response, differentiated from that on negative symptoms.
This is unsurprising, given the established association of this
SNP with depression25 and its treatment.38 An association with
depression as well as negative symptoms has been found for
the 5-HT transporter gene in patients receiving antipsychotics,
although the influence of treatment on this finding was not
determined.39 However it is notable that few pharmacogene-
tic studies have investigated separately the depression syn-
drome in schizophrenia, although it is an important deter-
minant of relapse in patients receiving antipsychotics.40
CLOZAPINE RESPONSE
The unique efficacy of clozapine in the treatment of other-
wise non-responsive patients has resulted in clozapine being
a prime target for pharmacogenetic investigation. Approxi-
mately 50% of patients not otherwise responding to antipsy-
chotic drug treatment benefit from clozapine; much early
work on antipsychotic pharmacogenetics addressed this pro-
blem. A pharmacological basis for its clinical efficacy remains
elusive; among the receptor mechanisms implicated, in addi-
tion to the 5-HT2A receptor antagonism common to most aty-
pical antipsychotics, are effects at alpha2 adrenoceptors, 5-HT1A
receptors and dopamine D1 receptors, although no single re-
ceptor action is likely to explain clozapine’s action in full.41
In some early work Arranz et al.42 studied a range of candi-
date genes, primarily chosen on the basis of the known phar-
macology of clozapine. They looked for association of re-
sponse with 19 polymorphisms in 10 genes associated with
monoamine neurotransmission; six polymorphisms together
gave a (retrospective) sensitivity of 96% in identifying clo-
zapine responders. The strongest components in this profile
of polymorphisms were two SNPs in the HTR2A gene: one
synonymous (silent) 102T/C in linkage disequilibrium with
a promoter SNP (-1438A/G) with functional activity43 and one
nonsynonymous his452tyr. These findings have not been con-
sistently replicated9 but they nevertheless led to the establish-
ment of a pharmacogenetic test for clozapine response, al-
though this is no longer available. A confirmatory prospective
trial to assess the predictability and value in practice of such
pharmacogenetic testing for drug response has yet to be un-
dertaken. Reflecting our incomplete understanding of the
mechanism of clozapine’s action, a consistent pharmacogenet-
ic finding that might relate selectively to clozapine response
still eludes us. Many pharmacogenetic studies, including sev-
eral cited in this chapter, have been carried out on cohorts of
clozapine-treated subjects as well as those receiving other an-
tipsychotic drugs,44 but as yet there is no reliable evidence for
distinct clozapine-specific pharmacogenetic associations with
response.
OTHER GENETIC ASSOCIATIONS WITH
RESPONSE - CANDIDATE GENES TO
GWAS
The positive and replicated findings with SNPs in dopa-
mine and serotonin genes, reviewed more extensively elsewh-
ere,45 are reassuring in terms of our very limited understand-
ing of pharmacological mechanisms. However they are are st-
rongly influenced by a research bias towards testing these
more obvious hypotheses and unfortunately do not consis-
tently emerge from GWAS, as discussed below. Variation in
these genes can usually only explain a small percentage of the
variance in response, and further factors inevitably contrib-
ute to antipsychotic-induced improvement in symptoms.
Those other genetic factors might include SNPs in a wide va-
riety, perhaps many hundreds, of genes potentially influenc-
ing neuronal function, including other neurotransmitter re-
ceptors, enzymes and transporters, as well as second messenger
systems or signalling pathways. Just one of many examples is
the SNP in the G-protein beta3 subunit gene (GNB3), involv-
ed in receptor signal transduction, and which reportedly shows
weak association with symptom response to antipsychotic tr-
eatment.46-48 However, there are few associations with symp-
tom response outside the genes involving dopamine and se-
rotonin systems that have yet been consistently replicated.
The independent and influential CATIE trial of the relative
effects of several antipsychotic drugs5 has been very valuable
in provide a large set of data on the consequences of treatment
of a carefully controlled and rigorously assessed sample of
people with schizophrenia. Although it is not without limita-
tions, pharmacogenetic studies from this trial are beginning to
yield interesting and novel findings.

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GP Reynolds
www.psychiatryinvestigation.org 5
An investigation of a large series of 118 candidate genes49
identified several significant associations with change in the
Positive and Negative Syndrome Scale (PANSS) in the CATIE
sample, the numbers of which were roughly in line with the
expected false discovery rate (22 of 2769 SNPs reached signi-
ficance at p<0.01). Seven of the significant SNPs were in gluta-
mate receptor genes, which might be of more interest were it
not for the fact that such genes were represented by over 1000
of the SNPs studied. This choice of candidates clearly reflects
the increasing evidence of the importance of glutamate neuro-
transmission in in the pathology of schizophrenia50 particular-
ly in relation to cognitive dysfunction.51 Nevertheless the au-
thors also identified significant association with SNPs on
HTR2A, DRD3, the nicotinic receptor alpha7 subunit gene
and the excitatory amino acid transporter 4 gene (SLC1A6),
among other candidates. None of the significant findings cl-
early differentiated effects on positive and negative symptoms.
In their investigation of association with cognitive outcomes,
some interesting findings emerged, again with strong contribu-
tions from glutamate receptors but also identifying effects of
genes for the 5-HT4 receptor and for a neuronal adenylate cy-
clase.49
A GWAS study of the same sample has provided very differ-
ent results, with the strongest effect on change in PANSS sh-
own with a SNP in an inter-gene sequence on chromosome
4; other novel results close to the significance threshold were
in ANKS1B, CNTNAP5 and TRPM1, all of which are poten-
tially involved in neuronal development or neurotransmis-
sion.52 How exactly they might be involved in drug response
is far from clear, however; certainly replication as candidate
genes in other samples is needed. The same group has looked
at neurocognition as an outcome measure of response in this
series,53 finding significance in several genes of which the top
two are EHF (a transcription factor with little evidence for a
neuronal role) and SLC26A9 (a chloride ion transporter). In-
terpretation of these findings is not straightforward, although
more reassuring are the findings of (somewhat weaker) asso-
ciation with DRD2 and ANKS1B, the latter found also to be
associated with negative symptom response in the previous
analysis.
A further study of the CATIE sample employed a theoreti-
cal model-based approach54 which found that several SNPs
in the developmental gene EN1 (engrailed1) are associated
with antipsychotic response. This study used data sets for
schizophrenia risk genes and for mouse SNPs affecting pre-
pulse inhibition of the startle reflex, a physiological effect which
is consistently deficient in schizophrenia and reversed by an-
tipsychotic drug treatment, to generate candidates for study
in the CATIE database, of which only EN1 was found to be
significant.
There have been other approaches using such unbiased in-
dependent methods to select candidate genes. Homer-1, a
gene associated with glutamatergic transmission and identifi-
ed as a candidate from animal studies of gene expression fol-
lowing haloperidol administration, shows SNP associations
with response to treatment.55 An equivalent approach56 inves-
tigated changes in gene expression following risperidone ad-
ministration to mice which were compared with findings from
a GWAS of response to risperidone treatment. This identified
several novel candidates, of which PDE-7 was found to have
association both with disease, internally replicated, and with
treatment response. Unfortunately, despite the apparent va-
lidity of these two approaches, there appears to be little con-
sistency between them. Such criticism, to which much of the ph-
armacogenetic literature is susceptible, can always be coun-
tered by highlighting the differences between study samples
in ethnicity, drug treatment and other such factors, but it re-
mains a problem for the generalizability of any findings.
Iloperidone, an antipsychotic that was recently approved in
the USA, underwent substantial pharmacogenetic study dur-
ing its phase III trials. One investigation involved a GWAS that
identified six SNPs in six genes associated with drug treatment
response57; this data was re-analaysed in a retrospective as-
sessment to identify response-dependent genetic subgroups
of patients.58 How specific these findings are to iloperidone
remains unclear; these authors report that the six SNPs iden-
tified did not significantly associate with ziprasidone resp-
onse, although another group observed that two of the genes
(XKR4 and GRIA4) were also associated with risperidone res-
ponse.59
CONCLUSIONS
For more than the past decade much effort has been spent
in attempting to determine the genetic predictors of the effects
of antipsychotic drugs, particularly in their positive effects
on symptom response. It is clear that, despite this effort, iden-
tification of the major genetic contributors to the consequenc-
es of antipsychotic drug treatment still eludes us. There is a st-
riking paucity of consistently reproducible findings in the
pharmacogenetic studies reported. There are many reasons for
this. One particularly important factor is that many studies
are underpowered to identify what are often relatively small
effects; this will inevitably introduce variability of results be-
tween studies. Other factors include differences in sample
ethnicity, with the inevitable differences in genetic make-up
between different ethnic samples. Different drug treatments
may be associated with different pharmacogenetic influences,
although it is important to note that, contrary to some sugges-
tions in the literature, there is so far little evidence for truly

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6 Psychiatry Investig 2012;9:1-7
Pharmacogenetics of Antipsychotic Response
drug-specific genetic associations. Other differences between
samples may introduce inconsistencies; the response to treat-
ment in first-episode and previously drug naïve patients may
well differ in underlying pharmacological mechanisms from
equivalent effects in patients with a chronic treatment history,
resulting in different pharmacogenetic associations. Further-
more the clinical phenotypes measured may often be com-
plex and multifactorial, composed of several physiological re-
sponses under different genetic control mechanisms, of which
the negative and positive syndromes provide just one example.
It should of course be remembered that symptom response
to drug treatment is inevitably dependent on treatment adher-
ence, and thus factors influencing compliance, such as unwant-
ed side effects, will also be important in determining good re-
sponse. Genetic factors also influence the emergence of ad-
verse drug effects, and thus pharmacogenetic associations
relating to the side effects of antipsychotic treatment, which
have not been reviewed here, may indirectly contribute to the
pharmacogenetic factors influencing symptom response.
Future work will need to overcome these many limitations
and discrepancies reported in the current literature. There is
need for a greater recognition of the potential importance of
gene-gene interactions and, as is increasingly apparent in un-
derstanding disease pathogenesis, gene-environment inter-
actions in understanding properly the risk factors contribut-
ing to poor response to antipsychotic treatment.
Nevertheless, the pharmacogenetics of antipsychotic drugs
has progressed enormously, and new findings are beginning
to take us towards a better understanding of the mechanisms
underlying the effects of these drugs. As the technology devel-
ops and genotyping of large numbers of SNPs in large samples
becomes cheaper and more accessible, findings from further
GWAS studies will, we hope, converge to give us consistent re-
sults. Identifying such results will open up opportunities for
predictive genetic testing, once their validity and, importantly,
utility in the clinic are established.
REFERENCES
1. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al.
Comparative efficacy and acceptability of antimanic drugs in acute ma-
nia: a multiple-treatments meta-analysis. Lancet 2011;378:1306-1315.
2. Vojvoda D, Grimmell K, Sernyak M, Mazure CM. Monozygotic twins
concordant for response to clozapine. Lancet 1996;347:61.
3. Mata I, Madoz V, Arranz MJ, Sham P, Murray RM. Olanzapine: concor-
dant response in monozygotic twins with schizophrenia. Br J Psychiatry
2001;178:86.
4. Reynolds GP. The impact of pharmacogenetics on the development
and use of antipsychotic drugs. Drug Discov Today 2007;12:953-959.
5. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Per-
kins DO, et al. Effectiveness of antipsychotic drugs in patients with
chronic schizophrenia. N Engl J Med 2005;353:1209-1223.
6. Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, et al. Ani-
mal models of cognitive dysfunction and negative symptoms of schizo-
phrenia: focus on NMDA receptor antagonism. Pharmacol Ther 2010;
128:419-432.
7. Meltzer HY, Massey BW. The role of serotonin receptors in the action of
atypical antipsychotic drugs. Curr Opin Pharmacol 2011;11:59-67.
8. Reynolds GP, Templeman LA, Godlewska BR. Pharmacogenetics of
schizophrenia. Expert Opin Pharmacother 2006;7:1429-1440.
9. Malhotra AK, Murphy GM Jr, Kennedy JL. Pharmacogenetics of psy-
chotropic drug response. Am J Psychiatry 2004;161:780-796.
10. Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and
clinical response to antipsychotic drug treatment: a meta-analysis. Am
J Psychiatry 2010;167:763-772.
11. Hwang R, Zai C, Tiwari A, Muller DJ, Arranz MJ, Morris AG, et al. Ef-
fect of dopamine D3 receptor gene polymorphisms and clozapine tr-
eatment response: exploratory analysis of nine polymorphisms and
meta-analysis of the Ser9Gly variant. Pharmacogenomics J 2010;10:
200-218.
12. Xuan J, Zhao X, He G, Yu L, Wang L, Tang W, et al. Effects of the dopa-
mine D3 receptor (DRD3) gene polymorphisms on risperidone resp-
onse: a pharmacogenetic study. Neuropsychopharmacology 2008;33:
305-311.
13. Xu MQ, St Clair D, Feng GY, Lin ZG, He G, Li X, et al. BDNF gene is a
genetic risk factor for schizophrenia and is related to the chlorproma-
zine-induced extrapyramidal syndrome in the Chinese population.
Pharmacogenet Genomics 2008;18:449-457.
14. Zhang A, Xing Q, Wang L, Du J, Yu L, Lin Z, et al. Dopamine transport-
er polymorphisms and risperidone response in Chinese schizophrenia
patients: an association study. Pharmacogenomics 2007;8:1337-1345.
15. Serretti A, Drago A, De Ronchi D. HTR2A gene variants and psychiat-
ric disorders: a review of current literature and selection of SNPs for fu-
ture studies. Curr Med Chem 2007;14:2053-2069.
16. Benmessaoud D, Hamdani N, Boni C, Ramoz N, Hamon M, Kacha F,
et al. Excess of transmission of the G allele of the -1438A/G polymor-
phism of the 5-HT2A receptor gene in patients with schizophrenia re-
sponsive to antipsychotics. BMC Psychiatry 2008;8:40.
17. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. As-
sociation of anxiety-related traits with a polymorphism in the serotonin
transporter gene regulatory region. Science 1996;274:1527-1531.
18. Dolzan V, Serretti A, Mandelli L, Koprivsek J, Kastelic M, Plesnicar BK.
Acute antipyschotic efficacy and side effects in schizophrenia: associa-
tion with serotonin transporter promoter genotypes. Prog Neuropsy-
chopharmacol Biol Psychiatry 2008;32:1562-1566.
19. Wang L, Yu L, He G, Zhang J, Zhang AP, Du J, et al. Response of ris-
peridone treatment may be associated with polymorphisms of HTT
gene in Chinese schizophrenia patients. Neurosci Lett 2007;414:1-4.
20. Lee HY, Kim DJ, Lee HJ, Choi JE, Kim YK. No association of serotonin
transporter polymorphism (5-HTTVNTR and 5-HTTLPR) with ch-
aracteristics and treatment response to atypical antipsychotic agents in
schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry
2009;33:276-280.
21. Mossner R, Schuhmacher A, Kuhn KU, Cvetanovska G, Rujescu D,
Zill P, et al. Functional serotonin 1A receptor variant influences treat-
ment response to atypical antipsychotics in schizophrenia. Pharmaco-
genet Genomics 2009;19:91-94.
22. Reynolds GP, Arranz B, Templeman LA, Fertuzinhos S, San L. Effect of
5-HT1A receptor gene polymorphism on negative and depressive symp-
tom response to antipsychotic treatment of drug-naive psychotic pa-
tients. Am J Psychiatry 2006;163:1826-1829.
23. Wang L, Fang C, Zhang A, Du J, Yu L, Ma J, et al. The --1019 C/G poly-
morphism of the 5-HT(1)A receptor gene is associated with negative
symptom response to risperidone treatment in schizophrenia patients.
J Psychopharmacol 2008;22:904-909.
24. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, et al.
Serotonin transporter promoter gain-of-function genotypes are linked
to obsessive-compulsive disorder. Am J Hum Genet 2006;78:815-826.
25. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, et al.

Page 7

GP Reynolds
www.psychiatryinvestigation.org 7
Impaired repression at a 5-hydroxytryptamine 1A receptor gene poly-
morphism associated with major depression and suicide. J Neurosci
2003;23:8788-8799.
26. Vazquez-Bourgon J, Arranz MJ, Mata I, Pelayo-Teran JM, Perez-Iglesias
R, Medina-Gonzalez L, et al. Serotonin transporter polymorphisms and
early response to antipsychotic treatment in first episode of psychosis.
Psychiatry Res 2010;175:189-194.
27. Adams DH, Close S, Farmen M, Downing AM, Breier A, Houston JP.
Dopamine receptor D3 genotype association with greater acute posi-
tive symptom remission with olanzapine therapy in predominately cau-
casian patients with chronic schizophrenia or schizoaffective disorder.
Hum Psychopharmacol 2008;23:267-274.
28. Meary A, Brousse G, Jamain S, Schmitt A, Szoke A, Schurhoff F, et al. Ph-
armacogenetic study of atypical antipsychotic drug response: involve-
ment of the norepinephrine transporter gene. Am J Med Genet B Neu-
ropsychiatr Genet 2008;147B:491-494.
29. Schuhmacher A, Mossner R, Quednow BB, Kuhn KU, Wagner M,
Cvetanovska G, et al. Influence of 5-HT3 receptor subunit genes HTR3A,
HTR3B, HTR3C, HTR3D and HTR3E on treatment response to anti-
psychotics in schizophrenia. Pharmacogenet Genomics 2009;19:843-
851.
30. Silver H. Selective serotonin re-uptake inhibitor augmentation in the tr-
eatment of negative symptoms of schizophrenia. Expert Opin Pharma-
cother 2004;5:2053-2058.
31. Bertolino A, Caforio G, Blasi G, Rampino A, Nardini M, Weinberger
DR, et al. COMT Val158Met polymorphism predicts negative symptoms
response to treatment with olanzapine in schizophrenia. Schizophr Res
2007;95:253-255.
32. Fijal BA, Kinon BJ, Kapur S, Stauffer VL, Conley RR, Jamal HH, et al.
Candidate-gene association analysis of response to risperidone in Af-
rican-American and white patients with schizophrenia. Pharmacoge-
nomics J 2009;9:311-318.
33. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan
MF, et al. Catechol-O-methyltransferase val108/158met genotype pre-
dicts working memory response to antipsychotic medications. Biol Psy-
chiatry 2004;56:677-682.
34. Bishop JR, Ellingrod VL, Moline J, Miller D. Association between the
polymorphic GRM3 gene and negative symptom improvement during
olanzapine treatment. Schizophr Res 2005;77:253-260.
35. Bishop JR, Miller DD, Ellingrod VL, Holman T. Association between
type-three metabotropic glutamate receptor gene (GRM3) variants and
symptom presentation in treatment refractory schizophrenia. Hum
Psychopharmacol 2011. in press.
36. Zuo L, Luo X, Krystal JH, Cramer J, Charney DS, Gelernter J. The effi-
cacies of clozapine and haloperidol in refractory schizophrenia are relat-
ed to DTNBP1 variation. Pharmacogenet Genomics 2009;19:437-446.
37. Mossner R, Schuhmacher A, Wagner M, Lennertz L, Steinbrecher A,
Quednow BB, et al. The schizophrenia risk gene ZNF804A influences
the antipsychotic response of positive schizophrenia symptoms. Eur
Arch Psychiatry Clin Neurosci 2011. in press.
38. Lemonde S, Du L, Bakish D, Hrdina P, Albert PR. Association of the C
(-1019)G 5-HT1A functional promoter polymorphism with antide-
pressant response. Int J Neuropsychopharmacol 2004;7:501-506.
39. Goldberg TE, Kotov R, Lee AT, Gregersen PK, Lencz T, Bromet E, et al.
The serotonin transporter gene and disease modification in psychosis:
evidence for systematic differences in allelic directionality at the 5-HT-
TLPR locus. Schizophr Res 2009;111:103-108.
40. Tollefson GD, Andersen SW, Tran PV. The course of depressive symp-
toms in predicting relapse in schizophrenia: a double-blind, randomiz-
ed comparison of olanzapine and risperidone. Biol Psychiatry 1999;46:
365-373.
41. Reynolds GP. Receptor mechanisms in the treatment of schizophrenia.
J Psychopharmacol 2004;18:340-345.
42. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, et al.
Pharmacogenetic prediction of clozapine response. Lancet 2000;355:
1615-1616.
43. Parsons MJ, D’Souza UM, Arranz MJ, Kerwin RW, Makoff AJ. The
-1438A/G polymorphism in the 5-hydroxytryptamine type 2A recep-
tor gene affects promoter activity. Biol Psychiatry 2004;56:406-410.
44. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to anti-
psychotics in patients with schizophrenia. CNS Drugs 2011;25:933-969.
45. Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: thera-
peutic efficacy and side effects prediction. Expert Opin Drug Metab To-
xicol 2011;7:9-37.
46. Muller DJ, De Luca V, Sicard T, King N, Hwang R, Volavka J, et al. Sug-
gestive association between the C825T polymorphism of the G-protein
beta3 subunit gene (GNB3) and clinical improvement with antipsychot-
ics in schizophrenia. Eur Neuropsychopharmacol 2005;15:525-531.
47. Anttila S, Kampman O, Illi A, Rontu R, Lehtimaki T, Leinonen E. Asso-
ciation between 5-HT2A, TPH1 and GNB3 genotypes and response to
typical neuroleptics: a serotonergic approach. BMC Psychiatry 2007;
7:22.
48. Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-
de-Abreu P, Hutz MH. G-protein gene 825C>T polymorphism is asso-
ciated with response to clozapine in Brazilian schizophrenics. Pharma-
cogenomics 2008;9:1429-1436.
49. Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP, et al. Ph-
armacogenetics of antipsychotic response in the CATIE trial: a candi-
date gene analysis. Eur J Hum Genet 2009;17:946-957.
50. Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dys-
function or dysregulation: the final common pathway on the road to
schizophrenia? Brain Res Bull 2010;83:108-121.
51. Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin
Psychiatry 2006;67(Suppl 9):9-13.
52. McClay JL, Adkins DE, Aberg K, Stroup S, Perkins DO, Vladimirov VI,
et al. Genome-wide pharmacogenomic analysis of response to treat-
ment with antipsychotics. Mol Psychiatry 2011;16:76-85.
53. McClay JL, Adkins DE, Aberg K, Bukszar J, Khachane AN, Keefe RS,
et al. Genome-wide pharmacogenomic study of neurocognition as an
indicator of antipsychotic treatment response in schizophrenia. Neuro-
psychopharmacology 2011;36:616-626.
54. Webb BT, Sullivan PF, Skelly T, van den Oord EJ. Model-based gene se-
lection shows engrailed 1 is associated with antipsychotic response.
Pharmacogenet Genomics 2008;18:751-759.
55. Spellmann I, Rujescu D, Musil R, Mayr A, Giegling I, Genius J, et al. Ho-
mer-1 polymorphisms are associated with psychopathology and re-
sponse to treatment in schizophrenic patients. J Psychiatr Res 2011;45:
234-241.
56. Ikeda M, Tomita Y, Mouri A, Koga M, Okochi T, Yoshimura R, et al.
Identification of novel candidate genes for treatment response to ris-
peridone and susceptibility for schizophrenia: integrated analysis among
pharmacogenomics, mouse expression, and genetic case-control asso-
ciation approaches. Biol Psychiatry 2010;67:263-269.
57. Lavedan C, Licamele L, Volpi S, Hamilton J, Heaton C, Mack K, et al.
Association of the NPAS3 gene and five other loci with response to the
antipsychotic iloperidone identified in a whole genome association
study. Mol Psychiatry 2009;14:804-819.
58. Volpi S, Potkin SG, Malhotra AK, Licamele L, Lavedan C. Applicability
of a genetic signature for enhanced iloperidone efficacy in the treat-
ment of schizophrenia. J Clin Psychiatry 2009;70:801-809.
59. Fijal BA, Stauffer VL, Kinon BJ, Conley RR, Hoffmann VP, Witte MM,
et al. Analysis of gene variants previously associated with iloperidone
response in patients with schizophrenia who are treated with risperi-
done. J Clin Psychiatry 2011. in press.