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1.
KEYWORDS
Abstract
Antipsychotic;
Drug response;
Neuroleptic;
Pharmacogenetics;
Pharmacogenomics;
Schizophrenia;
Tolcapone
One justication for the major scientic and nancial investments in genetic and genomic
studies in medicine is their therapeutic potential, both for revealing novel targets for drugs
which treat the disease process, as well as allowing for more effective and safe use of existing
medications. This review considers the extent to which this promise has yet been realised
within psychopharmacology, how things are likely to develop in the foreseeable future, and the
key issues involved. It draws primarily on examples from schizophrenia and its treatments. One
observation is that there is evidence for a range of genetic inuences on different aspects of
psychopharmacology in terms of discovery science, but far less evidence that meets the
standards required before such discoveries impact upon clinical practice. One reason is that
results reveal complex genetic inuences that are hard to replicate and usually of very small
effect. Similarly, the slow progress being made in revealing the genes that underlie the major
psychiatric syndromes hampers attempts to apply the ndings to identify novel drug targets.
Nevertheless, there are some intriguing positive ndings of various kinds, and clear potential
for genetics and genomics to play an increasing and major role in psychiatric drug discovery.
& 2013 Elsevier B.V. and ECNP. All rights reserved.
Introduction
Corresponding author.
E-mail address: paul.harrison@psych.ox.ac.uk
0924-977X/$ - see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved.
http://dx.doi.org/10.1016/j.euroneuro.2013.02.005
672
P.J. Harrison
Table 1 Genetic associations of selected antipsychotic side-effects: replicated ndings from case-control studies, and
positive ndings from GWAS.
Phenotype, gene, and SNP
42 positive reports?
Meta-analysis?
GWAS-positive?
Overall evidence
Weight gain
ADRA2A-1291C/G
GNB3 rs5443
HTR2A 267C/T
HTR2C 759C/T
Leptin 2548A/G
MC4R rs489693
MEIS2 rs1568679
Yes
Yes
Yes
Yes
Yes
No
No
N/A
Trend
N/A
Positive
N/A
N/A
N/A
No
No
No
No
No
Yes
Yes
+
++
+
+++
++
+++
++
Agranulocytosis
HLA-DRB1
HLA-DRB5
HLA-DQB1
Yes
Yes
Yes
N/A
N/A
N/A
No
No
No
+
+
++
Tardive dyskinesia
COMT rs4680 158V/M
CYP2D6
D2R/ANKK1 rs1800497
MnSOD rs4880 9A/V
Yes
Yes
Yes
Yes
Positive
Mixed
N/A
Mixed
No
No
No
No
++
+
+
+
The table is based on results presented or summarised in Adkins et al. (2011), Arranz et al. (2011), Arranz and Munro (2011), Lett et al.
(2012), Malhotra et al. (2012a) and Risselda et al. (2011), N/A, not available. Overall evidence is a subjective interpretation of the
available data, on a + to ++++ scale.
673
674
unique. In addition, the fact we only studied homozygotes
(to enhance the genetic effect), and selected a homogeneous (in terms of age and intelligence) group of young men
may have reduced the scope for age- and gender-related
variation in COMT function (Harrison and Tunbridge, 2008).
P.J. Harrison
test. Formally, the NNS is the reciprocal of the absolute
change in the likelihood of the outcome as a result of the
test. It reects both the frequency of the marker being
tested (i.e. genotype) as well as the size of its effect.
As noted by McMahon and Insel (2012), different NNS may be
appropriate in different situations. For example, a relatively high NNS may still be valuable if it relates to a severe
adverse event (e.g. agranulocytosis), whereas a much lower
NNS would be needed to be useful when choosing between
two otherwise comparable treatments. Consideration of the
appropriate NNS could be factored into the further
discussion which is required as to the criteria to be adopted
when deciding when and how to introduce a pharmacogenetic test into clinical practice (and into clinical trials;
Relling and Klein, 2011), as well as on how to monitor the
tests implementation and impact (Khoury et al., 2010).
Thought also needs to be given on how to educate clinicians
in genomics (Winner et al., 2010), and in how to use such
information to guide actuarial decision-making (Khoury
et al., 2010).
4.1.
675
Table 2 Drug targets under investigation for cognitive improvement in schizophrenia for which genetic evidence to the
disorder has emerged.
Gene
Description/therapeutic rationale
DAO
GRM3
Type of
drug
Linkage to
schizophrenia
Association to
schizophrenia
Inhibitor
Agonist
+
+
++
++
Inhibitor
+++
Agonist
++
Antagonist +
Inhibitor
+
Inhibitor
+
Inhibitor
++
+
+
++
+
++
++
Linkage: evidence that the gene locus shows linkage to schizophrenia. Association: evidence for genetic association to schizophrenia.
Ratings are a subjective interpretation of the evidence, on a + to ++++ scale.
676
other KCNH2 transcripts were not) and shown to encode a
protein with distinct electrophysiological properties which
they speculated might contribute to disorganised neuronal
ring in schizophrenia. They further suggested that a
selective inhibitor of KCNH2-3.1 could restore normal
potassium conductance kinetics in schizophrenia and thence
be an effective treatmentand free of the cardiac sideeffects which a drug acting on all forms of hERG1 would be
likely to have. Whilst this prediction remains to be tested, it
is of interest that rs1036145 has now been shown to affect
therapeutic response to existing antipsychotics (Apud et al.,
2012). Other examples where genetically-inuenced expression of specic isoforms may be therapeutically relevant
include an exon-skipping variant of GRM3 (Sartorius et al.,
2006, 2008), and the short and long isoforms of DRD2 (Barrie
et al., 2012).
A second issue is that all the known psychosis-associated
SNPs confer only a small increase in disease risk, usually
with an odds ratio of less than 1.2, meaning that the overall
functional impact (or therapeutic potential) of any given
SNP is correspondingly modest. Thus, the impact of a drug
correcting whatever effect the risk allele of rs1344706 (odds
ratio 1.1; Williams et al., 2011) might have on ZNF804A
function is not obvious. On the other hand, there are
examples from diabetes and psoriasis where drugs which
target genes of similarly small effect have proven to have
efcacy, so there is some room for optimism (Muglia, 2012).
Thirdly, the function of the encoded protein is itself often
unknown or, if known, does not seem likely to be a tractable
therapeutic target. ZNF804A also illustrates this point. Its
name comes from its zinc nger protein motif suggesting
that it belongs to this family of transcription factors (genes
encoding proteins which bind to DNA and regulate expression of other genes). However, little direct information is
available, for example, as to the genes which it regulates
(Girgenti et al., 2012; Hill et al., 2012) and the biological
consequences of allelic variation in rs1344706 (Hill and Bray,
2011). Moreover, if ZNF804A is indeed a transcription factor,
it is difcult to predict the consequences of pharmacologically modifying its actions (because it has so many downstream effects), and it may not be a readily druggable
target anyway (Hopkins and Groom, 2002) since it is likely to
act primarily in the nucleus and during development. Likewise, therapeutic targeting of MIR137, a microRNA would be
a substantial challenge since microRNAs do not encode a
protein product, but are small intracellular molecules which
are functional in their own right.
Fourthly, as noted earlier, in addition to common SNPs of
small effect, there are also CNVs which are risk factors for
psychosis conferring much higher odds ratios (typically 6 or
more; Mowry and Gratton, 2013). As such, correction of
whatever deleterious consequence the CNV causes would
seem more likely to be benecial, but this type of genetic
target has its own therapeutic limitations. The rarity of any
given CNV means that there would be very few patients with
the abnormality; on the other hand, if the CNV reveals a
gene which is in fact important more broadly in patients
with the disorder, then any therapeutic benets might also
generalise (Talkowksi et al., 2012). Also, many CNVs disrupt
multiple genes and so it is not clear what the therapeutic
target(s) would be. One notable exception is the VIPR2
locus, duplication of which is associated with schizophrenia
P.J. Harrison
(Vacic et al., 2011). VIPR2 encodes the vasoactive intestinal
peptide 2 receptor (VPAC2) which activates cAMP, and
represents a plausible therapeutic target, not least since
drugs acting on the receptor have already been developed
for a range of disorders (Groneberg et al., 2006).
p110
PIP3*
CYT2
SHC
P110*
MAPK
AKT1/PKB*
677
5.
Conclusions
678
sufcient amounts of the variance to be clinically useful,
either as predictors of response, or to be considered effective
(and druggable) targets. These notes of caution are not
intended to diminish the importance of, nor enthusiasm for,
genetics and genomics as an essential component of neuropsychopharmacological research programs and trial designs.
They do, however, suggest that premature or exaggerated
claims as to the signicance of ndings, especially with regard
to their clinical therapeutic utility, should be avoided.
Contributors
I was the author of this manuscript and take sole responsibility
for it.
Conict of interest
In the past three years, I have received honoraria for lectures from
AstraZeneca, Janssen, Otsuka and Takeda, for consulting from
Merck, and an unrestricted educational grant from Takeda. I have
acted as an expert witness in a pharmaceutical patent case.
Acknowledgement
I am grateful to the many current and past members of the group,
and our collaborators, whose ideas and ndings have shaped my
thoughts and the opinions expressed here. Particular thanks are due
to Elizabeth Tunbridge, Amanda Law and Daniel Weinberger.
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