645269

research-article2016
JOP0010.1177/0269881116645269Journal of PsychopharmacologyGoetghebeur and Swartz

Commentary

True alignment of preclinical and

clinical research to enhance success in
CNS drug development: a review of the Journal of Psychopharmacology

current evidence
1­–9
© The Author(s) 2016
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0269881116645269
jop.sagepub.com

Pascal JD Goetghebeur1 and Jina E Swartz2

Abstract
Central nervous system pharmacological research and development has reached a critical turning point. Patients suffering from disorders afflicting
the central nervous system are numerous and command significant attention from the pharmaceutical industry. However, given the numerous failures
of promising drugs, many companies are no longer investing in or, indeed, are divesting from this therapeutic area. Central nervous system drug
development must change in order to develop effective therapies to treat these patients. Preclinical research is a cornerstone of drug development;
however, it is frequently criticised for its lack of predictive validity. Animal models and assays can be shown to be more predictive than reported
and, on many occasions, the lack of thorough preclinical testing is potentially to blame for some of the clinical failures. Important factors such as
translational aspects, nature of animal models, variances in acute versus chronic dosing, development of add-on therapies and understanding of the
full dose–response relationship are too often neglected. Reducing the attrition rate in central nervous system drug development could be achieved by
addressing these important questions before novel compounds enter the clinical phase. This review illustrates the relevance of employing these criteria
to translational central nervous system research, better to ensure success in developing new drugs in this therapeutic area.

Keywords
CNS, translation, U-shape

Date received: 6 November 2015; revised: 15 March 2016; accepted: 28 March 2016

Introduction
Research into effective pharmacological treatments to alleviate
psychiatric and neurological disorders has, especially in recent
years, suffered from a critical lack of success, resulting in expen-
sive and often spectacular failures in phase III clinical trials
(Carroll, 2013; Kidwell et al., 2001; Kresge, 2014; Sadeghi-Nejad,
2012). A spate of recent costly unsuccessful development path-
ways in central nervous system (CNS) indications, including
Alzheimer’s disease and schizophrenia, have resulted in smaller
companies leaving this therapeutic area, while many larger ones
have dramatically downscaled their CNS development pro-
grammes or pulled out of the arena altogether (Abbott, 2011;
Kaitin and Milne, 2011; Miller, 2010). Tellingly, GSK, AstraZeneca
and Novartis have closed their neuroscience divisions, while
Pfizer, Sanofi, Janssen and Merck have significantly downsized
their CNS facilities and programmes (Skripka-Serry, 2013).
One of several of the significant contributors to this high attri-
tion rate is purportedly a potential lack of predictive validity of
the animal models used in early phase CNS drug development
(Akhtar, 2015; Matthews, 2008; Witten et al., 2016). Although it
is simultaneously recognised that animal research is an essential,
necessary and mandatory component of the development path-
way, it is self-evident that humans and animals, rodents in par-
ticular, are different biological entities at many levels. However,
a relatively high number of complex mechanisms and circuitries
are shared between species at the CNS level, among them cogni-
tive constructs and processes including executive function, spa-
tial memory, working memory, impulsivity and attention.
One example, among many, of a cognitive mechanism pre-
served across species, is that of sensorimotor gating, the ability to
filter out irrelevant from relevant information. This phenomenon,
present in humans (Hashimoto, 2005; Witten et al., 2016), rodents
(Ma et al., 2015; Yang et al., 2015) and zebrafishes (Burgess and
Granato, 2007; Knogler and Drapeau, 2014), can be disrupted in
all three species with a dopamine agonist (Burgess and Granato,
2007; Larrauri et al., 2015; Talledo et al., 2009), thus mimicking
the deficit seen in patients with schizophrenia. The abnormal
response can further be reversed by antipsychotic agents in these
three species (Burgess and Granato, 2007; Csomor et al., 2014;
Zangrando et al., 2013). On the other hand, doubts are raised
1Cognition Research Group, Takeda Cambridge Ltd, Cambridge, UK
2CNS Therapeutic Area Unit, Takeda Development Centre Europe Ltd,
London, UK
Corresponding author:
Pascal Goetghebeur, SynAging, 2 rue du Doyen Marcel Roubault, TSA
70605 54518 Vandoeuvre-les-Nancy, France.
Email: pascal.goetghebeur@synaging.com

Downloaded from jop.sagepub.com at Oakland University on June 5, 2016

2 Journal of Psychopharmacology
about human to rat cross-species translational capabilities in this
assay (Witten et al., 2016) because drugs reversing sensorimotor
gating deficit in rodents are inefficacious clinically. However, as
explained below, assessing the effect of a single dose of a drug in
such an assay is not informative enough and a full dose response
is necessary in order to make a valid comparison of like for like.
More importantly, for truly valid comparison the same endpoint
should be evaluated in both species along with assessment of the
circuitries involved. As pointed out in the paper there is no con-
sensus among scientists for the rodent equivalent of the human
P50, therefore no definite conclusion about its cross-species
translational capabilities can be drawn.
In order best to compare animal and human research it is
important to ensure that, in both instances, the same ‘signal’
(assay) is measured, using an analogous or comparable ‘protocol’
(methodology) including the use of multiple disease model(s)
and that several doses are tested, given the potential Yerkes–
Dodson effect (also known as the inverted U-shape model). All
these components should be commonly applied to animal and
human investigation, to ensure the translatability of the overall
research paradigm.
Signal measured
If a potential new drug shows efficacy pre-clinically in a specific
cognition test like the novel object recognition test (investigating
visual memory), then a true comparison in the clinical investiga-
tion process must be a similar visual memory task that engages
the same brain area(s), using a comparable range of memory
retention intervals that is species-specific. In these instances, a
composite cognitive assessment tool in which visual memory is a
contributory subcomponent of the overall scale (e.g. as in the
Alzheimer’s disease assessment scale-cognitive subscale, also
known as the ADAS-Cog, a well-established tool used in the
assessment of mild to moderate Alzheimer’s disease and some
disorders of cognition) is an inappropriate outcome measure
(Cano et al., 2010), not least because the signal generated by the
relevant cognitive subdomain assessed is subsumed within the
‘noise’ of the total score. In this respect preclinical back-trans-
lated assays, that is, preclinical assays derived from human ones
in a specific animal (i.e. rodent), simultaneously measuring the
same cognitive subdomain as in the human and showing the
involvement of the same circuitry(ies) are the best options for use
in the drug development pathway, as these will ensure optimal
and relevant translation into the clinic. A potential comparable
human version of the spontaneous object recognition test could
be the visual paired comparison (Wallace et al., 2015) and this
test seems to be of relevance for Alzheimer’s disease (Crutcher
et al., 2009; Zola et al., 2013). These two paradigms do not only
share face validity but also construct validity because they are
temporal lobe-mediated in many species, including humans
(Buffalo et al., 1999; Crutcher et al., 2009; Pihlajamaki et al.,
2004; Winters et al., 2004). It is, however, striking that no drug
studies have been published thus far using this paradigm in
humans. These studies would help to unveil the true potential
translational value of spontaneous object recognition.
Back-translated assays are few and far between in CNS drug
discovery and it is essential that more of them are successfully
developed and utilised, to facilitate better chances of success
in the clinic. One such assay is the attentional set-shifting task
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
(ASST) paradigm, which aims to evaluate alterations in a spe-
cific aspect of executive control and cognitive flexibility, namely
attentional set-shifting abilities. This assay has successfully dem-
onstrated improvement of the extra-dimensional shift with sev-
eral pharmacological interventions in patients with schizophrenia
or schizophrenia-like rodent models including erythropoietin
(Ehrenreich et al., 2007; Goetghebeur et al., 2010), sertindole
(Gallhofer et al., 2007; Goetghebeur and Dias, 2009) and
modafinil (Goetghebeur and Dias, 2009; Morein-Zamir et al.,
2007; Scoriels et al., 2012, 2013; Turner et al., 2004).
However, as a counterpoint, the potential failure of the pre-
dictive validity of this assay has been demonstrated by the recent
development programme of CX516 (Goff et al., 2008), an
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-
tor positive allosteric modulator for schizophrenia and a small
clinical trial with modafinil (Clinical Trial ID: NCT00057707,
NCT00573417). The authors try not to argue that animal
research is always tightly correlated to human research.
However, in the case of CX516, only its acute effects in rodents
have been investigated and no combination studies with antipsy-
chotics have been reported, as in the human context. Both
chronic treatment effects and the use of CX516 as an add-on to
antipsychotic therapies must be investigated before any conclu-
sions about the predictive validity (the ability of the preclinical
assay to predict a modulation of the behaviour that can be trans-
posed to humans) of the assay can be drawn. The same applies to
modafinil, which is efficacious acutely in the ASST in patients
with schizophrenia (Turner et al., 2004) as well as in a rodent
schizophrenia disease model (Goetghebeur and Dias, 2009). Yet,
this effect was not replicated in a small clinical trial in patients
with chronic schizophrenia, as mentioned above. It is therefore
important to pay close attention to the differences between pre-
clinical and clinical studies for any given compound. Firstly, just
like the CX516 studies, no preclinical studies were conducted to
investigate chronic treatment; neither were antipsychotic combi-
nation studies reported preclinically. Secondly, the small clinical
trial used the (–)-(R)-enantiomer of the compound, unlike the
rodent (Goetghebeur and Dias, 2009) and clinical (Turner et al.,
2004) studies, which could further account for the observed dis-
crepancies between the outcome in the animal and human schiz-
ophrenia studies. Finally, modafinil has been shown to
demonstrate an inverted U-shape dose–response curve on cogni-
tion in humans (Finke et al., 2010) and rodents (Shuman et al.,
2009), but this effect pattern has never been investigated in the
attentional set-shifting paradigm. Hence, we do not know
whether such a hormetic response can be used to explain the
observed difference between the animal and human studies. To
date the closest, and the only, comparison to be made between
preclinical and clinical investigation of modafinil are between
the Turner et al. (2004) and Goetghebeur and Dias (2009) stud-
ies. These two studies showed that preclinical assays can be of
good predictive validity.
Clinical versus preclinical protocol
The second factor for consideration when comparing animal and
human studies is that of the methodology used in both. Preclinical
investigational set ups cannot always be devised to mimic clini-
cal ones; however, it is sometimes possible to ensure similarity
between such assessment and investigational protocols. This is
Goetghebeur and Swartz 3
very important for translation from animals to humans, as ele-
gantly presented by Professor Grace’s group (Gill et al., 2014).
This group investigated the impact of short antipsychotic with-
drawal, as performed in the clinical set up, in an animal model of
schizophrenia, and demonstrated the lack of efficacy of the
investigational treatment when antipsychotic withdrawal is per-
formed before treatment is initiated. The likely hypothesis is that
the dopamine hypersensitivity resulting from antipsychotic with-
drawal results in difficulties in developing and successfully test-
ing novel antipsychotics in isolation, and renders the development
of new drugs as an add-on strategy for either negative or cogni-
tive symptoms of schizophrenia more attractive. However, for
add-on therapy, this would require preclinical testing of new
compounds as an add-on to a relevant antipsychotic subchronic
or chronic treatment. Publications describing this approach are
currently very scarce or non-existent.
One of the main and recurrent issues in preclinical testing is
the lack of complete understanding as to what the assays really
measure and the potential impact of other behaviour(s) on the
measure of interest in the considered assay. This is why: (a) sin-
gle use of behavioural assays (e.g. marble burying test; forced
swim test) potentially responding to a specific mechanism of
action should be avoided for proof of efficacy; and (b) thorough
behavioural investigation of the effect of a drug in relevant
behavioural assays is necessary to rule out any other masking
behaviour(s). Obviously behavioural homology between humans
and animals, namely behavioural similarities observed across
species manifesting as a similar behavioural pattern, resulting
from outputs from a specific shared brain structure (Roberts,
1996) or gene/gene pathway (Reuame and Sokolowski, 2011) is
a prerequisite. Moreover, one could be even more stringent and
use only tasks in which learning is similar (Mennenga et al.,
2014, Possin et al., 2016; Woolley et al., 2013).
One of the major initiatives in the neuroscience field for
enhancing translational research has been the cognitive neuro-
science treatment research to improve cognition in schizophre-
nia (CNTRICS) (Carter et al., 2008). This has led to the selection
of defined preclinical tools (imaging, biomarker and behavioural
assays) aligned with the clinical initiative equivalent: measure-
ment and treatment research to improve cognition in schizophre-
nia (MATRICS) (Green et al., 2004; Marder and Fenton, 2004).
The CNTRICS initiative gives a theoretical preclinical road map
for the development of drugs designed to improve cognition in
schizophrenia; however, in the authors’ view, it is very unlikely
that the industry, in the current climate, will adhere preclinically
to this road map to facilitate cutting down drug development
time. Although the MATRICS initiative has successfully pro-
vided a brief battery of cognitive assessment tools to evaluate
key cognitive domains in schizophrenia, several additional
domains of function impaired in patients with schizophrenia
could not be categorised according to the MATRICS domains. In
addition, these initiatives only cover specific Diagnostic and
Statistical Manual of Mental Disorders (DSM)-V-defined dis-
eases; therefore, initiatives covering other diseases or symptom
complexes are needed, but remain elusive. Rather, initiatives
looking at behavioural domains in a disease agnostic way, like
the research domain criteria (RDoC) initiative, may prove to be
more relevant.
This scrupulous alignment of assays and protocols between
the clinical and preclinical context is a prerequisite; yet it still
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
does not ensure clinical success. In addition, rodent disease mod-
els must be carefully selected with respect to the patient popula-
tion. However, these are only models of the disorders or, indeed,
a component aspect of the complete syndrome. This could be the
main reason for lack of translatability. Therefore, testing a drug
in different models of the target disease is important, to increase
probability of success (Jucker, 2010). The scope of this review is
not to debate the modelling of CNS diseases in animals as these
are reviewed elsewhere (McGonigle, 2014; Nestler and Hyman,
2010); however, selecting a disease model displaying some face,
construct and predictive validity and sharing similarities, not
only behavioural ones, but also at a cellular and biochemical
level, with the targeted patient population is important for subse-
quent clinical testing. Patient stratification then becomes an
important factor, yet it is very often neglected. For successful
drug development one may consider the benefit derived from
investigating drug effect in multiple disease models for a given
disease from which positive results will then guide a clinical trial
in a specific patient population(s) – not only for phase II, but also
phase III, clinical studies.
Notwithstanding, the RDoC initiative is paving the way to a
different approach towards diseases, investigating symptoms and
associated circuitries rather than diseases as defined by the DSM-
V. Thus modelling of specific symptoms in animals rather than a
disorder (see Fernando and Robbins, 2011, for review) is becom-
ing more attractive and more realistic at the preclinical level. This
approach could bring preclinical and clinical research closer
together, making the preclinical approaches more translational
and thereby proving to be a better approach for clinical success.
Another important aspect to consider is that the clinical meas-
urement of functional outcome is frequently achieved by using
questionnaires or test batteries that generate a composite score.
Indeed, it is obvious that a better overall functional outcome is
achievable if multiple impaired behavioural domains are
addressed rather than just one. In addition, the present regulatory
framework dictates that drugs cannot be approved on the basis of
a positive or significant impact on one, or even several, cognitive
domains. However, the recent US Food and Drug Administration
approval of vortioxetine for certain aspects of cognitive dysfunc-
tion in major depressive disorder (Fiore, 2016) may signal a new,
and more encouraging, regulatory approach, that may further
encourage the use of cognitive and/or behavioural stratification
in phase III or pivotal studies.
Historically, a licence is only granted if a significant and rel-
evant improvement in patients’ global outcome can be shown,
with a clear and definite demonstration of clinical meaningful-
ness and impact on quality of life measures. These complex per-
formance and functional outcomes are not measured by any
single assay. It is therefore necessary preclinically to assess the
potential effect of a drug on various subdomains as one given
drug will have different effects on different behavioural domains,
with an efficacious dose in one given domain being potentially
very different from another one.
In this respect, Canal and Imbimbo (1996) investigated the
effect of the acetylcholinesterase (AchE) inhibitor eptastigmine
on different cognitive tests in patients with probable Alzheimer’s
disease, and reported a differential effect of AchE inhibition on
these domains. In that study, an effect on logical memory and
semantic word fluency is seen at 30% AchE inhibition, whereas
an effect on trail making B is seen only at 40% inhibition. Hence,
4 Journal of Psychopharmacology
a different dose response curve can be delineated for each differ-
ent cognitive subdomain in response to the same drug therapy at
the same efficacious dose. Müller and colleagues (2012)
described the effect of the antipsychotic amisulpiride on several
symptoms and similarly demonstrated differential modulation.
Recently Fallon et al. (2015) demonstrated the inverted U-shape
nature of two different cognitive tasks (investigating two cogni-
tive domains) in Parkinson’s disease patients and, of equal
importance, a differential optimal dopamine levels for these two
tasks. The same phenomenon can be found preclinically. Berridge
and colleagues (2012) demonstrated differential effects of a dose
of methylphenidate in rats on two cognitive domains, namely
sustained attention and working memory. Therefore, drug devel-
opment should take into consideration not only one, but several,
domains impacted in a given disease when considering optimum
dose selection.
Dose selection: the Yerkes–Dodson
principle
To complicate the picture further, the dose–effect relationship is
very often non-linear within the CNS, as well as in the periphery.
The concept of the inverted U-shape comes from animal studies
and was first demonstrated in 1908 by Yerkes and Dodson (1908)
in their ‘dancing mice’ experiment, in which they established the
biphasic effect of arousal on cognition. This principle established
a relationship between stress and performance whereby stress
improves performance to a certain level, after which performance
then decreases. Clinical investigation has continued to demon-
strate this effect in humans (de Veld et al., 2014; Ossewaarde
et al., 2011; Schilling et al., 2013) and this paradigm is now well
recognised. Further clinical evidence has shown that numerous
drugs can exert a biphasic effect on different and various behav-
ioural domains, although these data are scarce given the cost of
testing multiple drug doses of a drug in experimental settings
(Canal and Imbimbo, 1996; Fallon et al., 2015). Antihypertensive
medication (Peng et al., 2014; Razay et al., 2009), cholinergic
modulators (Canal and Imbimbo, 1996; Poltavski et al., 2012;
Soncrant et al., 1993; Wilens et al., 2006), antipsychotics (Müller
et al., 2012; Santos et al., 1989), dopaminergic agents (Chowdhury
et al., 2012; Tipper et al., 2005) and antidepressants (Ericksen,
1979) are all shown to modulate various clinical endpoints
according to an inverted U-shape dose–response curve.
Bridging clinical and preclinical research, Soncrant et al.
(1993) tested the effect of the non-selective muscarinic acetyl-
choline receptor agonist arecoline, administered as an infusion,
in Alzheimer’s disease patients and demonstrated an inverted
U-shape relationship between the dose of the drug and verbal
memory. A biphasic effect of arecoline was later demonstrated
(Bartolomeo et al., 1997) in the rat in a spatial working memory
assay. In a similar fashion, the AchE inhibitor eptastigmine
showed a biphasic effect upon the mini mental state examination
(MMSE) score and several cognitive domains (Canal and
Imbimbo, 1996). Others have demonstrated such a biphasic
curve preclinically with other AchE inhibitors in primates (Ou
et al., 1997) and rodents (Braida et al., 1996, 1998; Flood et al.,
1981; Waite and Thal, 1995; Wanibuchi et al., 1994).
Indeed, this phenomenon has been shown preclinically in a
number of species including non-human primates (Aigner and
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
Mishkin, 1998; Arnsten et al., 1994; Castner et al., 2014; Eddins
et al., 2014; Matsuoka and Aigner, 1996; Vijayraghavan et al.,
2007) and rodents (Braida et al., 1996; Clark et al., 1998;
Hosseini-Sharifabad et al., 2012; Salehi et al., 2010; Stoiljkovic
et al., 2015; Uslaner et al., 2009). It is important to note that the
described inverted U-shape dose–response curves are not due to
the appearance of other drug-related competitive behaviours or
toxic effects.
These biphasic curves are not assay or domain dependent
because they have been described for executive function in an
attentional set-shifting paradigm (Jones et al., 2014), working
memory (Berridge et al., 2012), spatial memory (Park et al.,
2010; Wise and Lichtman, 2007), social investigation (Gacsályi
et al., 2013), anxiety (Foreman et al., 2009; Hendrie et al., 1993;
Vaidya et al., 2005) and visual memory (Horiguchi et al., 2013;
Uslaner et al., 2009), among many others.
Various classes of drugs including dopamine agonists
(Horiguchi et al., 2013; Khroyan et al., 1995), acetylcholine ester-
ase inhibitors (Braida et al., 1996; Van Dam et al., 2005), alpha7
nicotinic acetylcholine receptor agonists (Jones et al., 2014), neu-
ropeptide Y (Flood et al., 1987), metabotropic glutamate receptor
5 positive allosteric modulators (Uslaner et al., 2009), NMDA
receptor potentiators (Matsuoka and Aigner, 1996), histamine H3
receptor antagonists (Esbenshade et al., 2012), interleukin-1
(Goshen et al., 2007), pituitary adenylate cyclase-activating poly-
peptide hormone (Sacchetti et al., 2001), phosphodiesterase type
5 inhibitors (Prickaerts et al., 2005) and others (Quevedo et al.,
1998) have demonstrated a similar effect in rodents.
These biphasic dose–response curves can further be explained
at the cellular or molecular level. For example, AchE inhibitors
modulate the cognitive signal in a biphasic manner in humans
(Canal and Imbimbo, 1996) and rodents (Godley et al., 2014). At
a cellular level donepezil modulates long-term potentiation of
population spike in the CA1 region of rat hippocampal slices in a
similar fashion (Kapai et al., 2012), providing a rationale for this
phenomenon at the supra-behavioural level.
Glycine transporter 1 (GlyT1) inhibitors are also shown to
exert an inverted U-shape dose–response curve upon cognition in
rhesus monkeys (Castner et al., 2014; Eddins et al., 2014) and
rodents (Harada et al., 2012). To the authors’ knowledge, limited
cognitive clinical data with GlyT1 inhibitors have been published
(Tsai et al., 2014); only the effect on negative symptoms of schiz-
ophrenia indicating an inverted U-shape dose–response curve has
been demonstrated. Recently Spiros et al. (2014) investigated the
effect of glycine upon negative symptoms of schizophrenia using
a computer-based quantitative system pharmacological approach
and found an inverted U-shape dose response, with low dose gly-
cine being optimal. However, and in disagreement with the view
of this paper’s authors on the lack of predictive validity of animal
models, GlyT1 inhibition showed an inverted U-shape in animal
models as referenced above. Moreover, at a non-behavioural
level GlyT1 inhibitors do modulate excitatory postsynaptic cur-
rent in a biphasic manner, again providing a rationale for the
observed behaviour (Alberati et al., 2012). The same could apply
for the putative cognition enhancer H3 antagonist, as it displays
biphasic modulation of rodent cognition (Esbenshade et al.,
2012) and the hippocampal neural cell adhesion molecule poly-
sialylation state (Foley et al., 2009).
Preclinically, other biological entities or phenomena such as
neurotransmitter modulation (Huang et al., 2014), brain-derived
Goetghebeur and Swartz 5
neurotrophic factor levels (Mamounas et al., 2000), electrophysi-
ological assessments (Hiyoshi et al., 2014; Stoiljkovic et al.,
2015), long-term depression (Zhang et al., 2008), long-term
potentiation (Kroker et al., 2011; Otani et al., 2015), oestrogens
(Luine and Frankfurt, 2012) and N-methyl-d-aspartate receptor
subunits (Uslaner et al., 2009) display a biphasic modulation in
relation to the dose of a drug.
In summary, evaluating a drug effect upon a specific behav-
ioural domain between species or between laboratories in the
same species should carefully take into consideration the dosage
being assessed and preferably test a broad range of doses. It is
especially important to be cognisant that, as a consequence of
this effect, higher drug concentrations or doses do not always
(and indeed, rarely) mean a better response. This inverted
U-shape could therefore explain many of the contradictory find-
ings reported in the scientific literature.
The preceding discussion has concentrated on describing the
inverted U-shape relative to one specific domain. However, over-
all individual functionality is composed of many behavioural
domains that could be potentially impacted in a given disease.
Neurotransmitters or drugs could modulate various behavioural
domains, but not in a similar way or at the same dosage. The
interrelations between the different inverted U-shape curves
should be taken into detailed consideration when effectively tar-
geting a positive functional outcome in the clinic. Very few pre-
clinical studies investigate the effect of a drug upon various
cognitive domains using the same species, strain and disease
model across a wide range of doses. Modulation of only one spe-
cific behavioural domain is often the rule for compound progres-
sion in the clinic and, if several domains are investigated, the
relationship between them is rarely further assessed. A full
behavioural profile of the drug is necessary preclinically to
ensure increased likelihood of clinical success.
A positive functional outcome in the clinic may only be
observed if the potential for multiple (and non-aligned) inverted
U-shapes are taken into consideration. As elegantly demon-
strated by Hills and Hertwig (2011), an optimum gain on behav-
ioural domain A could have a high impact on behavioural
domain B if the two biphasic dose–response curves are not
overlapping. Methylphenidate shows a biphasic modulation of
both these cognitive subdomains (Berridge et al., 2012).
However, these curves do not overlap. While the optimal dose
of the drug for working memory is 0.5 mg/kg, the optimum
dose for sustained attention is 2 mg/kg. If this drug is to be used
to improve the overall symptoms of a disease in which both
working memory and attentional processes are perturbed, dose
selection would need to be tightly defined in order not to exceed
the dose at which working memory is no longer positively
responsive.
Furthermore, it is not only the positive modulation of dys-
functional behavioural domain(s) by the drug that should be
addressed, but also the potential of a novel compound to impact
negatively on some domains. There could feasibly be a dose
range above which a drug would negatively modulate one or sev-
eral behavioural domains, thus impacting on the overall benefit
of the treatment. A primary example of such complex inverted
U-shape interrelations has been demonstrated with the neuro-
transmitter dopamine: dopamine modulates circuitries differen-
tially with different optimum responses (Fallon et al., 2015;
Fern-Pollak et al., 2004; Metha et al, 2001).
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
Finally, it is also crucial that the specific biological abnormal-
ity at a given stage in a disease process is considered. As neuro-
degenerative disorders progress, the neuronal architecture is
progressively eroded, such that the potential target upon which a
drug acts may change in structure or biochemical make-up, or
even entirely disappear. Hence, it is important to consider that a
drug effect may interact with, or be dependent upon, pathological
processes during the progression of a disease and vary according
to the disease stage or severity. The dose–response curve of a
given agent may therefore change as a disease progresses, such
that therapeutic benefit is only observable at a given severity or
pathological stage of the disease. Parkinson’s disease, and the
change in responsiveness to dopamine replacement therapies, is a
good example of such a disorder demonstrating this effect.
However, it is not only the change in response to l-dopa respon-
siveness, but evidence of differential frontostriatal and visuospa-
tial cognitive impairment at differing disease stages, which
exemplifies this (Owen et al., 1992, 1993). Hence, the need for a
specific therapeutic intervention will change during the course of
the disorder, depending on the disease stage.
This review has mainly focused on behavioural aspects of
preclinical and clinical research because the endpoint(s) of clini-
cal studies are ultimately amelioration of the symptoms.
However, in addition to the discussion above, differences in phar-
macokinetic parameters between animals and humans, target
engagement measures (e.g. electroencephalogram, magnetic res-
onance imaging, positron emission tomography occupancy data
and/or other imaging parameters and biochemical readouts) in
both animals and humans whenever possible must also be part of
the decision process to progress a drug further into the clinic.
Indeed, it is essential (but somehow often remains elusive in the
current state of knowledge of numerous CNS diseases) to obtain
a reliable biomarker and to show engagement of the target and
circuitry(ies). This could be further linked to the optimal effec-
tive dose if the drug showed an inverted U-shape dose response.
All these aspects need to be taken into account when optimising
dose selection in the clinic. For example, Bakker et al. (2015)
recently showed that levetiracetam enhanced cognition in mild
cognitive impairment patients consistent with an inverted
U-shape dose–response curve, while the functional MRI signal
followed the same pattern.
From phase II to phase III
The genesis of a drug starts several years, if not decades, before
its potential launch and should be based on a strong scientific
hypothesis. Preclinical research brings together all the scientific
disciplines in order to establish proof of mechanism and, ulti-
mately, proof of concept (POC) in animals, thereby understand-
ing the biology of the target while, potentially, finding relevant
biomarkers that can be taken into the clinic to define the respon-
sive patient population or aid in predicting a therapeutic
response. As the compound is progressed into humans, tradition-
ally from healthy volunteers into the targeted patient population,
POC must be demonstrated by the end of phase II to facilitate
confidence in moving into the larger, registration studies of
phase III. As discussed above, a selected compound that is likely
to demonstrate a biphasic dose response preclinically and clini-
cally, potentially impacts positively upon deficiencies in one or
several specific behavioural domains (but not all) and is linked
6 Journal of Psychopharmacology
to a strong scientific rationale. All these factors define the spe-
cific clinical population that the drug should target.
Yet many companies may prematurely or inappropriately
embark on the phase IIb/III clinical trials setting based on mar-
ginal efficacy readouts, inappropriate subgroup findings, ineffi-
cient data analyses and questionable conclusions generated by
both preclinical and preceding clinical studies. It is also worrying
that many CNS development programmes do not truly benefit
from the POC studies that are run. POC studies are often designed
and powered as potential back-up registration trials, but should
take the form of a precise innovative experiment that specifically
addresses one or two major objectives in a rigorous manner and,
often, in enriched patient groups. The use of targeted patient
population/s with a specific pattern of cognitive (and/or behav-
ioural) deficits, should be selected in these early studies, to assess
whether an effective signal can be generated, confirming proof of
drug mechanism and giving confidence to allow progression into
larger registration studies. However, care should be taken that the
relevant positive efficacy signal/s observed in such POC studies
are not subsumed in a broader, significantly more heterogeneous
population, in which the deficits targeted by the drug are no
longer present or are not seminal characteristics of the population
being studied. The mechanistic targeting of a specific symptom
in a particular patient subgroup should guide the clinical approach
(and, indeed, the regulatory pathway), rather than the current and
historical model in which very large, expensive phase III studies
are conducted, in which the link between intended drug response
and clinical outcome measure is likely to be lost or diluted.
This means that in many phase III programmes in CNS clini-
cal development, few distinctions are made when selecting
patients for study participation in terms of specific behavioural
domains impacted, the extent of the deficit or the duration of the
disease. The ‘one size fits all’ approach that has traditionally
driven phase III trials in the CNS area aligns similarly to devel-
oping a cancer drug to cure all cancers, irrespective of their geno-
type, size and location. Indeed, this is not the approach adopted
in oncology research. Therefore, the progression of a drug from
phase II to phase III can result in a dramatic dilution of the origi-
nal underlying scientific rationale with consequent loss of the
measured ‘signal’, which might help to explain some of the fail-
ures of these drugs to reach the market.
Perhaps the best approach from a clinical development per-
spective, CNS should embrace the use of more concrete and rel-
evant endpoints in clinical trials. Thomas Insel, the director of the
National Institute of Mental Health (NIMH) in the United States
recently stated: ‘Unlike our definitions of ischaemic heart dis-
ease, lymphoma or AIDS, the DSM diagnoses are based on a
consensus about clusters of clinical symptoms, not any objective
laboratory measure. In the rest of medicine, this would be equiva-
lent to creating diagnostic systems based on the nature of chest
pain or the quality of fever’ (Insel, 2013). It is telling that, despite
the advancements made over decades of successful pharmaceuti-
cal research and drug development, clinical trial assessment in
CNS studies still relies on symptom manuals, some of which
were written nearly half a century ago. A compelling and urgent
need for more discriminatory tools is driving progress in these
neuropsychiatric disorders – but we still have to make significant
progress (Skripka-Serry, 2013). It is essential that clinicians use
the data generated from their preclinical colleagues and the ani-
mal models they employ to guide both small and large, early and
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
later, clinical studies, rather than (as is so often the case cur-
rently) ignoring or overlooking the signals generated by such
work. The RDoC approach, in which ‘dimensionality’ of an ill-
ness characterises its definition, rather than the use of standard-
ised and, in some instances, out-dated diagnostic features, is one
that many in the field are beginning to advocate (Adam, 2013).
In conclusion, preclinical research plays an important part in
facilitating the progress of a compound towards final marketing
as an approved and effective drug. The failure of clinical trials in
CNS drug development may not always reside in the lack of pre-
dictive validity of animal models and assays, but in the minimal
preclinical package provided prior to entering the clinical phase.
Back-translation is obviously an important part of preclinical
research but focus should be on better understanding the dose
effect of a given drug on multiple behaviours for a given disease.
In addition, patient stratification, which is currently uncommon
particularly in phase III clinical studies, becomes a greater neces-
sity. Finally, measuring specific behavioural domains in the
clinic, and potentially in a disease agnostic way, by selecting a
relevant patient population according to deficiencies in specific
behavioural domains and not according to the diagnostic criteria
of the DSM-V, much like the way in which preclinical research
assesses behaviour in its animal models, might be the way for-
ward. In this respect, approaches like those advocated by the
RDoC initiative from the NIMH is a highly relevant exemplar
and might steer CNS drug discovery into a new and more suc-
cessful era.
Acknowledgements
The authors would like to thank Dr Sarah Almond, Dr Rebecca Dias and
Dr Gavin Kilpatrick for their critical reviews of the manuscript.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article: both
authors were employees of Takeda Pharmaceutical Company Ltd. when
this paper was written.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
References
Abbott A (2011) Novartis to shut brain research facility. Nature 480:
161–162.
Adam D (2013) On the spectrum. Nature 496: 416–418.
Aigner TG and Mishkin M. (1998) Improved recognition memory in
monkeys following naloxone administration. Psychopharmacology
94: 21–23.
Akhtar A (2015) The flaws and human harms of animal experimentation.
Camb Q Health Ethics 24: 407–419.
Alberati D, Moreau JL, Lengyel J, et al. (2012) Glycine reuptake inhibi-
tor RG1678: a pharmacologic characterization of an investigational
agent for the treatment of schizophrenia. Neuropharmacology 62:
1152–1161.
Arnsten AF, Cai JX, Murphy BL, et al. (1994) Dopamine D1 receptor
mechanisms in the cognitive performance of young adult and aged
monkeys. Psychopharmacology 116: 143–151.
Bakker A, Albert MS, Krauss G, et al. (2015) Response of the medial
temporal lobe network in amnestic mild cognitive impairment to
Goetghebeur and Swartz 7
therapeutic intervention assessed by fMRI and memory task perfor-
mance. Neuroimage Clin 7: 688–698.
Bartolomeo AC, Morris H and Boast CA (1997) Arecoline via minios-
motic pump improves AF64A-impaired radial maze performance in
rats: a possible model of Alzheimer’s disease. Neurobiol Learn Mem
68: 333–342.
Berridge CW, Shumsky JS, Andrzejewski ME, et al. (2012) Differen-
tial sensitivity to psychostimulants across prefrontal cognitive tasks:
differential involvement of noradrenergic α1- and α2-receptors. Biol
Psychiatry 71: 467–473.
Braida D, Paladini E, Griffini P, et al. (1996) An inverted U-shaped curve
for heptylphysostigmine on radial maze performance in rats: com-
parison with other cholinesterase inhibitors. Eur J Pharmacol 302:
13–20.
Braida D, Paladini E, Griffini P, et al. (1998) Long-lasting antiamnesic
effect of a novel anticholinesterase inhibitor (MF268). Pharmacol
Biochem Behav 59: 897–901.
Buffalo EA, Ramus SJ, Clark RE, et al. (1999) Dissociation between the
effects of damage to perirhinal cortex and area TE. Learn Mem 6:
572–599.
Burgess HA and Granato M. (2007) Sensorimotor gating in larval zebraf-
ish. J Neurosci 27: 4984–4994.
Canal N and Imbimbo BP (1996) Relationship between pharmacody-
namic activity and cognitive effects of eptastigmine in patients with
Alzheimer’s disease. Eptastigmine Study Group. Clin. Pharmacol
Ther 60: 218–228.
Cano SJ, Posner HB, Moline ML, et al. (2010) The ADAS-cog in
Alzheimer’s disease clinical trials: psychometric evaluation of the
sum and its parts. J Neurol Neurosurg Psychiatry 81: 1363–1368.
Carroll J (2013) Updated: Baxter adds Gammagard to growing roster of
PhIII Alzheimer’s failures. Available at: http://www.fiercebiotech.
com/story/baxter-adds-gammagard-growing-roster-phiii-alzheim-
ers-failures/2013-05-07.
Carter CS, Barch DM, Buchanan RW, et al. (2008) Identifying cognitive
mechanisms targeted for treatment development in schizophrenia: an
overview of the first meeting of the Cognitive Neuroscience Treat-
ment Research to Improve Cognition in Schizophrenia Initiative.
Biol. Psychiatry 64: 4–10.
Castner SA, Murthy NV, Ridler K, et al. (2014) Relationship between
glycine transporter 1 inhibition as measured with positron emission
tomography and changes in cognitive performances in nonhuman
primates. Neuropsychopharmacology 39: 2742–2749.
Chowdhury R, Guitart-Masip M, Bunzeck N, et al. (2012) Dopamine
modulates episodic memory persistence in old age. J Neurosci 32:
14193–14204.
Clark KB, Smith DC, Hassert DL, et al. (1998) Posttraining electrical
stimulation of vagal afferents with concomitant vagal efferent inac-
tivation enhances memory storage processes in the rat. Neurobiol
Learn Mem 70: 364–373.
Crutcher MD, Calhoun-Haney R, Manzanares CM, et al. (2009) Eye
tracking during a visual paired comparison task as a predictor of
early dementia. Am J Alzheimers Dis Other Demen 24: 258–266.
Csomor PA, Preller KH, Geyer MA, et al. (2014) Influence of aripip-
razole, risperidone, and amisulpride on sensory and sensorimotor
gating in healthy ‘low and high gating’ humans and relation to psy-
chometry. Neuropsychopharmacology 39: 2485–2496.
de Veld DM, Riksen-Walraven JM and de Weerth C (2014) Acute psy-
chosocial stress and children’s memory. Stress 17: 305–313.
Eddins D, Hamill TG, Puri V, et al. (2014) The relationship between
glycine transporter 1 occupancy and the effects of the glycine
transporter 1 inhibitor RG1678 or ORG25935 on object retrieval
performance in scopolamine impaired rhesus monkey. Psychophar-
macology 231: 511–519.
Ehrenreich H, Hinze-Selch D, Stawicki S, et al. (2007) Improvement of
cognitive functions in chronic schizophrenic patients by recombinant
human erythropoietin. Mol Psychiatry 12: 206–220.
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
Ericksen SE (1979) Recent advances in antidepressant drug treatment.
West J Med 131: 104–113.
Esbenshade TA, Browman KE, Miller TR, et al. (2012) Pharmacological
properties and procognitive effects of ABT-288, a potent and selec-
tive histamine H3 receptor antagonist. J. Pharmacol Exp Ther 343:
233–245.
Fallon SJ, Smulders K, Esselink RA, et al. (2015) Differential optimal
dopamine levels for set-shifting and working memory in Parkinson’s
disease. Neuropsychologia 77: 42–51.
Fernando AB and Robbins TW (2011) Animal models of neuropsychiat-
ric disorders. Annu Rev Clin Psychol 7: 39–61.
Fern-Pollak L, Whone AL, Brooks DJ, et al. (2004) Cognitive and motor
effects of dopaminergic medication withdrawal in Parkinson’s dis-
ease. Neuropsychologia 42: 1917–1926.
Finke K, Dodds CM, Bublak P, et al. (2010) Effects of modafinil and
methylphenidate on visual attention capacity: a TVA-based study.
Psychopharmacology 210: 317–329.
Fiore K (2016) FDA Advisors Support New Indication for Brintellix
– Panel debates vortioxetine for treating cognitive dysfunction in
major depression. Available at: http://www.medpagetoday.com/Psy-
chiatry/Depression/55999.
Flood JF, Landry DW and Jarvik ME. (1981) Cholinergic receptor inter-
actions and their effects on long-term memory processing. Brain Res
215: 177–185.
Flood JF, Hernandez EN and Morley JE. (1987) Modulation of memory
processing by neuropeptide Y. Brain Res 421: 280–290.
Foley AG, Prendergast A, Barry C, et al. (2009) H3 receptor antagonism
enhances NCAM PSA-mediated plasticity and improves memory
consolidation in odor discrimination and delayed match-to-position
paradigms. Neuropsychopharmacology 34: 2585–2600.
Foreman MM, Hanania T and Eller M. (2009) Anxiolytic effects of
lamotrigine and JZP-4 in the elevated plus maze and in the four plate
conflict test. Eur J Pharmacol 602: 316–320.
Gacsályi I, Nagy K, Pallagi K, et al. (2013) Egis-11150: a candidate anti-
psychotic compound with procognitive efficacy in rodents. Neuro-
pharmacology 64: 254–263.
Gallhofer B, Jaanson P, Mittoux A, et al. (2007) Course of recovery of
cognitive impairment in patients with schizophrenia: a randomised
double-blind study comparing sertindole and haloperidol. Pharma-
copsychiatry 40: 275–286.
Gill KM, Cook JM, Poe MM, et al. (2014) Prior antipsychotic drug treat-
ment prevents response to novel antipsychotic agent in the methyl-
azoxymethanol acetate model of schizophrenia. Schizophr Bull 40:
341–350.
Godley A, Havolli E, Hill M, et al. (2014) Alzheimer’s disease therapeu-
tics in a pre-clinical spatial recognition paradigm: further evidence
for cognition-related bell-shaped dose response curve. J Psycho-
pharmacol 28: A16, MA09.
Goetghebeur P and Dias R (2009) Comparison of haloperidol, risperi-
done, sertindole, and modafinil to reverse an attentional set-shifting
impairment following subchronic PCP administration in the rat – a
back translational study. Psychopharmacology 202: 287–293.
Goetghebeur P, Lerdrup L, Sylvest A, et al. (2010) Erythropoi-
etin reverses the attentional set-shifting impairment in a rodent
schizophrenia disease-like model. Psychopharmacology 212:
635–642.
Goff DC, Lamberti JS, Leon AC, et al. (2008) A placebo-controlled add-
on trial of the Ampakine, CX516, for cognitive deficits in schizo-
phrenia. Neuropsychopharmacology 33: 465–472.
Goshen I, Kreisel T, Ounallah-Saad H, et al. (2007) A dual role for inter-
leukin-1 in hippocampal-dependent memory processes. Psychoneu-
roendocrinology 32: 1106–1115.
Green MF, Nuechterlein KH, Gold JM, et al. (2004) Approaching a
consensus cognitive battery for clinical trials in schizophrenia: the
NIMH-MATRICS conference to select cognitive domains and test
criteria. Biol Psychiatry 56: 301–307.
8 Journal of Psychopharmacology
Harada K, Nakato K, Yarimizu J, et al. (2012) A novel glycine trans-
porter-1 (GlyT1) inhibitor, ASP2535 (4-[3- isopropyl-5- (6-phenyl-
3-pyridyl)-4H-1,2,4- triazol-4-yl]-2,1,3-benzoxadiazole), improves
cognition in animal models of cognitive impairment in schizophrenia
and Alzheimer’s disease. Eur J Pharmacol 685: 59–69.
Hashimoto K (2005) Targeting of α7 nicotinic acetylcholine receptors in
the treatment of schizophrenia and the use of auditory sensory gating
as a translational biomarker. Curr Pharm Des 21: 3797–3806.
Hendrie CA, Neill JC, Shepherd JK, et al. (1993) The effects of CCKA
and CCKB antagonists on activity in the black/white exploration
model of anxiety in mice. Physiol Behav 54: 689–693.
Hills T and Hertwig R (2011) Why aren’t we smarter already: evolution-
ary trade-offs and cognitive enhancements. Curr Direct Psycholog
Sci 20: 373–377.
Hiyoshi T, Kambe D, Karasawa J, et al. (2014) Differential effects of
NMDA receptor antagonists at lower and higher doses on basal
gamma band oscillation power in rat cortical electroencephalograms.
Neuropharmacology 85: 384–396.
Horiguchi M, Hannaway KE, Adelekun AE, et al. (2013) D(1) receptor
agonists reverse the subchronic phencyclidine (PCP)-induced novel
object recognition (NOR) deficit in female rats. Behav Brain Res
238: 36–43.
Hosseini-Sharifabad A, Ghahremani MH, Sabzevari O, et al. (2012)
Effects of protein kinase A and G inhibitors on hippocampal cho-
linergic markers expressions in rolipram- and sildenafil-induced
spatial memory improvement. Pharmacol Biochem Behav 101:
311–319.
Huang M, Felix AR, Kwon S, et al. (2014) The alpha-7 nicotinic receptor
partial agonist/5-HT3 antagonist RG3487 enhances cortical and hip-
pocampal dopamine and acetylcholine release. Psychopharmacology
231: 2199–2210.
Insel T (2013) Director’s Blog: Transforming Diagnosis. Available at:
http://www.nimh.nih.gov/about/director/2013/transforming-diagno-
sis.shtml.
Jones KM, McDonald IM, Bourin C, et al. (2014) Effect of alpha7
nicotinic acetylcholine receptor agonists on attentional set-shifting
impairment in rats. Psychopharmacology 231: 673–683.
Jucker M (2010) The benefits and limitations of animal models for
translational research in neurodegenerative diseases. Nat Med 16:
1210–1214.
Kaitin KI and Milne CP (2011) A dearth of new meds: Drugs to treat
neuropsychiatric disorders have become too risky for big pharma.
Scientific American 305: 16.
Kapai NA, Bukanova JV, Solntseva EI, et al. (2012) Donepezil in a nar-
row concentration range augments control and impaired by beta-
amyloid peptide hippocampal LTP in NMDAR-independent manner.
Cell Mol Neurobiol 32: 219–226.
Khroyan TV, Baker DA and Neisewander JL. (1995) Dose-dependent
effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors
and place conditioning. Psychopharmacology 122: 351–357.
Kidwell CS, Liebeskind DS, Starkman S, et al. (2001) Trends in acute
ischemic stroke trials through the 20th century. Stroke 32: 1349–
1359.
Knogler LD and Drapeau P (2014) Sensory gating of an embryonic
zebrafish interneuron during spontaneous motor behaviors. Front
Neural Circuits 8: 121.
Kresge N (2014) Roche schizophrenia drug at risk after failing in trials.
Available at: http://www.bloomberg.com/news/articles/2014-01-21/
roche-schizophrenia-drug-at-risk-after-failing-in-trials.
Kroker KS, Rast G and Rosenbrock H (2011) Differential effects of sub-
type-specific nicotinic acetylcholine receptor agonists on early and
late hippocampal LTP. Eur J Pharmacol 671: 26–32.
Larrauri JA, Burke DA, Hall BJ, et al. (2015) Role of nicotinic receptors
in the lateral habenula in the attenuation of amphetamine-induced
prepulse inhibition deficits of the acoustic startle response in rats.
Psychopharmacology 232: 3009–3017.
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
Luine VN and Frankfurt M. (2012) Estrogens facilitate memory process-
ing through membrane mediated mechanisms and alterations in spine
density. Front Neuroendocrinol 33: 388–402.
Ma J, Mufti A and Stan Leung L (2015) Effects of memantine on hip-
pocampal long-term potentiation, gamma activity, and sensorimotor
gating in freely moving rats. Neurobiol Aging 36: 2544–2554.
McGonigle P (2014) Animal models of CNS disorders. Biochem Phar-
macol 87: 140–149.
Mamounas LA, Altar CA, Blue ME, et al. (2000) BDNF promotes the
regenerative sprouting, but not survival, of injured serotonergic
axons in the adult rat brain. J Neurosci 20: 771–782.
Marder SR and Fenton W (2004) Measurement and Treatment Research
to Improve Cognition in Schizophrenia: NIMH MATRICS initia-
tive to support the development of agents for improving cognition in
schizophrenia. Schizophr Res 72: 5–9.
Matsuoka N and Aigner TG (1996) D-cycloserine, a partial agonist at
the glycine site coupled to N-methyl-d-aspartate receptors, improves
visual recognition memory in rhesus monkeys. J Pharmacol Exp
Ther 278: 891–897.
Matthews RA (2008) Medical progress depends on animal models –
doesn’t it? J R Soc Med 101: 95–98.
Mehta MA, Swainson R, Ogilvie AD, et al. (2001) Improved short-term
spatial memory but impaired reversal learning following the dopa-
mine D(2) agonist bromocriptine in human volunteers. Psychophar-
macology 159: 10–20.
Mennenga SE, Baxter LC, Grunfeld IS, et al. (2014) Navigating to new
frontiers in behavioral neuroscience: traditional neuropsychologi-
cal tests predict human performance on a rodent-inspired radial-arm
maze. Front Behav Neurosci 2014: 294.
Miller G (2010) Is pharma running out of brainy ideas? Science 329:
502–504.
Morein-Zamir S, Turner DC and Sahakian BJ (2007) A review of the
effects of modafinil on cognition in schizophrenia. Schizophr Bull
33: 1298–1306.
Müller MJ, Wetzel H, Eich FX, et al. (2012) Amisulpride Study Group.
Dose-related effects of amisulpride on five dimensions of psychopa-
thology in patients with acute exacerbation of schizophrenia. J Clin
Psychopharmacol 22: 554–560.
Nestler EJ and Hyman SE (2010) Animal models of neuropsychiatric
disorders. Nat Neurosci 13: 1161–1169.
Ossewaarde L, Qin S, Van Marle HJ, et al. (2011) Stress-induced reduction
in reward-related prefrontal cortex function. Neuroimage 55: 345–352.
Otani S, Bai J and Blot K (2015) Dopaminergic modulation of synaptic
plasticity in rat prefrontal neurons. Neurosci Bull 31: 183–190.
Ou LY, Tang XC and Cai JX (2001) Effect of huperzine A on working
memory in reserpine- or yohimbine-treated monkeys. Eur J Phar-
macol 433: 151–156.
Owen AM, James M, Leigh PN, et al. (1992) Fronto-striatal cognitive def-
icits at different stages of Parkinson’s disease. Brain 115: 1727–1751.
Owen AM, Beksinska M, James M, et al. (1993) Visuospatial memory
deficits at different stages of Parkinson’s disease. Neuropsychologia
31(7): 627–644.
Park SJ, Kim DH, Lee IK, et al. (2010) The ameliorating effect of the
extract of the flower of Prunella vulgaris var. lilacina on drug-induced
memory impairments in mice. Food Chem Toxicol 48: 1671–1676.
Peng J, Lu F, Wang Z, et al. (2014) Excessive lowering of blood pressure
is not beneficial for progression of brain white matter hyperintensive
and cognitive impairment in elderly hypertensive patients: 4-year
follow-up study. Am Med Dir Assoc 15: 904–910.
Pihlajamaki M, Tanila H, Kononen M, et al. (2004) Visual presentation
of novel objects and new spatial arrangements of objects differen-
tially activates the medial temporal lobe subareas in humans. Eur J
Neurosci 19: 1939–1949.
Poltavski DV, Petros TV and Holm JE (2012) Lower but not higher doses
of transdermal nicotine facilitate cognitive performance in smokers on
gender non-preferred tasks. Pharmacol Biochem Behav 102: 423–433.
Goetghebeur and Swartz 9
Possin KL, Sanchez PE, Anderson-Bergman C, et al. (2016) Cross-
species translation of the Morris maze for Alzheimer’s disease.
J Clin Invest 126: 779–783.
Prickaerts J, Sik A, van der Staay FJ, et al. (2005) Dissociable effects of
acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibi-
tors on object recognition memory: acquisition versus consolidation.
Psychopharmacology 177: 381–390.
Quevedo J, Vianna M, Daroit D, et al. (1998) L-type voltage-dependent
calcium channel blocker nifedipine enhances memory retention
when infused into the hippocampus. Neurobiol Learn Mem 69:
320–325.
Razay G, Williams J, King E, et al. (2009) Blood pressure, dementia
and Alzheimer’s disease: the OPTIMA longitudinal study. Dement
Geriatr Cogn Disord 28: 70–74.
Reaume CJ and Sokolowski MB (2011) Conservation of gene
function in behaviour. Philos Trans R Soc Lond B Biol Sci 366:
2100–2110.
Roberts AC. (1996) Comparison of cognitive function in human and non-
human primates. Brain Res Cogn Brain Res. 3: 319–27.
Sacchetti B, Lorenzini CA, Baldi E, et al. (2001) Pituitary adenylate
cyclase-activating polypeptide hormone (PACAP) at very low dos-
ages improves memory in the rat. Neurobiol Learn Mem76: 1–6.
Sadeghi-Nejad N (2012) The Lessons of Failure: What We Can Learn
from Bapineuzumab’s Blowup. Available at: http://www.forbes.
com/sites/natesadeghi/2012/08/07/the-lessons-of-failure-what-we-
can-learn-from-bapineuzumabs-blowup/#3d1cad2c5da6.
Salehi B, Cordero MI and Sandi C. (2010) Learning under stress: the
inverted U-shape function revisited. Learn Mem 17: 522–530.
Santos JL, Cabranes JA, Vazquez C, et al. (1989) Clinical response and
plasma haloperidol levels in chronic and subchronic schizophrenia.
Biol Psychiatry 26: 381–388.
Schilling TM, Kölsch M, Larra MF, et al. (2013) For whom the bell
(curve) tolls: cortisol rapidly affects memory retrieval by an inverted
U-shaped dose–response relationship. Psychoneuroendocrinology
38: 1565–1572.
Scoriels L, Barnett JH, Soma PK, et al. (2012) Effects of modafinil on
cognitive functions in first episode psychosis. Psychopharmacology
220: 249–258.
Scoriels L, Jones PB and Sahakian BJ (2013) Modafinil effects on cogni-
tion and emotion in schizophrenia and its neurochemical modulation
in the brain. Neuropharmacology 64: 168–184.
Shuman T, Wood SC and Anagnostaras SG. (2009) Modafinil and mem-
ory: effects of modafinil on Morris water maze learning and Pavlov-
ian fear conditioning. Behav Neurosci 123: 257–266.
Skripka-Serry J (2013) The great neuro-pipeline brain drain (and why
Big Pharma hasn’t given up on CNS disorders). Available at: http://
www.ddw-online.com/therapeutics/p216813-the-great-neuro-pipe-
line-brain-drain-(and-why-big-pharma-hasn-t-given-up-on-cns-
disorders)-fall-13.html.
Soncrant TT, Raffaele KC, Asthana S, et al. (1993) Memory improve-
ment without toxicity during chronic, low dose intravenous arecoline
in Alzheimer’s disease. Psychopharmacology 112: 421–427.
Spiros A, Roberts P and Geerts H (2014) A computer-based quantitative
systems pharmacology model of negative symptoms in schizophre-
nia: exploring glycine modulation of excitation-inhibition balance.
Front Pharmacol 5: 229.
Stoiljkovic M, Leventhal L, Chen A, et al. (2015) Concentration–
response relationship of the α7 nicotinic acetylcholine receptor ago-
nist FRM-17874 across multiple in vitro and in vivo assays. Biochem
Pharmacol 97: 576–589.
Talledo JA, Sutherland Owens AN, Schortinghuis T, et al. (2009)
Amphetamine effects on startle gating in normal women and female
rats. Psychopharmacology 204: 165–175.
Tipper CM, Cairo TA, Woodward TS, et al. (2005) Processing efficiency
of a verbal working memory system is modulated by amphetamine:
an fMRI investigation. Psychopharmacology 180: 634–643.
Downloaded from jop.sagepub.com at Oakland University on June 5, 2016
Tsai G, Lane HY, Yang P, et al. (2014) Glycine transporter I inhibitor,
N-methylglycine (sarcosine), added to antipsychotics for the treat-
ment of schizophrenia. Biol Psychiatry 55: 452–456.
Turner DC, Clark L, Pomarol-Clotet E, et al. (2004) Modafinil improves
cognition and attentional set shifting in patients with chronic schizo-
phrenia. Neuropsychopharmacology 29: 1363–1373.
Uslaner JM, Parmentier-Batteur S, Flick RB, et al. (2009) Dose-depen-
dent effect of CDPPB, the mGluR5 positive allosteric modulator, on
recognition memory is associated with GluR1 and CREB phosphory-
lation in the prefrontal cortex and hippocampus. Neuropharmacol-
ogy 57: 531–538.
Vaidya AH, Rosenthal DI, Lang W, et al. (2005) Oral buspirone causes
a shift in the dose–response curve between the elevated-plus maze
and Vogel conflict tests in Long–Evans rats: relation of brain levels
of buspirone and 1-PP to anxiolytic action. Methods Find. Exp Clin
Pharmacol 27: 245–255.
Van Dam D, Abramowski D, Staufenbiel M, et al. (2005) Symptomatic
effect of donepezil, rivastigmine, galantamine and memantine on cogni-
tive deficits in the APP23 model. Psychopharmacology 180: 177–190.
Vijayraghavan S, Wang M, Birnbaum SG, et al. (2007) Inverted-U dopa-
mine D1 receptor actions on prefrontal neurons engaged in working
memory. Nat Neurosci 10: 376–384.
Waite JJ and Thal LJ (1995) The behavioral effects of heptylphyso-
stigmine on rats lesioned in the nucleus basalis. Neurosci Res 21:
251–259.
Wallace TL, Ballard TM and Glavis-Bloom C (2015) Animal paradigms
to assess cognition with translation to humans. Handb Exp Pharma-
col 228: 27–57.
Wanibuchi F, Nishida T, Yamashita H, et al. (1994) Characterization
of a novel muscarinic receptor agonist, YM796: comparison with
cholinesterase inhibitors in in vivo pharmacological studies. Eur J
Pharmacol 265: 151–158.
Wilens TE, Verlinden MH, Adler LA, et al. (2006) ABT-089, a neuro-
nal nicotinic receptor partial agonist, for the treatment of attention-
deficit/hyperactivity disorder in adults: results of a pilot study. Biol
Psychiatry 59: 1065–1070.
Winters BD, Forwood SE, Cowell RA, et al. (2004) Double dissociation
between the effects of peri-postrhinal cortex and hippocampal lesions
on tests of object recognition and spatial memory: heterogeneity of
function within the temporal lobe. J Neurosci 24: 5901–5908.
Wise LE and Lichtman AH (2007) The uncompetitive N-methyl-d-as-
partate (NMDA) receptor antagonist memantine prolongs spatial
memory in a rat delayed radial-arm maze memory task. Eur J Phar-
macol 575: 98–102.
Witten L, Bastlund JF, Glenthøj BY, et al. (2016) Comparing pharma-
cological modulation of sensory gating in healthy humans and rats:
the effects of reboxetine and haloperidol. Neuropsychopharmacol-
ogy 41: 638–645.
Woolley DG, Laeremans A, Gantois I, et al. (2013) Homologous involve-
ment of striatum and prefrontal cortex in rodent and human water
maze learning. Proc Natl Acad Sci USA 110: 3131–3136.
Yang YY, Lu CL, Lo SM, et al. (2015) Early antipsychotic intervention
and schizophrenia. Med Hypotheses 85: 367–370.
Yerkes RM and Dodson JD (1908) The relation of strength of stimulus
to rapidity of habit formation. J Comp Neurol Psychol 18: 459–482.
Zangrando J, Carvalheira R, Labbate G, et al. (2013) Atypical antipsy-
chotic olanzapine reversed deficit on prepulse inhibition of the acous-
tic startle reflex produced by microinjection of dizocilpine (MK-801)
into the inferior colliculus in rats. Behav Brain Res 257: 77–82.
Zhang XL, Sullivan JA, Moskal JR, et al. (2008) A NMDA receptor gly-
cine site partial agonist, GLYX-13, simultaneously enhances LTP
and reduces LTD at Schaffer collateral-CA1 synapses in hippocam-
pus. Neuropharmacology 55: 1238–1250.
Zola SM, Manzanares CM, Clopton P, et al. (2013) A behavioral task
predicts conversion to mild cognitive impairment and Alzheimer’s
disease. Am J Alzheimers Dis Other Demen 28: 179–184.