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4 Relative Specificity of PAL for Other Disorders, Including Non-Alzheimer’s Dementias

4 Relative Specificity of PAL for Other Disorders, Including Non-Alzheimer’s Dementias

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The Paired Associates Learning (PAL) Test …



5.1



467



The Development of CANTAB Mobile



The CANTAB PAL’s good sensitivity and specificity in detecting AD make it

superior to most tests available to non-specialist clinicians such as general practitioners, who are probably the healthcare professionals most likely to interact with

at-risk older adults. The cognitive tests most familiar to GPs are pencil and paper or

interview-based tests which show a good sensitivity to frank dementia but poor

sensitivity to earlier stages of disease, including MCI. A systematic review of

cognitive screening measures commonly used in primary care (including the Mini

Mental State Exam, MMSE, and the General Practitioner Assessment of Cognition,

GP-COG) found that sensitivity to detect mild to severe dementia ranged from 69 to

100 % and specificity from 75 to 98 % in GP, community, or population samples

(Brodaty et al. 2006).

The properties that make a test optimally useful in academic research or clinical

trials are somewhat different from those required for widespread testing in mainstream healthcare. In order to address some of the practical barriers limiting the

usefulness of very sensitive cognitive tests in mainstream healthcare, the

CANTAB PAL software has recently been adapted for non-specialist use in the

form of CANTAB Mobile, an iPad-based assessment tool. The aim in doing so was

to create a tool that is easy to use by a healthcare professional with no specialist

training and that takes as short a time as possible to administer. In the UK, where

general practitioners act as gatekeepers to dementia diagnostic services, the major

use of cognitive tests in primary care is to provide a means of deciding whether an

individual is likely to be suffering from cognitive decline, and hence, whether they

would benefit from further assessment (i.e. referral to memory services). At the time

of writing, CANTAB Mobile has been used in this way at around 400 sites across

the UK, largely primary care practices. Analysis of the first 10,000 tests completed

found that in only 25 % of assessments did the test detect clinically significant

memory problems. This is important because it suggests that the real-world utility

of such tests is not only in identifying those patients who do have a significant

memory impairment, but also in reassuring the very large number of concerned

older adults who do not.

Several technical changes were made in order to better suit the CANTAB PAL

test for the primary care environment. The CANTAB Mobile app is adaptive so that

if a patient is struggling at a particular level of difficulty, the test automatically

terminates, limiting the duration of testing to around 5 min. The non-verbal nature

of the test makes it particularly useful in non-literate or ethnic minority groups, and

voiceover instructions in multiple languages makes it possible to accurately assess

patients from ethnic minorities in their native language without the need for a

translator. NICE guidelines for cognitive assessment in dementia state that relevant

demographic factors such as age, gender, and educational level should be taken into

account when deciding whether a person’s score is outside their personal expected

range (National Collaborating Centre for Mental Health 2007). In practice, this is

extremely difficult for non-specialists to achieve, so CANTAB Mobile results are



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compared with a large normative database and then automatically adjusted for age,

gender, and level of education. The scores are output in a report which indicates

whether memory performance was as expected for someone of these demographics,

or outside of the normal range and thus a potential clinical concern. These adaptations have made the PAL test of considerable use to GPs as an aid to clinical

triage and decision-making.



5.2



The Future of Cognitive Health



As touchscreen technologies become evermore ubiquitous in businesses, shops, and

homes, it is interesting to consider how touchscreen tests such as PAL can best

contribute to improving the cognitive health of the population.

Tackling the large and increasing public health burden that Alzheimer’s and

other dementias represent probably requires two parallel efforts. In one, a better

understanding of basic brain biology, and better use of translational tools such as

CANTAB to predict drug effects from animal studies into phase 1 and from

early-stage into late-stage clinical development, should hopefully result in increased

success in the development of new therapies. In particular, CANTAB’s use in phase

2 studies allows accurate early decisions to be made about efficacy, based on more

reliable data about the effect of new compounds in the clinical population. In the

second track, making CANTAB and other cognitive tools more widely available

and simple to use can contribute to tackling the overall impact of Alzheimer’s and

other cognitive disorders by making it easier to conduct large-scale cognitive

monitoring, for example in longitudinal prevention studies, or for determination by

the government of healthcare provision.

A technological analogy may be found here in the development of the sphygmomanometer (blood pressure monitor). Over many decades, blood pressure

monitoring moved from a specialist procedure to one that became standard in

outpatient and then primary care facilities, usable by healthcare providers in home

visits, and is now available directly to consumers for self-assessment. This progress

was driven by a number of factors, including the development of the technology

itself, such that devices became cheaper, more reliable, and more mobile, but also

increasing awareness of the benefits of monitoring blood pressure—including the

benefits of measurements taken at multiple time points, over the course of the day,

and in contexts other than the clinic. Alongside developments in the availability of

effective interventions to treat hypertension, the distal effect of the availability of

accurate and widespread monitoring of blood pressure has been a massive reduction

in incidence of coronary heart disease and stroke.

We believe that cognitive health is now primed for a similar increase in public

awareness, consumer, and home-based intervention, and, hopefully, consequent

impacts on public health (Sahakian 2014). One appealing vision for the future of

CANTAB is therefore that it will be one of the technological innovations that allow

an equivalent of blood pressure monitoring for the mind—simplifying cognitive



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assessment for non-specialist clinicians, increasing public awareness of the links

between behaviours such as diet, exercise, smoking, and brain health, and ultimately contributing to the pathway by which people at high risk of dementia-related

diseases are identified, monitored, diagnosed, and treated.

Like blood pressure monitors, there may well be a case for making sensitive

well-validated cognitive tests such as the PAL available in a wider range of

healthcare environments such as pharmacies, nursing homes, and other places

where people at high risk of undetected AD may be accessible, and ultimately to

consumers themselves. Such tests would need to be presented in a way that

appropriately takes into account aspects of the at-home testing environment,

including the capabilities and limitations of users’ own computers or mobile

devices, they should use test feedback as a means to encourage appropriate utilisation of healthcare systems and increase healthy behaviour, and they should

empower patients to take responsibility for and control of their own brain health,

without increasing worry or unnecessary interventions.

As technology moves on further, we also see a role for well-established cognitive tests such as the PAL in benchmarking new methods of cognitive assessment

and monitoring which will inevitably develop. This might include means of

inferring cognitive performance and risk of cognitive disorders from the day-to-day

use of devices such as computers, smartphones, and, eventually, ubiquitous monitoring of patterns of behaviour throughout a wired home environment.

Declaration of Interest and Acknowledgements JHB is an employee of and ADB a director of

Cambridge Cognition, the company that develops and markets the CANTAB cognitive testing

system. JB, AB, and BJS own shares and/or share options in Cambridge Cognition. BJS consults

for Cambridge Cognition, Peak, Otsuka, Lundbeck, and Servier, holds a grant from Janssen/J&J,

and owns shares in CeNeS. TWR consults for Cambridge Cognition, Eli Lilly, Shire, Lundbeck,

Teva, Otsuka, and Chempartners. He holds grants from Lilly, Lundbeck, and GSK and receives

royalties from Cambridge Cognition for CANTAB.



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Experimental Medicine in Psychiatry New

Approaches in Schizophrenia, Depression

and Cognition

Gerard R. Dawson



Abstract The use of experimental medicine studies to bridge the gap between Phase

1 and 2 drug trials and so to enhance translation of basic neuroscience studies using

experimental animals to the clinic is proposed. Illustrative examples are provided for

affective disorders and schizophrenia in relation also to cognitive dysfunction.

Keywords Experimental medicine

Clinical trials



Á



Schizotypy



Á



Depression



Á



Cognition



Á



Contents

1

2

3



Introduction ........................................................................................................................

Experimental Medicine and Schizophrenia.......................................................................

Schizotypy and Its Prevalence in the General Population................................................

3.1 Effects of Schizotypy and Treatment on the Performance of Cognitive Tasks ......

3.2 Effects of Schizotypy and Treatment on Signal Detection, Biconditional

Learning and Aberrant Salience ...............................................................................

3.3 Effects of Schizotypy and Treatment on Eye Movements ......................................

4 The Neuropharmacology of Depression and Cognition ...................................................

5 Summary and Conclusions ................................................................................................

References ................................................................................................................................



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1 Introduction

It is often stated that in the last 50 years, the rate of production of new treatments

for psychiatric diseases by pharmaceutical companies has been relatively constant

and despite large increases in investment is now actually on the decline. In the last



G.R. Dawson (&)

P1vital LTD, Manor House, Howbery Park, Wallingford, Oxfordshire OX10 8BA, UK

e-mail: gdawson@p1vital.com

© Springer International Publishing Switzerland 2016

Curr Topics Behav Neurosci (2016) 28: 475–498

DOI 10.1007/7854_2015_5016



476



G.R. Dawson



three decades, industry and academia have invested strongly in biomedical research

aimed at discovering new pathways and mechanisms that might lead to new

treatments for anxiety, cognitive disorders and depression. They have often worked

together under new initiatives, such as the Innovative Medicines Initiative (IMI),

much of it directly aimed at elucidating the mechanisms underlying disease and

brain function. Indeed, our knowledge of basic brain systems and functions

increases by the day with sometimes remarkable new findings. New experimental

techniques have been developed, and a wealth of new drug targets aimed at

improving the treatment of psychiatric and other brain disorders has been suggested

and investigated at enormous expense to the pharma industry. However, the clinical

translation of these research findings to the benefit of psychiatric patients has been

disappointing. These results and other late-stage failures has led to pressure from

investors and shareholders that has resulted in a number of pharmaceutical companies withdrawing from the active development of new psychiatric treatments.

Late-stage, Phase III failures such as Roche’s Bitopertin (RO-4917838) a glycine

reuptake inhibitor, developed as an adjunct to antipsychotics for the treatment of

persistent negative symptoms, is a case in point. Results from a Phase II

proof-of-concept study were promising showing a significant reduction in negative

symptoms and a trend towards improved functioning (Umbricht et al. 2014). On the

strength of these results, six Phase III trial studies were initiated, but development

was terminated when early results from two of the studies failed to reach their

primary endpoints. These results, other late-stage failures and the complexity of

developing drugs for diseases that have no clear pathology, have led pharmaceutical

companies to reprioritise or withdraw from drug development in psychiatry. This is

particularly problematic as there remains a huge unmet need for new treatments for

psychiatric disorders as many existing treatments are only partially effective and

many have significant side effects that led to non-compliance among patients.

The past 20 years has shown that it is clearly very difficult to develop new drugs

for the treatment of psychiatric disorders. New drug classes such as selective

inhibitors of glycine reuptake and phosphodiesterase inhibitors of brain enzyme

have been identified. They have shown promising results in animal assays and

cleared safety hurdles in animals and humans. However, while potent molecules

can be generated, the gap between their effects in animal assays and their efficacy in

patients remains. The failure in patients often raises the question of whether in

diseases such as major depressive disorder (MDD) and schizophrenia that have

specific but also overlapping functional constructs, the compound was assessed for

efficacy in the right patient population. Moreover, patients with schizophrenia are

usually treated with multiple drugs which may mask or nullify the effects of a new

compound under investigation. Similarly, patients with MDD may have a history of

treatment resistance or partial response or may be misdiagnose as unipolar when

they are in fact bipolar with low levels of mania (Angst et al. 2011). Consequently,

there are now significantly more human experimental and translational medicine

studies that are conducted between Phase 1 and Phase 2 clinical trials that focus on

detecting the efficacy of new compounds before large patient trials. These studies

often employ tasks that activate specific brain circuits that may be modulated by



Experimental Medicine in Psychiatry New Approaches …



477



compounds of interest or surrogate patient populations that are drug free but have

symptoms or a subset of symptoms that are present in patient populations and are

hypothesised to respond to the compound of interest (Dawson and Goodwin 2005).

The hope is that experimental medicine studies will provide more detail and precision on the effects of new treatments on brain circuits and systems rather than

symptoms per se. This is seen as essential to bridging the gap between animal and

human studies and to increase the probability of success in this particularly difficult

area of drug development (Gould and Manji 2004). A second aim of experimental

medicine is to use existing drugs to probe neural systems with existing or new drugs

to provide insight to the aetiology of a disease and potential methods of treatment.

The focus of this chapter is the latest experimental medicine approaches in psychiatry particularly those that relate to depression, schizophrenia and cognition and

the new light they have shone on the neuropharmacology of these disorders. Much

of the focus is on new methods and surrogate’s populations for determining the role

of brain systems in these disorders and the neuropharmacology underpinning them.

Experimental medicine provides a path forward at the interface between Phase 1

and 2 trials that may bridge the gap between animal and human studies and provide

an early indication of efficacy for a particular psychiatric disorder or a symptom that

is prevalent across psychiatric disorders. The classic solutions are to: (a) measure

the biomarkers in healthy volunteer or “surrogate patient” models of illness rather

than in clinical groups and (b) measure treatment effects on biomarkers for the

underlying disease process rather than treatment effects on symptoms.

Consequently, early trials in surrogate patient populations, such as health volunteers

with high schizotypy (see below for a description), incorporate objective measures

that can bridge to symptom ratings and provide insight into the neuropharmacology

unpinning these symptoms. In addition, new biomarkers that reveal the interplay

between neuropharmacology and the brain systems that subserve motivation and

reward may identify new therapeutic targets.



2 Experimental Medicine and Schizophrenia

Schizophrenia is a common and typically lifelong disorder, and despite drug

treatment, most patients continue to experience symptoms with impaired quality of

life. Positive symptoms (delusions, hallucinations and thought disorder) respond to

antipsychotic drugs, but the benefit is often incomplete. The second generation

drugs may not have the advantages initially claimed (Lieberman 2007), and only

clozapine has some limited efficacy in treating the negative symptoms of anhedonia

and flattened affect. It is also recognised increasingly that impaired cognitive

function is a third and separate domain of symptoms (Kremen et al. 2000) with

attention, memory and executive function being the most affected (Heinrichs 1998;

Saykin et al. 1991). These impairments probably contribute to poor social functioning and quality of life although the precise connection is unclear. Current

antipsychotics are also generally ineffective against cognitive impairment in



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