Schizophrenia Bulletin

Schizophrenia Bulletin Advance Access originally published online on September 21, 2005
Schizophrenia Bulletin 2005 31(4):830-853; doi:10.1093/schbul/sbi058

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Predicting Drug Efficacy for Cognitive Deficits in Schizophrenia

Jim J Hagan
Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline plc., New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW UK

Declan N C Jones
Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline plc., New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW UK

	Abstract

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The purpose of this article is to discuss the prediction of cognitive enhancement in schizophrenia from preclinical data. Despite increasing focus on the significance of cognitive impairment in schizophrenia, the progress of novel treatments has been slow. Hyman and Fenton's identification of a "translational gap" between preclinical and clinical science underscores the need to revise preclinical, clinical, and regulatory practice. A review of the clinical literature identifies evidence for some cognitive benefits with current antipsychotics. The magnitude of these effects may, in some cases, be too small to be functionally relevant, and many studies are methodologically flawed, but the data might nevertheless allow translational links to be identified between clinical and preclinical studies. The literature is reviewed to determine if the cognitive signal reported in clinical studies is detectable in preclinical studies. The effects of antipsychotics on prepulse-inhibition deficits in animals is robust and demonstrates a reversal of drug-induced and developmentally induced deficits, although predictive links to the clinic are not well established. The preclinical literature on antipsychotic effects on attention, learning and memory, and recognition and executive function shows, with rare exceptions, impaired learning or task performance, rather than improvement. In general, therefore, preclinical studies have not detected the small pro-cognitive signal evident in the clinical literature. A number of factors may account for this. Effective closure of the translation gap for cognitive deficits in schizophrenia will require the design of a coherent preclinical strategy, and some of the potential elements of such a strategy are outlined and discussed.

Keywords: schizophrenia / cognition / efficacy / prediction / translational strategy

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	Introduction

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The purpose of this article is to address the issue of predicting cognitive enhancement in schizophrenia from preclinical, behavioral data. Kraepelin's designation "dementia praecox" identified the importance of impaired cognition in schizophrenia, and this viewpoint has been given increased prominence recently as it becomes clearer that impaired cognition contributes to poor long-term morbidity¹ and that it precedes, accompanies, and often outlasts other symptoms.²

Evidence of cognitive impairment is consistent and robust and is reflected in multiple domains, including recognition memory,³ but it is particularly evident in verbal memory, attention, reasoning, and problem solving. Some domains such as semantic knowledge and visual perception appear to be less impaired.^4–6 Deficits are often manifest against a generalized decrease in IQ,^{5, 7} and evidence suggests that similar deficits are found in nonaffected relatives,^8–9 consistent with the hypothesis of a familial disposition. Cognitive impairments appear to be relatively stable from first episode through to late middle age.¹⁰ A longitudinal study comparing schizophrenics with controls over periods of up to 5 years has demonstrated that neuropsychological deficits are stable, trait-like dimensions rather than state-like features of the disease.¹⁰ Whether such loss of function reflects static deficits in all patients or the aggregate of dynamic functional instability in each patient is a matter of debate.¹¹

Meta-analyses have identified cognitive impairment in schizophrenia, measured by a variety of tests, as the variable yielding the greatest overall effect size. Healthy comparator groups perform at a level that is approximately 1 standard deviation higher than that of patients.² The effect size for cognition exceeds those associated with changes detected by structural magnetic resonance neuroimaging studies based on a variety of regional blood flow measures and measures derived from studies of postmortem tissue (e.g., receptor densities, cytoarchitectural changes). Studies comparing patients with healthy controls estimate that the number of schizophrenics who fail to show performance deficits 1 SD below the normal mean varies between 27 and 55%. However, when estimated in terms of their predicted level of cognitive functioning (based on factors such as parental educational level), more than 98% of patients fall below expectations for cognitive performance (¹² and references therein). The significance of the cognitive defect in schizophrenics compared to other symptoms is encapsulated in Heinrich's observation: "Make the brain do cognitive work and measure performance in behavioral terms to maximize differences between patients and healthy people."^{2(p 239)}

Much of the evidence suggests that impaired cognition represents a dimension of the illness that is partially independent of other symptom domains.⁴ Deficits in pure motor speed, perceptual-motor speed, and executive function are correlated in concordant, but not discordant, sib pairs, suggesting that some cognitive measures may be genetically linked to the disease.⁹ Poorer verbal learning and memory, but not working memory, appear be associated with earlier disease onset and related to increased genetic susceptibility.¹³ Some evidence suggests that episodic memory impairment may be a risk factor for early onset, possibly mediated through environmental factors, such as fetal hypoxia or viral infections.¹⁴ The developmental time courses for positive symptoms and cognitive impairment differ, and cognitive impairment appears to be a risk factor for the disease long in advance of the onset of psychosis or negative symptoms.^6–7 Furthermore, symptoms that show the most treatment responsiveness to antipsychotic medication appear to be only weakly associated to cognitive impairment. Negative symptoms and symptoms of thought disorganization tend to show modest but consistent correlations to cognitive performance. Most persuasively, while both typical and atypical antipsychotic drugs show efficacy in controlling psychotic positive symptoms, the impact on improving cognition is relatively modest (see below).⁶

Impaired cognitive function adversely effects daily activities and social interactions and is therefore related to poor functional outcome. A consensus on the link between cognition and functional outcome has been established on the basis of studies using cross-sectional methodology,¹⁵ and more recent longitudinal studies on cognition and community outcome strengthen this view.¹⁶ In a meta-analysis of studies linking cognitive function to outcome, Green has identified secondary verbal memory as a strong predictor.¹⁷ Somewhat surprisingly, although perhaps predictably, psychotic symptoms were not associated with functional outcome measures in any of the studies.

Effective intervention to improve cognition, by pharmacological or other means, is therefore predicted to lead to improvements in daily functional activities, facilitate normal social discourse, and reduce long-term morbidity. Realization of this objective requires the development of treatments that more effectively reverse the cognitive deficits in schizophrenia. The development of such novel treatments requires the definition of an appropriate conceptual, scientific, and regulatory framework.

	The Translation Bottleneck

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In their analysis, Hyman and Fenton identify a "translational bottleneck" between preclinical and clinical science.¹⁸ The growing scientific literature on cognition and schizophrenia over the preceding decade had not been paralleled by increased drug registrations or clinical trial activity for cognition in schizophrenia. Therefore, advances in basic science had not been effectively translated into patient benefit. The magnitude of the translational problem is underlined by the number of potential pharmacological approaches that have been identified and are discussed in the literature (see table 1).^19–22 The list of potential targets in table 1 is itself incomplete and does not take into account those targets likely to be identified through increased understanding of the genetic determinants of the disease,^23–24 increased understanding of neuropathology derived from transcriptional analysis of postmortem schizophrenic brain tissue,^25–28 antipsychotic effects on gene transcription in rodent brain tissue,^29–30 or other novel approaches. It seems unlikely that all of these potential pharmacological targets will deliver significant, or equivalent, clinical benefit free from unwanted side effects, but effective strategies are required to identify those most likely to succeed and eliminate those most likely to fail.

View this table: [in this window] [in a new window]   Table 1. Pharmacological Mechanisms Under Discussion in the Literature as Potential Cognition Enhancers

 
Hyman and Fenton propose a modified clinical and regulatory framework in which the DSM-IV disease entity is fractionated into component symptom clusters.¹⁸ This would allow the development of treatments for symptom clusters, rather than retaining sole focus on the identification of monotherapies targeting all symptoms in what is a highly heterogeneous condition. This would, they argue, facilitate the development of specific therapies to target the cognitive deficits in schizophrenia. Seven deficient cognitive domains have been identified in schizophrenia: speed of processing, attention/vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving, and social cognition.³¹

This frameshift may result in an increased focus on the core cognitive symptoms of the disease, but these initiatives alone will not be sufficient to close the translational gap. Parallel activities are needed to enable effective bridges to be built between early neurobiological research and clinical studies. In order to put this into context, briefly consider the steps involved in a drug-discovery project. The initial concept, which may be proposed on the basis of a variety of experimental data, requires the identification of suitable small molecules or proteins to enable confirmation of the proposed mechanism using in vitro and in vivo models. Through these tools, supportive evidence is sought from relevant animal models, in this case using tests of cognition. Though not obligatory, this step is often preferred before progressing on to man, given the cost and resources required to progress compounds into clinical trials.

The process is iterative and organic. Evidence generated at any stage enables a progression decision but also feeds back to inform the decision criteria at earlier stages. Rational preclinical strategies for hypothesis testing and compound characterization are therefore important in enabling informed choices between mechanisms and molecules. These strategies should not be restricted to behavioral tests or disease models, and a range of functional techniques may eventually prove useful. Establishing robust links between each stage of testing and building predictive algorithms is essential if preclinical approaches are to be relied upon to predict clinical efficacy.

The question therefore arises as to whether or not such predictive confidence is already evident in the area of cognition in schizophrenia. An answer to that question requires an evaluation of the evidence that antipsychotics improve cognition in clinical studies and an evaluation of the evidence for cognitive improvement in preclinical models using the same compounds.

Cognitive Improvement Following Antipsychotic Treatment: Clinical Data
The effects of typical antipsychotics on cognition are controversial. Some studies have suggested positive cognitive effects,^32–34 but the consensus view regarding the earlier, typical antipsychotic drugs (e.g., chlorpromazine, haloperidol, clopenthixol) in most reviews of the topic (e.g., ³⁵ and references in ³⁶) has been equivocal or negative. In many studies the cognition-impairing effects of anticholinergic medication, co-prescribed to combat drug-induced parkinsonian symptoms, often cloud the issue. Cassens et al., in their analysis of the earlier literature, identify the impairing effects of acute but not chronic treatment with neuroleptics on some, but not all, attentional tasks but also find evidence for improvements in some attentional and visuomotor tasks after chronic dosing.³⁷ A recent meta-analysis of data from 34 studies reported between 1957 and 2002, filtered through predefined quality criteria, identifies an overall positive cognitive effect size of 0.22 (95% confidence limits 0.13–0.29).³⁶ Greatest effects were seen in attention, automatic processing, language, and perceptual processing, with clear negative effects on motor function. Interestingly, the overall improvement detected was independent of changes in other symptoms, confirming the observations discussed in previous sections.

Evidence that atypical antipsychotics improve cognition is somewhat stronger, although the data should be interpreted with caution, given the methodological weaknesses associated with many of the studies.^38–39 A meta-analysis of studies comparing typical (haloperidol, fluphenazine) and atypical (clozapine, risperidone, zotepine, ziprasidone) antipsychotics analyzed the outcome of 3 double-blind and 12 open-label studies.⁴⁰ Double-blind studies identified atypicals as having overall superiority, with significant effects on attention subprocesses, executive function, and visuospatial analysis. Open-label data generally confirmed these conclusions, although effects on attention failed to reach significance, and a number of additional dimensions (e.g., verbal fluency, digit–symbol substitution, and fine motor function) showed greater effects associated with atypicals.

Several studies of clozapine (for references, see ³⁹) have found evidence for improved verbal fluency, attention, and reaction time, with some evidence for improvements in executive function, verbal learning, and verbal memory. Clozapine's effects may be domain specific, as tests of verbal working memory, visual learning, and visual memory are unaffected or even impaired. In their study of olanzapine, Meltzer and McGurk identified significant effects on executive function, verbal learning and memory, verbal fluency (immediate and delayed recall), and attention/reaction time.⁴¹ Findings from a study comparing olanzapine and risperidone with typical antipsychotics in treatment-resistant schizophrenics found a significant advantage for olanzapine in verbal memory.⁴² In an 8-week comparative study of olanzapine and amisulpiride conducted in schizophrenics who were switched from typical and atypical antipsychotics, overall analysis indicated significant effects on executive functions, working memory, and declarative memory, with no significant difference evident between the 2 compounds.⁴³ Both compounds improved positive and negative symptoms. Separate analysis within each treatment group identified significant effects with amisulpiride in overall cognitive index, attention, executive functions, and working memory. For olanzapine the significant improvements were restricted to working memory. The data suggest that selective blockade of dopamine D₂/D₃ receptors, by amisulpiride, may be sufficient to improve cognition, at least in some domains. Aripiprazole has been reported to have some beneficial effects upon verbal memory.⁴⁴

Direct comparisons between atypical antipsychotics are infrequent in the literature. When patients on typical antipsychotics were switched to risperidone, quetiapine, olanzapine, or perospirone and monitored for 4 weeks, only risperidone improved verbal working memory, while the switch to quetiapine worsened it.⁴⁵ Significant improvements in immediate memory were reported following olanzapine or risperidone. In a comparison of risperidone and haloperidol in stable schizophrenics using a double-blind assessment of fixed and flexible doses, risperidone-treated patients showed greater improvement in verbal learning during both phases.⁴⁶ Differences remained, although some were weaker, after correction for benztropine co-medication.

A double-blind prospective comparison of quetiapine and haloperidol showed quetiapine to have significant beneficial effects on cognition, particularly verbal reasoning and fluency, visuospatial fluency, and immediate recall.⁴⁷ In a further study comparing quetiapine with haloperidol, significant superiority for quetiapine was found in tests of verbal fluency (Stroop Color Word test and Paragraph Recall),⁴⁸ although differences in the incidence of benztropine coadministration in the haloperidol group (50% co-medication in haloperidol group versus 8% in quetiapine group) seriously undermine the interpretation of the data. An open-label, non-placebo-controlled study in a small patient group has reported small but significant effects of quetiapine on Digit Span, Trail Making Part A, and Stroop test in patients switched to quetiapine (400–700 mg/day) from a variety of other antipsychotic medications.⁴⁹

In their comparison of risperidone, clozapine, olanzapine, or quetiapine with placebo in a double-blind crossover study, Weickert et al. attempted to address some of the methodological shortcomings of previous studies.⁵⁰ The study design controlled for critical factors such as cohort or baseline effects, practice effects, and the secondary effects of symptom reduction. Comparison with a placebo period also reduced the potential confounds arising from comparing atypical effects against performance baselines that in many studies may already be reduced by the effects of treatment with typical antipsychotics. Consistent improvements in cognition were seen across all cognitive domains when patients were administered atypical antipsychotics and compared to placebo. Antipsychotic treatment improved performance on measures of general intellect, memory, and word production. Nearly all measures improved, and effect sizes ranged from 0.5 to 1.28. Symptom improvement, as measured by the Positive and Negative Syndrome Scale, did not predict for cognitive improvement.

While this brief survey of the literature is far from comprehensive, and individual studies suffer from a variety of methodological issues,^38–39 the evidence described gives some support to the hypothesis that atypical antipsychotics, and to a lesser extent, typical antipsychotics, can improve cognition in schizophrenia across a number of domains. Our understanding of which cognitive domains are affected by which compounds is poor. Further work is required to define the extent to which the statistically significant effects reported in experimental studies translate into functional benefit for patients when treatment effect sizes are relatively low on many cognitive domains (see figure 1).³⁸ Notwithstanding the clinical evidence for cognitive improvement with some current drugs, it is clear that greater efficacy will be required of future compounds if substantial improvements in functional clinical outcome are to be achieved.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Improvement in Specific Aspects of Cognition in 20 Studies in Which Cognitive Changes Were Reported in Patients With Schizophrenia Following Novel Antipsychotic Treatment. Note: Values represent average improvement as measured by changes from baseline in standard deviations. Source: Adapted from Harvey & Keefe, 200138.

 
Cognitive Improvement Following Antipsychotic Treatment: Preclinical Data
The majority of preclinical studies of antipsychotics deal with mechanisms of action and the prediction of efficacy against positive and negative symptoms. Attention to measuring pro-cognitive effects has been relatively limited. Nevertheless, one approach to the issue of predictive validity for animal tests of cognition is to establish the extent to which the mild cognitive benefits associated with antipsychotic treatment in the clinical literature (see above) are reflected in preclinical data. The studies reviewed (see also table 2) examine some of the effects of typical and atypical antipsychotics in preclinical tests of cognition following acute and repeated dosing, with the overall aim to identify tests that detect and predict the cognitive signal seen in clinical studies and which may therefore be useful starting points in predicting the pro-cognitive activities of novel agents.

View this table: [in this window] [in a new window]   Table 2. Examples of the Effects of Antipsychotics in Preclinical Tests of Cognition

 
Sensorimotor Gating: Pre-attentive Processing
Information processing that occurs prior to conscious attention, typically within the first 100 milliseconds of stimulus presentation (see ⁵¹), is referred to as pre-attentive. Different aspects of this processing can be investigated using prepulse inhibition (PPI) of a startle response or electroencephalograph-based auditory gating tests, and the characteristics and utility of these 2 different procedures have been reviewed.^51–54 PPI is thought to reflect the operation of a sensorimotor gating mechanism that protects the processing of weak stimuli during the conduct of a sensory task. It occurs upon first presentation of a stimulus, is independent of learning, and is found in nearly all mammals. PPI deficits have been reported in schizophrenia and other disorders^52–53 and can be induced in animals using a variety of pharmacological and environmental interventions, potentially providing a translational bridge across species.⁵⁴

Clinical studies investigating PPI in patients and normal subjects have been reviewed by Braff et al.⁵² There are mixed reports regarding the effects of antipsychotics on PPI deficits in schizophrenia. Some studies have reported PPI to have been improved in clinical responders treated with both typical and atypical antipsychotics, or in some studies, in only those patients treated with atypicals.^55–60 Other studies have reported that PPI deficits remain regardless of medication or clinical status.^61–63 A clear understanding of the effects of antipsychotics upon PPI is impeded by the fact that most clinical studies have used cross-sectional or naturalistic designs and suffer from a number of caveats. Gender, age, medication status including concomitant medication, and disease history are often confounding factors.^64–65 There are few studies in which premedication baseline PPI is established and the effects of antipsychotic treatment are determined at appropriate time points (but see ^{62, 66}). In one example of a longitudinal study, 3 months of treatment with either risperidone or zuclopenthixol did not improve PPI in 20 first-episode, drug-naive schizophrenics, despite overall clinical improvement.⁶⁶

The extensive preclinical literature on PPI and the effects of antipsychotics in animal models of impaired PPI have been reviewed (e.g., ^{51–52, 67–68}). Systematic evaluations have been conducted of the effects of antipsychotics and other drugs upon PPI deficits in a variety of procedural variants, although the majority of these studies have used acute treatment (but see ^69–70). In general, antipsychotics do not influence PPI in normal rats (table 2; but see ⁷¹) but do increase PPI in a number of mouse strains (e.g., DBA/2J, C57BL6, and others).^72–73 In their excellent review, Geyer et al. classify rodent studies of impaired PPI into those driven by dopamine-receptor agonists, by 5-HT₂-receptor agonists, by N-methyl D-aspartate–receptor antagonists, and by developmental intervention, for example, isolation rearing and maternal deprivation.⁵⁴ Further, Geyer et al. review mouse genetic models of impaired PPI.⁷⁴

Perhaps one of the most promising models is isolation rearing–induced PPI deficits.⁷⁵ Most studies show that isolation rearing–induced PPI deficits are reversed by typical and atypical antipsychotics (e.g.,^{54, 76–78}, but see ⁷⁹). In addition, there are a number of rat strains that show spontaneous deficits in PPI (see ⁸⁰), including Brattleboro rats, which are sensitive to antipsychotic treatment following acute and repeated treatments (e.g., ^{69–70, 81}).

Thus, robust PPI deficits have been described in schizophrenics, and in a variety of studies animals show antipsychotic-sensitive PPI deficits. However, as a result of the ambiguity in the clinical literature related to antipsychotic drug effects, the utility of PPI as a translational, predictive model is poorly established. Indeed, in their study, Mackenprang et al. conclude that, although preclinical models of PPI deficits may allow prediction of an antipsychotic effect in man, they may not directly translate to effects upon PPI deficits in man.⁶⁶ Kumari and Sharma⁶⁵ and Hamm et al.⁶⁴ have outlined proposals for more systematic clinical investigation of the effects of antipsychotics on PPI. Differences in PPI responses in healthy control groups represent a significant source of variation between studies, and a more precise understanding of the PPI response in healthy volunteers would be helpful.⁶⁴ A clearer understanding of PPI status prior to medication, the impact of age of symptom onset, and the effect of medication on PPI response is also needed.^64–65 Increased sample sizes, longitudinal study designs, and PPI sampling in parallel with clinical and cognitive testing will all improve our understanding.^64–65 Finally, there is limited insight into how PPI deficits in patients might relate to the 7 domains of cognitive impairment identified in schizophrenia. Most important, from the perspective of predicting therapeutic response, it remains to be established to what extent statistically significant drug-induced improvement in PPI deficits in schizophrenics might predict for cognitive improvement and functional recovery. Given the wealth of preclinical data and the cross-species nature of the phenomenon, these could be fruitful areas for further investigation.⁶⁵

In man, the inhibitory processing of the P50 auditory evoked potential (AEP) is assessed by evaluating the evoked response to identical paired auditory stimuli. The first stimulus activates an inhibitory response, the strength of which is measured by the response to the second stimulus, which should be reduced. In rodents, the analogous response is the P20-N40 AEP⁸² (although see ⁸³). It has been reported that schizophrenics have impaired gating when acutely ill and medicated with typical antipsychotics, acutely ill and unmedicated, or clinically stable and medicated with typical antipsychotics (for references, see ⁸⁴). Adler et al. evaluated P50 auditory gating in healthy subjects and schizophrenic patients who were either unmedicated, treated with typical antipsychotics, or treated with the atypical antipsychotics clozapine, olanzapine, risperidone, or quetiapine in a naturalistic design.⁸⁵ Only the mean gating ratio of the clozapine group was not statistically impaired compared with that of healthy controls. All remaining groups were significantly impaired compared with healthy controls, with the approximate order of impairment (mean P50 gating ratio) as follows: quetiapine = typicals > unmedicated schizophrenics = olanzapine = risperidone > clozapine healthy controls. Similarly, in a double-blind trial of treatment-resistant patients (no placebo or normal controls), neither 12 weeks of treatment with haloperidol and benztropine nor treatment with olanzapine improved the gating ratio compared with baseline levels.⁸⁶ However, there was no improvement in clinical symptoms in either group. In a longitudinal study in treatment-refractory patients (10 subjects), sensory gating of P50 was examined first while the patients were still on typical antipsychotic medication (baseline) and in the same patients 1 month and 15 months after starting clozapine treatment.⁸⁷ Clozapine caused both clinical improvement (i.e., >20% reduction in total Brief Psychiatric Rating Scale score) and normalization of the gating of the P50 response in the majority of patients.⁸⁴ There was a clear relationship between clinical improvement and improved auditory gating in this study.

Measuring auditory gating in rodents is technically more demanding than measuring PPI, which may explain the much smaller preclinical data set for auditory gating compared with that for PPI. Consequently, there is a relatively limited number of studies evaluating antipsychotics preclinically. Maxwell et al. evaluated the effects of continuous administration of olanzapine or haloperidol upon auditory gating in C57/BL6j mice using a varied interstimulus interval approach.⁸³ Olanzapine, but not haloperidol, increased the amplitude of the N40, P80, and P20/N40 component of the AEP, and on this basis the authors conclude that olanzapine, but not haloperidol, may improve N100 impairments in schizophrenia. Simosky et al. investigated the effects of clozapine, olanzapine, and haloperidol in DBA/2 mice, which show an impaired processing of the P20/N40 AEP.^82–83 Clozapine and olanzapine, but not haloperidol, improved the processing of the AEP. The effects of other antipsychotics have yet to be determined.

In summary, there has been limited systematic evaluation of treatments upon sensorimotor gating in schizophrenics using AEPs. Firm conclusions are difficult to draw from a sparse data set, although a tentative hypothesis worthy of further investigation is that clozapine improves gating in this paradigm in man. Despite the interpretational issues and technical complexities of conducting studies in rodents and primates, this approach might provide an informative translational link between preclinical and clinical research.

	Attention/Vigilance and Speed of Processing

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During latent inhibition (LI), noncontingent presentation of a stimulus attenuates the ability of that stimulus to enter into subsequent associations and is considered an index of learned inattention.⁸⁸ The limited LI studies conducted in man have been reviewed recently.^88–89 Studies of antipsychotic drug effects in normal volunteers have produced mixed results. Barrett et al. report that chlorpromazine, risperidone, and amisulpiride had no effect upon auditory LI, while risperidone and amisulpiride disrupted visual LI.⁸⁹ These findings contrast with the potentiation of low LI levels by haloperidol and chlorpromazine (for references, see ⁸⁹). Impaired LI has been reported in acute-episode schizophrenic patients but less often in chronic patients, a reduction that some authors suggest results from chronic antipsychotic treatment.^{60, 88} However, consistency is poor, as Williams et al. report intact LI in antipsychotic-naive acute schizophrenics but impaired LI in treated patients.⁹⁰ Interestingly Leumann et al. show that patients who were treated with typical and atypical antipsychotics showed intact LI, but PPI was intact in only those patients treated with atypicals.⁶⁰ As in the case of PPI, the clinical literature suffers from a lack of longitudinal studies in which LI is measured before and after appropriate treatment.

The preclinical pharmacology of LI is extensive and has been thoroughly reviewed,^91–92 including evaluation of the effects of antipsychotics on weak LI and upon drug-induced impaired LI models (e.g., by amphetamine). Moser et al. conclude that there is good evidence that haloperidol caused a robust and reproducible potentiation of weak LI.⁹¹ In contrast, the data for clozapine are much less clear, with a variety of findings described, including lack of effect, impaired LI, and enhanced LI. Methodological differences critically determine drug response. Shadach et al. investigated clozapine and haloperidol using 2 test conditions (40 pre-exposures and either 5 or 2 conditioning trials), which resulted in the presence or absence of LI in the control group for the respective conditions.⁹³ Under those conditions that did not induce LI in controls, both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) enhanced LI when administered during conditioning. In contrast, under the conditions in which LI was induced in controls, clozapine, but not haloperidol, abolished LI when administered in pre-exposure. Therefore, subtle variations in methodology between studies may contribute to the variable findings with antipsychotics.

Aspects of attentional control, including sustained, selective, or divided attention as well as speed of processing, can be studied in rodents using the 5-choice serial reaction time task (5CSRTT).⁹⁴ Antipsychotics have not been systemically investigated in this test, and pharmacological studies have primarily focused on investigations of the neurotransmitter systems involved in attentional processes. For example, alpha-flupenthixol and sulpiride impaired response accuracy and latency measures,⁹⁵ and similar findings are reported for raclopride by Shoaib et al.⁹⁶ A systematic investigation of the effects of acute and chronic dosing of antipsychotics upon attention in rats would be fruitful.

Considering these data together, a number of common themes emerge. First, the clinical investigation of the effects of antipsychotics on pre-attentional and attentional processes is relatively underdeveloped, and much of the data are conflicting. This precludes any clear conclusion. Second, the links between the cognitive processes measured by these procedures and the 7 domains of cognitive impairment identified in schizophrenia need to be better understood in order to ascertain whether these procedures will be helpful in predicting functional clinical outcome. Finally, although an extensive preclinical literature exists in this area, and some consistent conclusions can be drawn, the link to clinical response has not been well established, and so the predictive validity of these procedures for clinical response remains uncertain.

	Executive Function: Reasoning and Problem Solving

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Impaired executive function, as measured by the Wisconsin Card Sorting Task (WCST), has frequently been reported in schizophrenia (e.g., ⁹⁷). Perceptual, attentional set shifting in primates⁹⁸ and rodents may be analogous to the WCST used in man.^99–101 In a single test session, rodents learn a discrimination and then perform a series of tasks, including reversal, intradimensional, and extradimensional shifts, in a manner that mirrors the WCST. The pharmacological investigation of this test in normal rats has been limited. Selective 5-HT₆-receptor antagonists improve reversal learning and set shifting,¹⁰² while tolcapone, a catechol-O-methyltransferase inhibitor, specifically improved extradimensional set shifting.¹⁰³ While these observations are encouraging, these are not yet clinically proven compounds, and so the data do not fully address the issue of predictivity. Numerous approaches have been adopted to model schizophrenia-like deficits in set shifting, including subchronic phencyclidine (PCP) administration^104–105 (but see ¹⁰⁶) and subchronic amphetamine treatment.¹⁰⁶ There are no published studies of the effects of antipsychotics in this test, although in a preliminary study, subchronic clozapine (9 days) had either no effect (5 mg/kg) or impaired performance relatively nonspecifically (10 mg/kg; Tait, Brown, & Jones, unpublished data). Therefore, this test measures cognitive processes that are thought to be impaired in schizophrenia and appears to be sufficiently sensitive to detect drugs that improve various aspects of performance. However, a systematic analysis of the effects of antipsychotics and novel compounds is required to fully address its utility as a predictor of cognitive effects in man. A focused effort to define an appropriate deficit model, in which baseline impairments mirror those reported in schizophrenia, would be fruitful.

The effects of antipsychotics upon performance in the WCST and other tests of executive function/cognitive flexibility are varied (e.g., ¹⁰⁷). For example, in a naturalistic study, patients treated with a variety of either typical or atypical drugs showed impaired WCST performance compared with normal controls.¹⁰⁸ In contrast, it has been suggested that risperidone, sertindole, or melperone, in particular, may offer some benefit for WCST performance.^{107, 109–112} The recent report that modafinil improves attentional set shifting in chronic schizophrenic patients, but not normal controls or attention deficit/hyperactivity disorder subjects, provides a positive control for preclinical studies¹¹³ and underlines the potential utility of the procedure. An alternative approach to modeling deficits in cognitive flexibility that resemble those found in schizophrenia includes acute or subchronic PCP-induced deficits in reversal learning (see also below), which have been shown to be reversed by clozapine, ziprasidone, olanzapine, and lamotrigine but not haloperidol or chlorpromazine.^114–116

	Learning and Memory

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In a study of delayed nonmatch to position (DNMTP) in rats, Didriksen showed that acute clozapine, risperidone, haloperidol, and raclopride reduced choice accuracy in a delay-independent manner in rats.¹¹⁷ In contrast, sertindole did not impair task performance. These findings are in agreement with those of Pemberton et al.,¹¹⁸ who show that acute treatment with haloperidol, clozapine, olanzapine, or aripiprazole (unpublished data) all reduced accuracy in a delay-independent manner and markedly increased the number of missed trials during a DNMTP test, suggesting a relatively nonspecific drug effect on behavior. In 1 study, acute treatment with iloperidone was reported to improve performance in this task at long delays (48 and 64 seconds), despite some impairment of other performance measures, while haloperidol, but not clozapine, impaired choice accuracy.¹¹⁹

In a variant of the delayed nonmatch to sample test carried out in an 8-arm radial maze, Wolff and Leander report that acute treatment with olanzapine and risperidone improved accuracy during the retention phase (dosed immediately after sample phase, 7 hours prior to testing retention) in a dose-independent manner.¹²⁰ Clozapine, ziprasidone, and haloperidol did not influence accuracy. All compounds, except risperidone and ziprasidone, influenced non-mnemonic performance measures, for example, time to completion.

There appears to have been only 1 study investigating the effects of chronic antipsychotic treatment upon performance in DNMTP.¹²¹ In comparison to the acute effects (described above), some tolerance developed to the effects of chronic clozapine and low-dose haloperidol. In contrast to acute studies, chronic treatment with sertindole caused a minor impairment in working memory on day 21 of treatment, although not on days 20 or 22.

There have been a limited number of studies carried out using the radial arm maze (RAM) task. For example, acute low-dose haloperidol and risperidone did not affect maze working memory performance, while clozapine impaired performance.^122–123 In another study, olanzapine did not alter measures of working or reference memory in the RAM, but the higher dose attenuated the cognitive impairment caused by intrahippocampal okadaic acid injection.¹²⁴ Rosengarten and Quartermain investigated the effects of chronic treatment (75 days) upon working memory in young (3 months) and aged (18 months) rats.¹²⁵ Drug doses were chosen that achieved striatal dopamine D₂–receptor occupancy of approximately 80% (haloperidol), 60% (olanzapine and clozapine), and 70% (risperidone). Clozapine, haloperidol, and risperidone, but not olanzapine, impaired acquisition of the task in both age groups. Further, clozapine, haloperidol, and risperidone impaired retention of the task.

Passive Avoidance
There has been limited systematic investigation of antipsychotics conducted using passive avoidance (PA) tests. Haloperidol impaired retention of PA after single or repeated (20 days) dosing in rats when injected prior to acquisition training.¹²⁶ In the same study, doses of risperidone that were sufficient to influence behavior in the open field, conditioned avoidance responding, and sexual behavior had no effect upon retention of the PA response. In contrast, Ichihara et al. show that haloperidol failed to alter the PA response in mice when administered before either the training or the retention session.¹²⁷ In the same study, low-dose sulpiride (20 mg/kg IP) impaired the PA response, although higher doses were ineffective. Ninan and Kulkarni show that post-training treatment with clozapine impaired PA in mice, but a low dose reversed a scopolamine-induced deficit.¹²⁸ Similarly, olanzapine (0.32 mg/kg but not higher doses) attenuated post-training scopolamine-induced deficits (Foley, Regan, & Jones, unpublished observation).

Recognition Tests
The novel object recognition (NOR) test allows study of the effects of compounds upon recognition memory in rodents.¹²⁹ The test conditions can be manipulated to show high (short delay between exposure [T1] and test [T2], e.g., 1 hour) or low (long delay between T1 and T2, e.g., 24 hours) levels of object recognition to evaluate detrimental or beneficial effects upon memory. However, a literature search failed to reveal any studies specifically describing the effects of antipsychotics upon baseline performance in the NOR test. In a variant of this test, in which rats were tested in a 3-compartment chamber and were confined in compartments with the sample object for two 5-minute periods, clozapine (3mg/kg but not 10 mg/kg) blocked novel object detection when administered after the sample object exposure.¹³⁰

The social recognition test relies on the ability of an adult rat to recognize a novel from a familiar, juvenile rat.¹³¹ As in the case of NOR, baseline levels of recognition can be manipulated by changing the test parameters (e.g., delay between T1 to T2). In a very recent report Terranova et al. show that clozapine (0.1–1 mg/kg ip), amisulpiride (1–3 mg/kg ip), and the putative antipsychotic SSR181507 (0.03–3 mg/kg ip) attenuated social recognition deficits caused by reducing the exposure time at T1 and by acute or neonatal PCP treatment.¹³² In contrast, haloperidol (0.3 mg/kg ip) reversed only deficits caused by manipulating T1 exposure time. Further studies in this task are warranted.

Spatial Learning in Water Mazes
Haloperidol, but not sertindole, has been reported to impair acquisition of spatial learning in a water maze.¹³³ In contrast, clozapine improved acquisition at low doses (1–2.5 mg/kg) and did not impair performance at higher doses (5–7.5 mg/kg). Skarsfeldt reports that acutely administered risperidone, clozapine, olanzapine, ziprasidone, or haloperidol, but not seroquel or sertindole, impaired acquisition of the water maze in young male Wistar rats.¹³⁴ Following repeated dosing (21 days), Didriksen reports no impairment in task acquisition with sertindole and some tolerance to the impairing effects of clozapine but not olanzapine.¹³⁵ Terry et al. describe the effects of 45 and 90 days of dosing with haloperidol (2 mg/kg/day), olanzapine (10 mg/kg/day), risperidone (2.5 mg/kg), and clozapine (20 mg/kg) upon acquisition and retention of spatial learning in a water maze, tested after a 4-day washout period.^136–137 There were no effects after 45 days of dosing upon either acquisition or retention. However, following 90 days of treatment, haloperidol, and to a lesser extent olanzapine, impaired acquisition of this task. Haloperidol, but not olanzapine, impaired retention. In contrast, risperidone improved acquisition performance slightly, and clozapine caused a trend toward improved acquisition (both following 90 days of treatment). Thus, the study identifies both compound-specific and temporally dependent effects upon the acquisition and retention of spatial learning.

Modeling the Cognitive Impairments Associated With Schizophrenia
The majority of sensorimotor gating studies have been carried out in models of impaired gating (table 2). LI studies have been conducted both in normal animals and in models of impaired LI (see above). However, in most other cognition studies of antipsychotics (e.g., spatial learning in a water maze, 5CSRTT, RAM), normal animals have been used and have, in general, revealed only cognitive or performance deficits. Investigation of the cognitive effects of antipsychotics and novel compounds will require the identification and validation of animal models of the cognitive deficits in schizophrenia or at least a subset of them. Candidate models have been extensively reviewed by a number of authors,^{51, 138–146} although there has been surprisingly little attention given to the issue of predictive validity.

Detailed consideration of animal models of schizophrenia-like cognitive deficits is beyond the scope of this article, but subchronic PCP treatment is one of the best-characterized models and provides a useful example to highlight some of the issues. This model is attractive for drug testing because compounds are tested in the absence of a challenge dose of PCP, thereby eliminating potential confounds due to pharmacokinetic interactions. However, contrasting effects of subchronic PCP have been reported on cognition (see ¹³⁸), and a review of the literature confirms this. PCP (5 mg/kg, BID for 5 days) has been reported not to impair alternation performance.¹⁴⁷ PCP (10 mg/kg for 14 days) did not impair 8-arm radial maze performance.¹⁴⁸ PCP (3mg/kg, 3 times per week on alternate days for 3 weeks) did not impair PPI, LI,¹⁴⁹ or attentional set shifting.¹⁰⁶ PCP (0.3–5 mg/kg, bid for 7 days) did not impair working memory in the DNMTP task (Pemberton et al., unpublished). In contrast, PCP (10 mg/kg for 14 days) caused delay-dependent reduction in alternation accuracy.¹³⁸ PCP (2 mg/kg, bid for 7 days) impaired serial reversal learning.¹¹⁵ Chronic, intermittent PCP (2.58 mg/kg) selectively impaired attentional set shifting.¹⁰⁴ PCP (0.3–5 mg/kg, bid for 7 days) impaired novel object recognition (J. Gartlon 2005, personal communication). In addition, neonatal treatment with PCP or MK801 (dizocilpine) causes PPI and cognitive deficits in adult rats.^{132, 150–151} Alternatively, impairments of recognition memory have been reported following acute treatment with MK801^152–153 or PCP¹⁵⁴ and neurodevelopmental interventions such as gestational disruption of neurogenesis¹⁴² or neonatal PCP treatment (¹³² and Gartlon et al., unpublished findings).

Direct comparisons between these studies are confounded by the variety of PCP dosing regimes and test methods used in different studies with no clear rationale established for selecting any particular protocol. Further, there have been few reports of the effects of antipsychotics or other compounds upon cognitive deficits induced by subchronic PCP (e.g., ¹¹⁵). A systematic, methodological investigation of the effects of PCP-dosing regimes would be helpful in identifying the most appropriate parameters in order to determine the predictive validity of this approach.

Nonhuman primates offer higher homology to human cortical architecture and function, higher cognitive capacities,¹⁵⁵ and the availability of computerized test batteries analogous to those used in man (e.g., ^156–157). For example, in a functional magnetic resonance imaging study, performance of an identical attentional set-shifting task recruited homologous regions of the ventrolateral prefrontal cortex in humans and macaques.¹⁵⁸ Castner et al. also suggest that nonhuman primate models of prefrontal cortical dysfunction (e.g., subchronic PCP, neurodevelopmental insults) are well suited for the testing of putative antipsychotics.¹⁵⁵ However, there are very few studies investigating the effects of typical or atypical antipsychotics upon cognition in nonhuman primates (e.g., ¹⁵⁹). Jentsch et al. show that haloperidol impaired the performance of an object-retrieval/detour task in vervet monkeys, a test of fronto-striatal function, and potentiated the impairment caused by repeated PCP treatment.¹⁶⁰ In contrast, clozapine attenuated the effects of PCP in vervet monkeys.¹⁶¹

Castner et al. have reviewed the potential models of prefrontal dysfunction, which include subchronic PCP, chronic amphetamine, amphetamine-induced sensitization, and neurodevelopmental models (e.g., fetal X-ray irradiation and neonatal ventral hippocampal lesion), that are appropriate for nonhuman primates.¹⁵⁵ These manipulations cause cognitive, behavioral, neuroanatomical, and neurochemical effects that can be mapped onto schizophrenia symptoms and disease hypotheses. However, the predictive value of these models is difficult to judge given the paucity of data with antipsychotics and putative cognition enhancers. Therefore, a systematic analysis of antipsychotics and putative cognition enhancers using an appropriate model of schizophrenia-like cognitive deficits and a computerized battery of tests would be helpful in understanding the translational utility of these procedures to the clinic.

In summary, various rodent and primate impairment models have been explored in the literature, and some of these models may yet provide appropriate procedures for testing compounds to predict cognitive benefit in man. To date, few studies of antipsychotics have been reported, and consensus on the most appropriate intervention regimes or behavioral end points is limited. A detailed consideration of how the 7 affected cognitive domains might best be modeled and measured would act as a catalyst in this area and accelerate progress.

	Developing a Preclinical Strategy

Top Abstract Introduction The Translation Bottleneck Attention/Vigilance and Speed of... Executive Function: Reasoning... Learning and Memory Developing a Preclinical... References

 
A number of broad conclusions may be drawn from this brief overview of the literature. First, apart from tests such as PPI and LI, there have been few systematic preclinical investigations of the effects of typical and atypical antipsychotics on tests of attentional control, executive function, avoidance learning and retention, recognition memory, spatial learning, memory, or recall. Second, apart from a few notable exceptions (e.g., iloperidone,¹¹⁹ clozapine¹³²), antipsychotics are not reported to improve cognitive performance in the majority of these tests. Indeed, in most studies antipsychotics actually impair task acquisition or performance.

Thus, despite modest evidence for cognitive benefits with some current antipsychotics in clinical studies, the preclinical data for antipsychotics have so far failed to identify a convincing and robust signal for improved cognition. This conclusion underlines the need for a coherent translational strategy that allows reliable prediction of cognitive benefit in schizophrenia from preclinical studies, and this does not yet exist.

Several factors might be considered to contribute to this situation. In contrast to the clinical situation, the vast majority of preclinical studies evaluate the effects of acute dosing only and then predominantly in normal animals. Where chronic dosing has been carried out, this has usually been at a single dose and with a limited number of compounds (but see ^136–137). Drug-induced side effects (e.g., motoric impairment and sedation; see table 3), particularly after acute administration, often confound interpretation of the effects observed. The issue of acute versus repeated/chronic is important, as evidence suggests that chronic treatment with psychoactive drugs induces plastic changes in central nervous system function that may be relevant to therapeutic responses.

View this table: [in this window] [in a new window]   Table 3. Comparison of Preclinical Efficacy and Side Effects for Antipsychotics

 
The impact of chronic antipsychotic dosing upon motor performance has been addressed by a number of researchers, including Varvel et al.¹⁶² In their study of the effects of acute and repeated (16 days) dosing with a number of antipsychotics on operant responding under a multiple FR30/FI60 schedule, all compounds markedly and dose-dependently suppressed responding after acute dosing. Following repeated dosing only clozapine, and, to a lesser extent, thioridazine, showed any tolerance to this effect. Similar tolerance to the effects of clozapine has been reported previously (for references, see ¹⁶²). Therefore, motoric and/or sedative effects are likely to represent major confounds in the preclinical, cognition literature. Further, as clearly illustrated in table 2, even those studies apparently using the same preclinical test, for example, DNMTP, have important methodological differences, including testing protocols, apparatus, rat strain, dosing regimes, route of administration, and so on, which make direct comparison across studies impossible.

Dose selection is a critical factor that receives limited attention in the preclinical literature.¹⁶³ In many studies the rationale for dose selection is unstated. A notable exception is the study by Rosengarten and Quartermain, who investigated the effects of chronic drug treatment (75 days) upon working memory in 3- and 18-month-old rats.¹²⁵ In this study doses of drug were chosen that targeted striatal dopamine D₂-receptor occupancy of approximately 80% (haloperidol), 60% (olanzapine and clozapine), and 70% (risperidone), thus attempting to mimic the clinical situation.¹⁶³ The study showed that clozapine, haloperidol, and risperidone, but not olanzapine, impaired acquisition of the task in both age groups and, further, that clozapine, haloperidol, and risperidone impaired retention of the task. Thus, although the data do not support the hypothesis that the drugs have pro-cognitive effects in this model, the study is informative; it bases dose selection on D₂-receptor occupancy levels that are targeted in clinical studies and therefore eliminates dose selection as a candidate variable in interpreting the results. We have studied antipsychotics in a range of efficacy and side effect models following acute dosing in order to define appropriate doses and receptor occupancies, and these data are summarized in table 3. Dose selection on the basis of receptor occupancy can only be achieved for a limited number of drugs (e.g., haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, amisulpiride).^164–167 Significant confusion is caused by the use of different dosing routes (oral, IP, SC, etc.) and regimes. Consequently, drug effects should ideally be described in relation to their associated plasma concentrations, which may yield a direct read across to clinical situations. Undoubtedly, much greater emphasis on pharmacokinetic parameters, rather than dose, will enhance translation between preclinical and clinical studies.

Numerous novel pharmacological approaches are currently under development for cognition enhancement. These and other clinical investigations of novel compounds will provide information regarding which preclinical tests successfully predict positive clinical outcome for compounds specifically designed to enhance cognition in man, and, if positive, this information can be used to refine the preclinical tests used on an empirical basis. For example, -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor positive modulators have been selected for clinical investigation as part of the Treatment Units for Research on Neurocognition and Schizophrenia initiative (Org 24448 a.k.a. CX691; www.turns.ucla.edu/turns-compound-content.html). The therapeutic potential for AMPA receptor positive modulators, in particular in neuronal plasticity and cognition, has been reviewed recently by Black,¹⁶⁸ Lynch,¹⁶⁹ and O'Neill et al.¹⁷⁰ Numerous molecules (e.g., CX516, aniracetam, ORG24448, S 18986-1, LY451395) have been shown to improve the performance of rodents in spatial learning in water maze, conditioned fear, 2-odor discrimination, radial arm maze, passive avoidance, and novel object recognition and in DNMTP in primates.¹⁷¹ CX717 improved wakefulness and task performance in young healthy volunteers sleep deprived for 27 hours (www.cortexpharm.com/html/news/05/05-02-05.html). CX516 has been reported to improve recall in normal healthy volunteers¹⁷² and in aged humans¹⁷³ and improved measures of attention and memory when added to clozapine treatment in a small-scale trial in schizophrenic patients.¹⁷⁴

An important aspect of clinical practice is the use of novel compounds as add-on therapies. It seems unlikely that all of the novel pharmacological approaches currently being developed for cognition will also adequately control the psychotic symptoms of schizophrenia, and they may eventually be used as treatments added on to atypical antipsychotic treatment regimes in order to boost cognition. It will be important to understand how efficacy might be affected by drug combinations. For example, will an atypical antipsychotic inhibit or potentiate the effects of some pro-cognitive therapies? Likewise, will novel pro-cognitive therapies inhibit or potentiate antipsychotic effects? These issues will require significant experimental attention.

Probably the single most important factor to consider is the nature of the animal tests and disease models that should form the focus for future research. The animal tests and the deficit models employed to date may not map well onto the cognitive domains that are impaired in schizophrenia or may not have the level of sensitivity required to detect the small clinical signal identified with current antipsychotics. To date no consensus has been reached on which of the current animal models of cognition map appropriately onto the 7 cognitive domains identified in schizophrenia. A broader debate on this issue would now be timely. For pragmatic reasons, our review of the literature grouped tests into categories that map, at a first-order approximation, onto the cognitive domains identified by the Measurement and Treatment Research to Improve Cognition in Schizophrenia group (table 4). However, this is a prima facie approach that needs further elaboration. This can now be built on solid foundations. Robbins discusses aspects of the homology between animal and human tests and argues that tests that utilize relatively simple forms of behavior in rodents bear predictable relationships with more complex forms of cognition in man.¹⁷⁵ Dudchenko¹⁷⁶ and Dalley et al.¹⁷⁷ provide excellent overviews of the neurobiology of working memory and prefrontal executive and cognitive function in rodents, respectively. Jentsch discusses the progress toward validating tests and models of schizophrenia-like deficits in working memory, episodic memory, and attention,¹³⁸ while Ellenbroek⁵¹ and Braff and Light¹⁷⁸ review approaches to measure pre-attentive processing in animals and map these onto the processes in man. Sarter¹⁷⁹ and Thorpe et al.¹⁸⁰ define and discuss in detail the issues associated with measuring cognition in animals and, in particular, investigations of novel compounds.

View this table: [in this window] [in a new window]   Table 4. Examples of Preclinical and Clinical Tests That May Map Onto Cognitive Domains Impaired in Schizophrenia

 
Several steps might be considered to evolve an effective preclinical strategy. First priority should be given to a discussion on the appropriateness of the current models with respect to the 7 affected domains in schizophrenia. This may require further experimental work to explore and consolidate the parallels between the preclinical and clinical arenas. Contingent upon that analysis, a better understanding of the likely clinical benefit of novel compounds might be achieved if available antipsychotics were studied in a defined test battery for which parallels to the clinical situation had been clearly articulated.

Efforts to refine animal models to detect the small clinical signal evident with current compounds would yield some potential benefits. First, it might avoid the evolution of indiscriminate testing and irrational empiricism that dominated the search for cognition enhancers in previous eras.^181–182 Second, the identification of a predictive battery might facilitate an understanding of those cognitive domains that a novel compound is likely to affect and therefore facilitate an understanding of its eventual clinical utility. Third, by benchmarking appropriate models with clinically active compounds and linking them to existing clinical data, it might be possible to evolve a degree of quantitation in animal experimentation with respect to the magnitude of enhancement that might be predicted for a novel compound. Finally, and most important, an increase in the predictive validity of animal models would focus efforts on those pharmacological approaches most likely to be efficacious and most likely to bring benefit to patients rapidly.

A coherent preclinical strategy is an essential element in closing the translation gap. Failure to define more coherent preclinical approaches may perpetuate the contradictions and inconsistencies that characterize the current preclinical literature and delay the identification of effective treatments for patients.

	Footnotes

 
To whom correspondence should be addressed; tel: +44 (0) 1279 622343, fax: +44 (0) 1279 644100, e-mail: jim.hagan-1{at}gsk.com

	Acknowledgments

 
We would like to acknowledge the assistance of Mrs. Jacqueline Pitkin in the preparation of this manuscript and thank Dr. Darrel Pemberton, Dr. Marie Woolley-Roberts, Dr. Charlie Reavill, and Ms. Jane Gartlon for their contributions.

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