Cognitive Impairment Associated With Schizophrenia Research Articles

Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia

BackgroundDopamine (DA) D4 receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D4 agonist, PD168077, at a sub-effective dose, together with a sub-effective dose of lurasidone, an atypical APD which is a weak D4 receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate D4Rs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D4 antagonists at clinical dosages, including clozapine, and risperidone. The D4 antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats. MethodsThe purpose of this study was to determine the effects of a selective D4 agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis. Results and discussionPD168077 alone, and in combination with sub-effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D4 receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D4 agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D4 antagonists.

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia.

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2A receptors (Rs), full agonism at α4β2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.

SA38. Assessment of Cognitive Impairment, Treatment Adherence, and Healthcare Resource Utilization Among Treated Schizophrenia Patients

Background: Cognitive impairment associated with schizophrenia (CIAS) is common and can impact health outcomes (1). Information on the use of cognitive testing in clinical practice is lacking, and the relationship between cognitive impairment and healthcare resource utilization (HCRU) is poorly understood. This study assessed the measurement of CIAS and the association between CIAS, treatment adherence, and HCRU. Methods: Claims data from the Henry Ford Health System, a vertically integrated healthcare system serving metropolitan Detroit, Michigan, were used to identify patients aged 18 to 64 years with schizophrenia and use of antipsychotics from January 01, 2009, to June 30, 2014. Patients had ≥12 months of continuous enrollment preindex and ≥6 months postindex. The index date was the date of first diagnosis of schizophrenia. Patients with cognitive decline independent of CIAS or schizoaffective disorder were excluded. Electronic medical records (EMR) were used to confirm diagnosis of schizophrenia and to assess measures of CIAS. Due to the lack of standardized measures of CIAS, 2 independent expert reviewers assessed mental status exam (MSE) records for evidence of CIAS and classified patients as “clearly impaired” or “not impaired” during the assessment period. Administrative claims were used to assess treatment adherence during the study period and HCRU in the 12 months following index among patients with ≥12 months of follow-up. Descriptive statistics were performed as the study was exploratory in nature. Results: Following application of the inclusion/exclusion criteria and EMR assessment, 65 subjects were confirmed schizophrenia patients. The sample was 59% male with average age at index date of 43 years; 22% of patients were white, 62% black, and the remaining were unclassified. Only 8% of patients had evidence of a standardized cognitive assessment. However, all patients had ≥1 MSE records; 60% (N = 39) of patients were classified with CIAS through MSE review. The average medication possession ratio (MPR) for antipsychotic medications was 0.4 ± 0.3 for cognitively impaired patients (N = 29) and 0.6 ± 0.4 for nonimpaired patients (N = 25). CIAS patients had 0.5 ± 0.4 outpatient visits, 0.08 ± 0.0 hospitalizations, and 0.15 ± 0.08 emergency department visits per patient per month (PPPM), whereas nonimpaired patients had 0.7 ± 0.7, 0 ± 0.0, and 0.08 ± 0.0 visits, respectively. Conclusion: Although cognitive impairment is prevalent in schizophrenia patients, the results suggest that CIAS is not formally assessed in clinical practice. Additional research is needed to understand the relationship between CIAS, HCRU, and outcomes. Reference 1. Kitchen H, Rofail D, Heron L, et al. Cognitive impairment associated with schizophrenia: a review of the humanistic burden. Adv Ther 2012;29:148–62.

21. Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Study

Background: Currently approved antipsychotics have not demonstrated efficacy in cognitive impairment associated with schizophrenia (CIAS). This study evaluated the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase 9 (PDE9) inhibitor, in patients with CIAS. Methods: This was a Phase II, multicenter, double-blind, placebo-controlled, parallel-group study. Patients (18–55 years) with a diagnosis of schizophrenia, maintained on stable doses of antipsychotics, were randomized (2:1:1:1:1) to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks (4-week follow-up). A novel, exploratory ‘learn-and-confirm’, 2-stage adaptive design was adopted. In Stage 1 (learn), meaningful cognitive endpoints were identified in an unblinded interim analysis of 8 Cambridge Neuropsychological Test Automated Battery (CANTAB) measurements (n = 120; change from baseline, analysis of covariance). In Stage 2 (confirm) the CANTAB endpoints differentiating between BI 409306 and placebo were to be tested. If no CANTAB endpoints were selected, the primary endpoint was change from baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 12. The primary endpoint(s) and an a priori hypothesis testing order were prespecified before Stage 2 database lock and unblinding. Change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) at Week 12 was a key secondary endpoint. Safety endpoints included adverse events (AEs), AEs of special interest (AESI), disease state worsening (Positive and Negative Syndrome Scale; PANSS), and Columbia Suicidal Severity Rating Scale (C-SSRS) score. Results: A total of 516 patients were randomized and treated; 421 (81.6%) completed. The majority (69.8%) of patients were male, of mean age 42.3 years. No endpoints were identified for CANTAB in Stage 1; thus, MCCB was the prespecified primary endpoint. Adjusted mean change from baseline in MCCB composite score at Week 12 ranged from 1.2 to 2.8. This was not statistically significant for any dose group vs placebo. Adjusted mean change from baseline in SCoRS was also not statistically significant vs placebo. AEs were reported in 204 (39.5%) patients overall and increased with BI 409306 dose (10 mg, 33.3%; 100 mg, 53.5%); the AE rate was 36.4% in the placebo group. Serious AEs occurred in 10 (1.9%) patients. No AESI were reported. No worsening psychopathology symptoms were observed in any group (PANSS). There were no reports of suicidal behavior. Conclusion: A novel methodology was adopted to investigate CIAS efficacy. The primary endpoint of improvement in cognition was not met. BI 409306 was well tolerated and demonstrated an acceptable safety profile. Funding: Boehringer Ingelheim (NCT02281773; BI study 1289.6)

Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242.

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects (n=29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. 'High-impact' AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR-NMDAR interactions in the hippocampus, highlights the translational value of this study.

Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia.

Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D4 receptor, but the relevance to the efficacy for the treatment of cognitive impairment associated with schizophrenia (CIAS) is poorly understood. The aim of this study was to investigate the effects of D4 receptor stimulation or blockade on novel object recognition (NOR) in normal rats and on the sub-chronic phencyclidine (PCP)-induced novel object recognition deficit. The effect of the D4 agonist, PD168077, and the D4 antagonist, L-745,870, were studied alone, and in combination with clozapine and lurasidone. In normal rats, L-745,870 impaired novel object recognition, whereas PD168077 had no effect. PD168077 acutely reversed the sub-chronic phencyclidine-induced novel object recognition deficit. Co-administration of a sub-effective dose (SED) of PD168077 with a sub-effective dose of lurasidone also reversed this deficit, but a sub-effective dose of PD168077 with a sub-effective dose of clozapine, a more potent D4 antagonist than lurasidone, did not reverse the sub-chronic phencyclidine-induced novel object recognition deficit. At a dose that did not induce a novel object recognition deficit, L-745,870 blocked the ability of clozapine, but not lurasidone, to reverse the novel object recognition deficit. D4 receptor agonism has a beneficial effect on novel object recognition in sub-chronic PCP-treated rats and augments the cognitive enhancing efficacy of an atypical antipsychotic drug that lacks affinity for the D4 receptor, lurasidone.

Realtime Single Molecular Motion Analysis of Nicotinic Acetylcholine Receptor Alpha 7 by Diffracted X-Ray Tracking Method

The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel. Binding of ligands (e.g. acetylcholine, nicotine) to nAChR induces ion flux through the channel formed by pentameric subunits, which leads to the changes of cell excitability, and then triggers the following signaling cascades in the peripheral and the central nervous system. In the previous study we applied Diffracted X-ray Tracking (DXT) method to acetylcholine binding protein (AChBP) and Torpedo nAChR. DXT is a method to track the X-ray diffraction spots from the gold nanocrystal labeled on an individual single protein in real time and real space. We observed molecular fluctuations of the proteins even without ligand, and enhancement of tilting and twisting motions with ligand [Sekiguchi, et al. (2014) Sci. Rep. 4: 6384].Here, to acquire more precise information on molecular motions of nAChR in the three sub-states (close, open, and desensitization) and their sate-to-state transitions, we applied the DXT for the neuronal nAChR alpha 7. The alpha 7 receptor in the central nervous system plays essential roles in the cholinergic neuro-signal transduction, and it is one of the drug targets for therapeutics of Alzheimer diseases and cognitive impairment associated with schizophrenia (CIAS). Alpha 7 receptor was recombinantly prepared from the cDNA expressed in Xenopus oocytes. To orderly configure the receptors defined tags were introduced at the defined positions; e.g. “Met tag” for labeling with gold nanocrystal in the N-terminal, and “His tag” for absorption on mica substrate in the second cytoplasmic loop of the receptor. Characteristic molecular motion(s) during the three states of the nAChR alpha 7 were revealed by the DXT analysis. Possible transition modeling will be discussed.

Nicotinic receptors and lurasidone-mediated reversal of phencyclidine-induced deficit in novel object recognition

BackgroundEnhancement of cholinergic function via nicotinic acetylcholine (ACh) receptor (nAChR) agonism is a potential approach for the treatment of cognitive impairment associated with schizophrenia (CIAS). Some atypical antipsychotic drugs (AAPDs) enhance ACh release in rodent brain, indirectly stimulating these receptors. Here, we elucidate which nAChR subtypes mediate novel object recognition (NOR) in normal rats and contribute to the ability of the AAPD, lurasidone, to improve the NOR deficit in sub-chronic (sc) phencyclidine (PCP)-treated rats, a model for CIAS. MethodsThe ability of lurasidone and nAChR ligands to reverse the scPCP-induced deficit in NOR was assessed in female, Long-Evans rats. ResultsThe broad acting nAChR antagonist, mecamylamine (MEC), induced a NOR deficit in normal rats. The NOR deficit secondary to scPCP was reversed by either selective α4β2* nAChR agonism (A-85380) or α7 nAChRs agonism (PNU-282987); these effects were blocked by DHβE and MLA, selective antagonists of α4β2* and α7 nAChR, respectively. The ability of lurasidone to reverse the scPCP-induced NOR deficit was blocked by MEC, but not MLA or DHβE. However, sub-effective doses (SED) of either A-85380 or PNU-282987 potentiated the ability of SED lurasidone to reverse the scPCP-induced NOR deficit. ConclusionsThese results identify both α4β2* and α7 nAChRs as candidates for enhancing the ability of lurasidone and other AAPDs, which increase the release of ACh, to improve CIAS.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.

Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus

Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons.These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS.This article is part of the Special Issue entitled ‘Synaptopathy – from Biology to Therapy’.

Donepezil and the alpha-7 agonist PHA 568487, but not risperidone, ameliorate spatial memory deficits in a subchronic MK-801 mouse model of cognitive impairment in schizophrenia

Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK-801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments.

Economic considerations of cognition and functional outcomes in patients with schizophrenia: A systematic literature review

BackgroundThe primary focus of research in schizophrenia has been on the positive symptoms, with findings that clearly establish their economic burden. More recently, research has expanded to focus on another core symptom of schizophrenia, namely cognitive impairments. While this work has established the adverse impact of cognitive impairments associated with schizophrenia (CIAS) on functional outcomes, their relationship to the economic impact of schizophrenia has not been systematically evaluated. ObjectiveThe aim of this research was to perform a systematic literature review identifying evidence that evaluates: 1) the economic impact of CIAS and its treatments, including health-state utilities, and 2) the economic evidence associated with improvements in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the University of California Performance Skills Assessment (UPSA). MethodA systematic search of articles published from January 1999–April 2013 was conducted. Studies reporting direct costs, indirect costs, and quality of life impacts of CIAS and costs of CIAS interventions were reviewed. ResultsForty-three studies met inclusion criteria. Twenty-four focused on indirect costs (work-related outcomes) associated with cognitive impairments and 14 studies included residential status outcomes. Four studies concentrated on the direct cost of cognitive remediation therapy. Three studies reported quality of life outcomes, but none used health-state utilities. Eight studies focused on the UPSA and its relationship to community outcomes. Only two studies were cost-effectiveness analyses. ConclusionsDespite the growing scientific literature relating CIAS to adverse outcomes, the translation of outcomes into economic outcomes is seldom reported. Should novel pharmacotherapies and/or psychosocial treatments require reimbursement from health authorities and/or other payers, many gaps warrant attention in order to demonstrate the economic value of these therapies.

A Randomized, Placebo-Controlled Study Investigating the Nicotinic α7 Agonist, RG3487, for Cognitive Deficits in Schizophrenia

Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.

Predictive validity of a MK-801-induced cognitive impairment model in mice: Implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically

Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.

SAR110894, a potent histamine H3-receptor antagonist, displays procognitive effects in rodents

SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3–3mg/kg, p.o.) or rats (0.3–1mg/kg, p.o.). Moreover, SAR110894 (1mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3–3mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10mg/kg, p.o.) or a parametric modification of the procedure (3 and 10mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01–10mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β25–35 in the object recognition test in mice (1 and 3mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.

Cognitive Impairment Associated with Schizophrenia: A Review of the Humanistic Burden

Nearly every individual with schizophrenia is affected by cognitive decline. The aim of this literature review was to: (a) describe the humanistic burden of cognitive impairment associated with schizophrenia (CIAS); (b) develop a conceptual model that depicts the signs and symptoms of CIAS along with key concepts important to patients; and (c) consider the adequacy of potential patient-reported outcome (PRO) instruments for assessing future treatments. The following electronic databases were searched for articles published between January 1999 and November 2009 related to CIAS and PROs, or cost of illness: Medline; Embase; PsycINFO; the Health Economic Evaluation Database; and the National Health Service Economic Evaluation Database and Health Technology Assessment databases at the Centre for Reviews and Dissemination, University of York. The literature search revealed 3950 abstracts, of which 101 articles were reviewed in detail. Cognitive functions affected include memory, attention/concentration, problem solving, learning, executive function, processing speed, and social cognition. Cognitive impairment impacts the ability of individuals to carry out activities of daily living, work productively, function socially, and adhere to treatment. These effects have economic ramifications through increased direct and indirect costs associated with the treatment of schizophrenia. The literature revealed 39 PRO instruments that have been used to assess functioning. However, no single instrument captures all key concepts of importance to patients with schizophrenia. The significant burden from CIAS for patients and society has implications for designing future treatments and health strategies to improve functional outcomes.

Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction

Working memory impairments are a core aspect of schizophrenia, yet current medicines do not address such cognitive dysfunction. We have developed a model of these working memory deficits by acutely disrupting glutamatergic synaptic transmission by administration of the N-methyl- d-aspartate (NMDA) antagonist ketamine in the nonhuman primate. The current studies evaluated the effect of positive allosteric modulators (“potentiators”) of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the working memory and behavioral effects of ketamine. AMPA receptors mediate fast excitatory synaptic transmission throughout the brain and play a critical role in the activity-dependent regulation of NMDA receptors. We find that positive modulation of AMPA receptors with LY451646 (0.1–1.0 mg/kg, SC) and structurally distinct PF-4778574 (0.01 mg/kg, SC) robustly ameliorates ketamine-induced working memory impairments without altering behavioral effects of acute ketamine we consider related to positive- and negative-like symptoms. These results support AMPA receptor potentiators as a potential adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS).

Translational Aspects of the Novel Object Recognition Task in Rats Abstinent Following Sub-Chronic Treatment with Phencyclidine (PCP): Effects of Modafinil and Relevance to Cognitive Deficits in Schizophrenia

Phencyclidine (PCP) induces a behavioral syndrome in rodents that bears remarkable similarities to some of the core symptoms observed in schizophrenic patients, among those cognitive deficits. The successful alleviation of cognitive impairments associated with schizophrenia (CIAS) has become a major focus of research efforts as they remain largely untreated. The aim of the present study was to investigate the effects of selected antipsychotic and cognition enhancing drugs, namely haloperidol, risperidone, donepezil, and modafinil in an animal model widely used in preclinical schizophrenia research. To this end, the novel object recognition (NOR) task was applied to rats abstinent following sub-chronic treatment with PCP. Rats were administered either PCP (5 mg/kg, i.p.) or vehicle twice a day for 7 days, followed by a 7-day washout period, before testing in NOR. Upon testing, vehicle-treated rats successfully discriminated between novel and familiar objects, an effect abolished in rats that had previously been exposed to PCP treatment. Acute treatment with modafinil (64 mg/kg, p.o.) ameliorated the PCP-induced deficit in novel object exploration, whereas haloperidol (0.1 mg/kg, s.c.), risperidone (0.2 mg/kg, i.p.), and donepezil (3 mg/kg, p.o.) were without significant effect. Given the negligible efficacy of haloperidol and risperidone, and the contradictory data with donepezil to treat CIAS in the clinic, together with the promising preliminary pro-cognitive effects of modafinil in certain subsets of schizophrenic patients, the sub-chronic PCP–NOR abstinence paradigm may represent an attractive option for the identification of potential novel treatments for CIAS.

Measuring Changes in Functional Status Among Patients With Schizophrenia: The Link With Cognitive Impairment

Cognitive impairment associated with schizophrenia (CIAS) includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits have been shown to be linked to impairment in functional status (eg, social behavior, work performance, and activities of daily living) among patients with schizophrenia in cross-sectional studies. Less is known about the relationship between cognitive and functional change over time, such as potential functional implications of treatment-related improvement in CIAS. The purpose of this review is to summarize research on the association between change in CIAS and change in functional status, to discuss responsiveness of functional outcomes measures, and to provide recommendations for future research and measure development. Nine longitudinal studies were located on the link between CIAS and functional status, and 8 functional outcomes measures were used across these studies. The 9 studies offer initial support for a link between change in cognitive function and change in functional status. However, inconsistent findings across studies indicate that available research is preliminary, and substantial questions remain unanswered. Shortcomings of functional status measures are noted: most instruments were not developed for the target population, and none have demonstrated responsiveness to cognitive change among schizophrenic patients. It is recommended that new functional outcome measures be developed that are specifically designed to be responsive to change in cognition, with domains previously shown to be related to cognitive ability. When creating new functional outcomes measures for assessment of patients with schizophrenia, responsiveness to change in CIAS should be evaluated as part of the development and validation process.