Cognitive Enhancement In Schizophrenia Research Articles

Working memory performance with online-tDCS in schizophrenia: A randomized, double-blinded, sham-controlled, partial cross-over proof-of-concept study.

Combining cognitive retraining with transcranial direct current stimulation (tDCS) has been hypothesized to improve cognitive deficits in schizophrenia. The effect of combining a neuropsychological/psychophysiological task with tDCS, called "online-tDCS" for cognitive enhancement in schizophrenia is not rigorously assessed. In this proof-of-concept study, we aimed at evaluating the effect of a single session online-tDCS on working memory(WM) and its transferability to other cognitive functions. Numerical n-back(NNB), digit symbol substitution test(DSST), emotional matching and labelling test(E-MALT), and anti-saccade eye movement beeforefore and after 20 min tDCS (anode: left dorsolateral prefrontal cortex and cathode: left temporoparietal junction) applied during Sternberg's task(WM-task) were assessed. Twenty-three schizophrenia patients with cognitive deficits were randomized to receive either online-tDCS or offline-tDCS (without simultaneous Sternberg's task) sessions. All patients received one session each of active and sham tDCS in a randomized counterbalanced double-blind cross-over design. RMANOVA revealed a significant interaction effect between tDCS type (Online/Offline) x activeness (active/sham) of tDCS; the reaction time during 2-back performance in the NNB test improved in online-sham (F = 5.23, p < 0.038) but not online-active tDCS session. No significant changes were noted in DSST, E-MALT, and anti-saccade performance. Improved performance after online-sham tDCS suggests that performing the Sternberg's task enhanced 2-back performance. The counterintuitive observation was noted with respect to the non-enhancement of WM performance on combining the task to tDCS. Aberrant plasticity in schizophrenia might attain a transitional ceiling that would have resulted in restriction of enhancement on combining the two plasticity modulators. The transferability of improvement to other cognitive domains could not be ascertained.

P.689 Cognitive enhancers in schizophrenia: A meta-analysis of Alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms

P.689 Cognitive enhancers in schizophrenia: A meta-analysis of Alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms

Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis

Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges’ g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges’ g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges’ g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

Cognitive Enhancement Therapy Improves Resting-State Functional Connectivity in Early Course Schizophrenia.

Cognitive remediation is emerging as an effective psychosocial intervention for addressing untreated cognitive and functional impairments in persons with schizophrenia, and might achieve its benefits through neuroplastic changes in brain connectivity. This study seeks to examine the effects of cognitive enhancement therapy (CET) on fronto-temporal brain connectivity in a randomized controlled trial with individuals in the early course of schizophrenia. Stabilized, early course outpatients with schizophrenia or schizoaffective disorder (N = 41) were randomly assigned to CET (n = 25) or an active enriched supportive therapy (EST) control (n = 16) and treated for 2 years. Functional MRI data were collected annually, and pseudo resting-state functional connectivity analysis was used to examine differential changes in fronto-temporal connectivity between those treated with CET compared with EST. Individuals receiving CET evidenced significantly less functional connectivity loss between the resting-state network and the left dorsolateral prefrontal cortex as well as significantly increased connectivity with the right insular cortex compared to EST (all corrected p < .01). These neural networks are involved in emotion processing and problem-solving. Increased connectivity with the right insula significantly mediated CET effects on improved emotion perception (z' = -1.96, p = .021), and increased connectivity with the left dorsolateral prefrontal cortex mediated CET-related improvements in emotion regulation (z' = -1.71, p = .052). These findings provide preliminary evidence that CET, a psychosocial cognitive remediation intervention, may enhance connectivity between frontal and temporal brain regions implicated in problem-solving and emotion processing in service of cognitive enhancement in schizophrenia.

A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia

Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ. We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint. There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS. These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.

From Theory to PrACTice: A Cognitive Remediation Program Based on a Neuropsychological Model of Schizophrenia.

Cognitive dysfunction is one of the hallmark deficits of schizophrenia. A wide range of studies illustrate how it is strongly interconnected to clinical presentation and daily life functioning [see Ref. (1, 2)]. Hence, cognition is an important treatment target in schizophrenia. To address the challenge of cognitive enhancement in schizophrenia, a large number of cognitive remediation programs have been developed and evaluated over the past several decades. First, an overview of these programs is presented highlighting their specificity to cognitive deficit in schizophrenia using an integrated method. In this case, cognitive training focuses on enhancing several elementary cognitive functions considered as a prerequisite to social skills or vocational training modules. These programs are based on the neurodevelopmental hypothesis of schizophrenia. However, moderate improvement for patients who benefit from these therapies has been observed as described in Wykes et al. review (3). Next, neuropsychological models of schizophrenia are then presented. They highlight the critical role of the internally generated intentions in appropriate willful actions. The cognitive control mechanism deals with this ability. Interestingly, available cognitive remediation programs have not been influenced by these models. Hence, we propose another alternative to set up a specific cognitive remediation program for schizophrenia patients by targeting the cognitive control mechanism. We describe the PrACTice program that is in the process of being validated.

Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction.

No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is.

May non-antipsychotic drugs improve cognition of schizophrenia patients?

Cognitive impairment in schizophrenia patients is associated with poor outcome and it represents one of main challenges of pharmacological treatment. Unfortunately, second-generation antipsychotics have not yielded the expected results in the improvement of these symptoms. The purpose of the present review paper is to summarize and discuss the available data about the efficacy of non-antipsychotic drugs in the treatment of cognitive symptoms of schizophrenia. A research in the main database sources has been performed to obtain a comprehensive overview. Studies with different methodologies (open and double-blinded) have been included, while studies with schizoaffective patients have been excluded. Several non-antipsychotic compounds have been tested with the purpose to improve cognitive symptoms in schizophrenia patients, but no molecule has a significant pro-cognitive activity. Available data do not support the superiority of non-antipsychotic drugs vs. placebo for cognitive enhancement in schizophrenia. Preliminary results indicate mirtazapine, mianserine, lamotrigine, tandospirone, cyproheptadine, valacyclovir and omega-3 fatty acids as the most promising compounds, however no definitive conclusions can be drawn in the light of small sample size studies.

Role of cognitive enhancement in schizophrenia

Role of cognitive enhancement in schizophrenia Cherrie Galletly Discipline of Psychiatry, School of Medicine, The University of Adelaide, Ramsay Health Care (SA) Mental Health Services, Northern Adelaide Local Health Network, Adelaide, SA, Australia Abstract: Schizophrenia is a severe and usually chronic psychiatric disorder characterized by dysfunction in many domains. Hallucinations, delusions, and behavioral disturbances are prominent symptoms of the illness, and are appropriately a focus for treatment, but less attention is given to the cognitive deficits that are also typically found in schizophrenia. Whilst impairments in learning, memory, and executive function have been recognized for many decades, deficits in more subtle aspects of cognition have been recognized more recently. These include biases in the evaluation of information and difficulties with emotional and social cognition. Cognitive deficits make a substantial contribution to real-world function, and improving cognition has the potential to improve social and vocational outcomes. This review provides an overview of potential treatments for cognitive deficits in schizophrenia, including medications, psychological therapies, and neurostimulation. Despite optimal medication and case management, many people with schizophrenia do not achieve full remission. There is sufficient evidence to encourage widespread adoption of at least some of the current cognitive enhancement strategies. However, individual patients differ in terms of their symptoms, patterns of cognitive dysfunction, medication response, and social and occupational situations. Considerable work is therefore needed to personalize cognitive remediation to maximize the benefits. However, at present, these methods are underutilized, even when applied in a universal manner where all subjects receive the same treatment. The barriers to wider availability of these treatments are discussed. Keywords: schizophrenia, psychosis, cognition, treatment, remediation

Coupling physical exercise with dietary glucose supplement for treating cognitive impairment in schizophrenia: a theoretical model and future directions

Metabolic dysregulation may disrupt the complex neuroprotective mechanisms essential for brain health. Recent studies have pointed out the possible aetiological role of metabolic dysregulation in the onset of schizophrenia and the associated cognitive impairment. In this paper, we aimed to generate a theoretical model of how a combination of physical exercise and dietary glucose supplement may help to alleviate cognitive impairment in schizophrenia. Literature on metabolic dysregulation, especially insulin resistance, in relation to the onset of schizophrenia and the associated cognitive impairment is reviewed. The cognitive enhancement effects of physical exercise and dietary glucose supplement are then summarised. Finally, we propose a theoretical model based on the concerted effects of physical exercise and glucose supplement. In general, the joint action of physical exercise and dietary glucose supplement could up-regulate glucose and insulin transport into the brain, as well as augmenting the release of insulin growth factor-1 and brain-derived neurotrophic factor. Physical exercise and glucose supplement could enhance energy supply and neuroplasticity in brain, subsequently leading to potential cognitive enhancement in schizophrenia. However, glucose supplement is not suitable for patients with abnormal metabolic profile. The combination of physical exercise and glucose supplement has potential therapeutic values in treating cognitive impairment in schizophrenia. Further research is necessary to investigate the optimal patterns of exercise and doses of glucose for treating cognitive impairment in schizophrenia.

The nicotinergic receptor as a target for cognitive enhancement in schizophrenia: Barking up the wrong tree?

Cognitive symptoms have increasingly been recognized as an important target in the development of future treatment strategies in schizophrenia. The nicotinergic neurotransmission system has been suggested as a potentially interesting treatment target for these cognitive deficits. However, previous research yielded conflicting results, which may be explained by several methodological limitations, such as the failure to include both a group of smoking and non-smoking schizophrenic patients, the use of only a single nicotine dose, and the inclusion of a very limited cognitive battery. The present study aims at investigating the cognitive effects of nicotine in schizophrenia while addressing these methodological issues. In a double-blind placebo-controlled randomized crossover design, cognitive effects are assessed in smoking (n =16) and non-smoking (n =16) schizophrenic patients after receiving active (1 or 2 mg) or placebo oromucosal nicotine spray. A modest improving effect of nicotine on attention in the smoking but not the non-smoking group was found. No enhancing effects were found on measures of visual memory, working memory, processing speed, psychomotor speed, or social cognitive functioning in either patient group. These findings suggest that the nicotinic receptor only has limited value as a cognitive treatment target in schizophrenia.

Applicability of the MATRICS Consensus Cognitive Battery in Singapore

The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a reliable, valid, and standard battery for clinical trials on cognitive enhancers in schizophrenia. In this study we tested the applicability of the MCCB to Singapore’s English speakers. Healthy ethnic Chinese, Malay, and Indian English speakers (N = 171) of both genders were recruited within three age groups and three levels of education to match as closely as possible the US norming sample, and were administered the MCCB. Descriptive data, T scores, age, gender, education, and ethnicity effects on performance were explored and compared with the US norming study. Age, education, and ethnicity affected the battery’s composite scores, with young and highly educated participants generally outperforming the old, less-educated ones. Male participants outperformed their female counterparts in two out of seven cognitive domains. Although generally lower when compared to the US norming sample, Singaporean scores reflected the same relationship with age, education, and gender, with the exception of a substantially worse performance in the social cognition domain. Differences among the ethnic groups in Singapore—and the poorer performance measured in these groups with respect to the US sample—call for the necessity of an extended norming study in Singapore.

Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia – A path model investigation

We aimed to evaluate predictors and mediators of enhancing effect of adjunctive mirtazapine on cognition in schizophrenia. Patients with difficult-to-treat schizophrenia received either mirtazapine (n = 19) or placebo (n = 18) in a double-blind fashion for six weeks. Mirtazapine outperformed placebo on the Block Design and Stroop Dots. In the present subsidiary study, factors underlying this difference were explored with Path Analysis. Add-on mirtazapine had an independent enhancing effect on the Block Design-measured visuo-spatial functioning. Further, this effect was mediated via changes in positive, depressive and parkinsonism symptoms, but not in negative symptoms. This effect was predicted by higher doses of FGAs, longer duration of illness and lower initial Block Design scores. Path Analysis model fit was good. Mirtazapine may have direct and indirect favorable effects on visuo-spatial functioning, but further research is needed. Path analysis may be a feasible statistical method for further research of neurocognition in psychopharmacological interventions in schizophrenia.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats

The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days' washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.

Cognitive enhancement in schizophrenia. Are atypical antipsychotics a step forward?

The 15th Biennial Winter Workshop in Psychoses, 15–18 November 2009, Barcelona, Spain: COGNITION AND MEMORY

Ultra-low exposure to alpha-7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in alpha-7 receptor expression in rodents: implications for low dose clinical efficacy

Αlpha-7 neuronal nicotinic receptors (NNRs) are considered targets for cognitive enhancement in schizophrenia and Alzheimer's disease. AZD0328 is an alpha-7 NNR partial agonist that enhances cognition in rodents and nonhuman primates at sub-microgram to microgram doses. We hypothesized that increased expression of the alpha-7 receptor contributes to this beneficial activity at low doses and tested this by examining the effect of AZD0328 using in vivo and ex vivo binding, RT-PCR and cognitive function in rodents. AZD0328 (0.00178 mg/kg) was subcutaneously administered to mice 4, 24, 48 and 72 hours prior to testing in novel object recognition and produced a significant increase in cognition at 4, 24 and 48 h post-dosing. In vivo binding was examined in rat brain using [(3)H]AZ11637326 and there was a dose-dependent reduction in receptor binding at higher doses of AZD0328 (0.001-3 mg/kg), and a second alpha-7 partial agonist, SSR180711 (0.01-30 mg/kg). Lower doses of both compounds (0.0001 mg/kg) produced a significant increase in binding of [(3)H]AZ11637326. Ex vivo binding using [(125)I]-α-bungarotoxin, showed a significant increase in receptor number (B(max.)) in the frontal cortex or hippocampus with no significant effect on receptor affinity (K(d)) 2 h post administration of AZD0328. [(3)H]AZ11637326 administered 1.5 h following AZD0328 produced a significant increase in specific binding in rat brain regions. We found that the effect on receptor number was long-lasting, with [(125)I]-α-bungarotoxin binding increased in rats given AZD0328 for 2-48 h, but this was not accompanied by increased mRNA synthesis. SSR180711 produced a similar increase in B(max.) and specific binding with no effect on K(d). Therefore, trace dose of alpha-7 partial agonists has rapid onset and produces a profound, sustained effect on novel object recognition in mice that corresponds by dose to an increase in receptor number in rat brain. These findings provide an explanation for the acute and sustained benefit of alpha-7 receptor activation in working memory in nonhuman primates and guidance for drug development initiatives and treatment regimens for nicotinic partial agonists.

A Randomized Clinical Trial of MK-0777 for the Treatment of Cognitive Impairments in People with Schizophrenia

In a previous pilot study, MK-0777--a γ-aminobutyric acid (GABA)(A) α2/α3 partial agonist--was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA(A) receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA(A) α2 site might be needed for cognitive enhancement in schizophrenia.

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

Rationale Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987 . Methods Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results Sub-chronic PCP produced significant deficits in both cognitive tasks (P < 0.01–0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.001), and in novel object recognition at 10 mg/kg on day 1 (P < 0.01) and on day 15 (P < 0.001). Conclusions These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

Cortical Kynurenine Pathway Metabolism: A Novel Target for Cognitive Enhancement in Schizophrenia

The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the alpha7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.