Current Pharmaceutical Design - Volume 20, Issue 31, 2014

1. Introduction The metabolic syndrome (MetS) is a cluster of abnormalities including abdominal obesity, glucose intolerance, hypertension, and dyslipidaemia, factors that are all associated with an increased cardiovascular (CV) risk [1]. Currently, there is a debate regarding the effective diagnosis, control and treatment of all the components of MetS, and in the consequences of the MetS itself [2]. In addition, in the past decade there has been a marked increase in the prevalence of the MetS in both Western and developing countries [3]. Yet, the exact pathogenesis of the MetS remains debatable, as well as the crucial factors (mediators) linked to the elevated CV risk [4]; indeed, CV diseases (CVD) still represents the leading cause of death worldwide [5]. Although guidelines emphasize the need of tight control of CV risk, current approaches for the prevention and treatment of CVD are not completely effective (‘residual risk’) in terms of risk reduction, even when using a number of combined strategies [6]. Therefore, there is a need for the identification of novel biomarkers of CV risk, as well their effective management in subjects with the MetS [7]. The present issue of the journal focuses on novel therapeutic targets for the MetS. We discuss the reviews included in this issue as well as additional topics. 2. The Reviews Included in this Issue Katsiki et al. [8] have discussed the role of the MetS in non-cardiac vascular diseases. They provide a comprehensive an up to-date review on this topic, highlighting the importance of treating these high-risk individuals, early and “to target”. In this context, multifactorial treatment, including a statin, has been proven beneficial. Rizzo et al. [9] have discussed the link between incretin-based therapies, glucometabolic health and endovascular inflammation in subjects with type-2 diabetes and the MetS. Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism; incretin-based therapies represent an important treatment option for patients with type-2 diabetes, with and without the MetS. Yet, these pharmaceutical agents are particularly beneficial in patients who are overweight or obese, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. Further, increasing evidence suggests that incretin-based therapies may also impact the CV system, including beneficial effects on lipids, blood pressure, systemic inflammation and endothelial dysfunction. Abate et al. [10] have highlighted the role of the inflammatory cytokine resistin in CVD, diabetes and the MetS. Resistin is an adipocyte- and monocyte-derived cytokine, which has been implicated in the modulation of insulin action, energy, glucose and lipid homeostasis. Resistin has been associated with insulin resistance and many of its known complications. Resistin seems to play a significant role in the heightened inflammatory state induced by metabolic stress linked to excessive caloric intake, thus contributing to the risk for MetS, type 2 diabetes and CVD. Barbagallo et al. [11] have reviewed the role of the heme oxygenase system in the MetS and further discussed the role of heme oxygenase-1 (HO-1) and how to exploit its beneficial effects as a therapeutic strategy to prevent complications and improve insulin sensitivity. Molecular chaperones and the heat shock response play a major role in the maintenance of cellular homeostasis under various pathological conditions. In particular, their role is to regulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellar networks. Among various heat shock proteins, HO-1 seems to play an important role in the MetS; indeed, the HO system seems to regulate the complex pathophysiological cascade involved in insulin resistance mechanisms and adipocyte function, as measured by the release of important adipokines. Li Vecchi et al. [12] have reviewed the link between the MetS and immunodeficiency virus (HIV)-infection. Considerable differences in the prevalence of the syndrome in human HIV-infected subjects have been reported, as a consequence of several limitations regarding the MetS diagnostic criteria. New evidence suggests that the use of optimal waist cut-off points specific for the various ethnic populations could represent a step forward in overcoming these limitations. Although metabolic disorders have been associated indirectly with highly active antiretroviral therapy, current circumstances could change the framework of MetS in the HIV setting; for example, the aging HIV population and newer, less metabolically toxic antiretroviral drugs. Lipotoxicity and adipokines have been focused as key issues for explaining MetS in HIV patients, and several studies have investigated the pathophysiology of MetS and CV complications in HIV infection. Evidence shows that both HIV infection per se and HIV-related chronic immune activation, despite antiretroviral therapy, are critical factors linking MetS and CV complications. Cerne and Lukac Bajalo et al. [13] have reviewed the available evidence on the role of cell-free nucleic acids as a non-invasive route for investigating atherosclerosis. Cell-free nucleic acids (cf-NA) are nucleic acids (DNA, mRNA, miRNA, mitochondrial DNA) found in plasma and cell-free fractions of various other biological fluids. They have all the characteristics of the nucleic acids in the cells of their origin, thus constituting an emerging field for non-invasive assessment. Novel applications for the quantitative and qualitative analysis of cf-NA are emerging. This analysis is currently investigated as a novel research tool for the diagnosis and prognostic evaluation of acute coronary syndrome, for prediction of CVD, for non-invasive early detection of atherosclerosis and understanding its pathological mechanism in vivo, for assessing various issues of treatment for atherosclerosis in vivo, as well as for the unique simultaneous measurement of mRNA levels and protein concentrations in a single sample of plasma. Since this is a novel field, the authors have carefully reviewed published data as well as the most important analytical considerations. Rosselli et al. [14] have performed a comprehensive review of the link between chronic liver disease and the MetS. The authors have highlighted that the MetS impacts on the liver in different ways. Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the MetS, and is characterized by triglyceride accumulation and a variable degree of hepatic injury, inflammation and repair. The appearance of NAFLD is mainly dependent on increased flow of fatty acids derived from an excess of lipolysis from insulin-resistant adipose tissue. Yet, in the presence of significant hepatocellular injury and inflammation, the picture is defined ‘steatohepatitis’ (NASH) that has the potential to progress to advanced fibrosis and cirrhosis. The presence of NASH is associated with lower life expectancy, both due to liverrelated death and an increase in CV events. Development of NASH is based on lipotoxicity and is influenced by signals derived from outside the liver, as well as from intrahepatic activation of inflammatory and fibrogenic pathways. The presence of the MetS is also associated with worse outcomes in patients with cirrhosis due to any cause, and has complex interactions with hepatitis C virus infection. Moreover, the MetSposes a higher risk of development of hepatocellular carcinoma. Therefore, the authors concluded that the presence of metabolic alterations has a severe and multifaceted impact on the liver, and is responsible for a higher risk of liver-dependent and -independent mortality. Gouni-Berthold et al. [15] have discussed the role of pharmacologic therapy for CV risk reduction in patients with the MetS. The authors have highlighted that the cornerstone of MetS treatment is lifestyle modification, encompassing weight reduction and physical exercise. However, pharmacotherapy is usually also required to achieve the recommended target values for the various components of the MetS, such as hypertension, dysglycemia and dyslipidemia. Regarding lipid treatment, statins are the main therapeutic agents while for blood pressure control a significant amount of pathophysiological and clinical evidence would suggest the use, as first line agents, of angiotensin-convertingenzyme inhibitor inhibitors or angiotensin receptor blockers. Metformin seems to be the drug of choice for dysglycemia, especially since recent evidence questions the safety of thiazolidinediones. In general, a multifactorial approach is recommended to decrease CV risk in patients with the MetS. Grosso et al [16] have reviewed the beneficial effects of Mediterranean diet on the MetS. The role of food and nutrients in the aetiology of chronic diseases has become clearer over the last 15 years. In their article the authors collected evidence on the beneficial impact of Mediterranean diet on MetS by analyzing epidemiological reports, documenting its prevalence in subjects adopting this dietary pattern. The authors also explored the role of the single components of the diet and the specific aspects characterizing the MetS (i.e. metabolic indices, body weight and blood pressure). Subjects adherent with the Mediterranean diet have lower prevalence and incidence rates of MetS; moreover, specific components of this dietary pattern may play a significant role in the prevention of several morbid conditions related to the MetS. 3. Brief Comment on Selected Biomarkers of CVD Risk not Considered in this Issue Several studies have suggested that measuring low-density lipoproteins (LDL) particle size, small dense (sd) LDL cholesterol content and LDL particle number provides additional assessment of CVD risk, and available evidence has been reviewed in 2011 with a consensus statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses [17,18]. Several mechanisms are involved in the enhanced atherogenicity of sdLDL, including enhanced oxidative susceptibility, increased filtration through the endothelium, reduced LDL receptor affinity, prolonged circulation time and higher proteoglycan binding [19-21]. In addition, several studies have reported an association between CVD risk and sdLDL (reviewed in [22,23]), including prospective epidemiologic studies, as well as clinical intervention trials. In 2000. Hulthe et al. [24] assessed the prevalence of MetS in a population-based sample of clinically 58 years old healthy men. The authors found that LDL size was significantly smaller in subjects with the MetS, in relation to those without it. This finding was consistent with previous observations. Haffner et al. had already shown in 1995 that LDL size was decreased in subjects with multiple metabolic disorders [25]. Further, they found that the association between LDL size and the number of metabolic disorders remained statistically significant even after adjustment for obesity, body fat distribution, gender, ethnicity, proinsulin and insulin concentrations [25]. More recently, several studies have highlighted that sdLDL may represent a valuable marker for the diagnosis and the severity of the MetS [26-28]. Using the Lipoprint system, Gazi et al. [26] have shown that subjects with the MetS exhibit significantly higher concentrations of sdLDL than individuals who do not fulfil the criteria for this syndrome. In another study [29], we have performed a 2-year follow-up study in subjects with the MetS: at the end of the follow-up period, we found an independent predictive role of elevated sdLDL for future cardio- and cerebro-vascular events, which was the same or even superior to that found for traditional CVD risk factors. Another European panel of experts recently produced a statement on the role of postprandial hypertriglyceridaemia [30,31]. There is evidence that this type of dyslipidaemia represents another risk marker. There is also a need to consider that there is evidence that MetS is associated with other non-vascular pathologies such as impaired kidney function (including calculi) and an increased risk of cancer [32-33]. 4. Conclusion CVD still represent a leading cause of death worldwide and is strongly associated with the MetS. Although guidelines recommend aggressive treatment, a large residual risk remains. Therefore, there is a need for new treatments and identification of novel biomarkers of CVD risk in subjects with the MetS. Atherogenic lipoproteins, including sdLDL, may represent a valuable marker, but further studies are needed in order to fully assess their role in clinical practice. Declaration of Interest This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Several international organizations have defined MetS using different diagnostic criteria that produced discrepancies in the results of previous studies, thus leading to the latest Joint Interim Societies (JIS) MetS definition. Other risk factors than the diagnostic criteria that have been associated with MetS include lipid abnormalities, uric acid, liver function, prothrombotic factors, cytokines, adipokines, vitamin D, arterial stiffness, polycystic ovary syndrome and obstructive sleep apnea. Apart from CVD and T2DM, MetS has been related to non-cardiac vascular diseases and in particular to stroke, carotid artery disease, peripheral artery disease, chronic kidney disease, atherosclerotic renal artery stenosis and abdominal aortic aneurysms. In this narrative review, the associations of these diseases with MetS and its components will be discussed. These associations may further increase CVD risk in MetS patients, highlighting the importance of treating such high-risk individuals early and “to target”. In this context, multifactorial treatment including a statin has been proven beneficial, and thus should be considered, in MetS patients.

Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 signaling, which results in enhanced glucose-dependent insulin secretion, inhibition of glucagon secretion and decreased appetite. This leads to improved regulation of glucose homeostasis accompanied by either no increase in body weight (with DPP-4 inhibitors) or a reduction (with GLP-1 receptor agonists). GLP-1 inhibits food intake and the increased GLP-1 response may contribute as a satiety signal. Although data regarding the effect of GLP-1 agonists and DPP-4 inhibitors on levels of peptides involved in the regulation of food intake in T2DM are few, an indirect effect of IBT on weight loss is possible (e.g. Exendin-4 induces adiponectin secretion in vitro). Results from animal models indicate reduction of food intake and body weight by GLP-1 agonists, but follow-up studies are required. A growing amount of evidence suggests that these peptides may also impact the cardiovascular system, including beneficial effects on myocardial cells, lipid profiles and blood pressure as well as reduced markers of systemic inflammation and improved endothelial dysfunction. The potential role of these agents in improving components of the metabolic syndrome and retardation of atherosclerosis needs to be fully elucidated. Although IBTs are currently recommended only for use in the early treatment of T2DM, the ‘non-glycemic’ actions of these drugs may have far reaching therapeutic implications. It is hoped that future studies will elucidate their potential strengths and weaknesses for use in various metabolic conditions.

Resistin is an adipocyte- and monocyte-derived cytokine which has been implicated in the modulation of insulin action, energy, glucose and lipid homeostasis. Resistin has been associated with insulin resistance and many of its known complications. As a molecular link between metabolic signals, inflammation, and vascular dysfunction, resistin can be proposed as playing a significant role in the heightened inflammatory state induced by metabolic stress linked to excessive caloric intake, thus contributing to the risk for metabolic syndrome (MetS), type 2 diabetes (T2DM), and cardiovascular diseases (CVD). In this review, we highlighted the role of resistin, as an inflammatory cytokine, in the development of CVD, T2DM and the MetS.

Molecular chaperones and the heat shock response play a major role in the maintenance of cellular homeostasis under various pathological conditions. In particular, their role is to regulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellarnetworks. Among variousheat shock proteins, Hsp32 also known as heme oxygenase-1 (HO-1), has demonstrated an important role in metabolic syndrome. In particular, the HO system seems to play a major role in the complex pathophysiological cascade involved in insulin resistance mechanisms, and adipocyte functions as measured by the release of important adipokynes. The aim of the present review is to point out the role of HO-1 in metabolic syndrome, and how to exploit its beneficial effects as a therapeutic strategy to prevent complicationsof andto improve insulin sensitivity.

The metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease and type 2 diabetes, has become an important public health problem. Considerable differences in the prevalence of the MetS in human immunodeficiency virus (HIV)-infected subjects have been reported, as a consequence of several limitations regarding the diagnostic critera for MetS. New evidence suggests that the use of optimal waist cut-off points specific for the various ethnic populations could represent a step forward in overcoming these limitations. Also the use of specific cut-off points for measuring upper trunk fat as an adjunctive criterion of MetS in HIV patients with lipodystrophy could represent an interesting new research topic. Although metabolic disorders have been associated indirectly with highly active antiretroviral therapy (HAART), directly with HIV infection per se or with host conditions, current circumstances could change the framework of MetS in the HIV setting: For example, the aging HIV population and newer, less metabolically toxic antiretroviral drugs. Lipotoxicity and adipokines have been focused as key issues for explaining MetS in HIV patients. Several studies have investigated the pathophysiology of MetS and cardiovascular complications in HIV infection. Evidence shows that both HIV infection per se and HIV-related chronic immune activation despite antiretroviral therapy are critical factors linking MetS and cardiovascular complications. Current epidemiological and pathogenetic data on MetS in HIV infection, prevention strategies and therapeutic options for all MetS components are reviewed in the light of the recent Adult Treatment Panel IV recommendations and the new antiretroviral drugs.

Metabolic syndrome is directly linked with atherosclerotic burden and cell-free nucleic acids (cf-NA) analysis has recently emerged as a novel research tool in atherosclerosis practice and research. cf-NA are nucleic acids (DNA, mRNA, miRNA, mitochondrial DNA) found in plasma and cell-free fractions of various other biological fluids. They have all the characteristics of the nucleic acids in the cells of their origin, thus constituting an emerging field for non-invasive assessment. Initially, quantitative and qualitative analysis of cf-NA has been accepted as clinically useful in non-invasive prenatal diagnosis, and in the diagnosis and monitoring of numerous cancers. As to atherosclerosis, cf-NA analysis poses an important challenge in diagnosis and prognostic evaluation of acute coronary syndrome, in prediction of cardiovascular disease, in non-invasive early detection of atherosclerosis and understanding its pathological mechanism in vivo, in assessing various issues of treatment for atherosclerosis in vivo, and in the unique simultaneous measurement of mRNA levels and protein concentrations in a single sample of plasma. Examples of its use are presented in this review. Besides the advances in technologies, the precise evaluation and optimization of pre-analytical and analytical aspects of cf-NA analysis have impacted importantly on the reliability of test results. We have, therefore, reviewed the most important analytical considerations. Further clinical studies and analytical improvements will answer the question as to whether cf-NA, as novel biomarkers, can be reliably applied clinically in non-invasive, early diagnosis and monitoring of the vulnerable atherosclerotic plaques of patients who could suffer from acute coronary syndrome.

The prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder is not only associated with a higher risk of appearance of type 2 diabetes and cardiovascular events, but impacts on the liver in different ways. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of MetS, and is characterized by triglyceride accumulation and a variable degree of hepatic injury, inflammation, and repair. In the presence of significant hepatocellular injury and inflammation, the picture is defined ‘nonalcoholic steatohepatitis’ (NASH), that has the potential to progress to advanced fibrosis and cirrhosis. Diagnosis of NASH is based on a liver biopsy, and active search for noninvasive tests is ongoing. Progression of steatohepatitis to advanced fibrosis or cirrhosis has been shown in at least one third of patients followed with paired biopsies. Presence of NASH is associated with lower life expectancy, both due to liver-related death and to an increase in cardiovascular events. The appearance of NAFLD is mainly dependent on increased flow of fatty acids derived from an excess of lipolysis from insulin-resistant adipose tissue. Development of NASH is based on lipotoxicity and is influenced by signals derived from outside the liver and from intrahepatic activation of inflammatory and fibrogenic pathways. The presence of the MetS is also associated with worse outcomes in patients with cirrhosis due to any causes, and has complex interactions with hepatitis C virus infection. Moreover, MetS poses a higher risk of development of hepatocellular carcinoma, not necessarily through the development of NASH-related cirrhosis. In conclusion, the presence of metabolic alterations has a severe and multifaceted impact on the liver, and is responsible for a higher risk of liver-dependent and –independent mortality.

The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. The cornerstone of treatment is lifestyle modification, encompassing weight reduction and physical exercise. However, pharmacotherapy is usually also required to achieve the recommended target values for the various components of the MetS, such as hypertension, dysglycemia and dyslipidemia. Regarding lipid treatment, statins are the main therapeutic agents while in blood pressure control a significant amount of pathophysiological and clinical evidence would suggest the use, as first line agents, of ACE inhibitors or angiotensin receptor blockers. Metformin seems to be the drug of choice for dysglycemia, specially since recent evidence questions the safety of thiazolidinediones. New drugs, targeting multiple components of the MetS, are under development but no data are currently available regarding their long-term efficacy and safety profile. In general, a multifactorial approach is recommended to decrease cardiovascular risk in patients with the MetS.

The metabolic syndrome (MetS) represents a cluster of medical disorders, such as hyperglycemia, dyslipidemia, hypertension, and abdominal obesity that, when occurring together, increase the risk of developing cardiovascular disease. The role of food and nutrients in the aetiology of chronic diseases has become clearer over the last 15 years. In this review we collected evidence on the beneficial impact ofthe Mediterranean diet on MetS by analyzing epidemiological reports documenting its prevalence in subjects who have adopted this dietary pattern. We also explored the role of the individual components of the diet on the specific aspects characterizing the MetS (i.e. metabolic indices, body weight and blood pressure). There is ample evidence showing that subjects adherent to the Mediterranean diet have lower prevalence and incidence rates of MetS than non-adherent. Moreover, it has been widely documented that specific components of this dietary pattern play a role in the prevention of several morbid conditions related to the MetS.

Cognitive impairment influencing memory, attentional focus and executive functions in schizophrenia have a significant impact on social functioning and quality of life. Cognitive functions depend on normal functioning of brain prefrontal cortex. Attempts to explain cognitive impairment in schizophrenia include hypotheses (based on among others post-mortem, genetic and imaging data) of dysfunctions involving dopamine, glutamate, GABA as well as acetylcholine neural transmission. Current antipsychotic drugs are not sufficiently effective against cognitive symptoms. Thus, while pharmacological treatment strategies earlier primarily focused on managing psychotic (so called positive) symptoms, current pharmacological strategies aim at identifying compounds with pro-cognitive properties, suitable for treatment of cognitive symptoms as manifested in schizophrenia. To this end, scientists are primarily working along two lines: i) developing animal models/tests in rodents with relevance either to cognitive symptoms as presented in schizophrenia and/or to brain abnormalities in schizophrenia believed to be causing these symptoms; ii) identifying pro-cognitive compounds with pharmacological properties acting on brain neurotransmitter functions believed to be involved in cognitive dysfunction in schizophrenia. The present special issue on ‘Current pro-cognitive therapeutic strategies for improved pharmacological treatment in schizophrenia’ includes presentation and discussion of the use of the attentional set-shifting test as a relevant model for attentional/executive functioning in schizophrenia as well as for the identification of pro-cognitive compounds with relevance to schizophrenia treatment Tait et al. [1] and Goetghebeur and Dias [2], presentation of the neurodevelopmental prenatal methylazoxymethanol acetate (MAM) model of schizophrenia by Gill and Grace [3], and discussion of the novel object recognition (NOR) task for memory functions by Rajagopal et al. [6]. In addition, putative procognitive treatment strategies for schizophrenia treatment such as the use of GABAA receptor agonists [3], the use of compounds acting at nicotinic acetylcholine receptors from a clinical perspective Boggs et al. [4], as well as the therapeutic significance of compounds (phosphodiesterase, PDE, inhibitors) influencing intracellular signaling Snyder and Vanover [5] are presented and discussed. Finally, data on the effects of atypical antipsychotics, as well as 5-HT1A partial agonists, 5-HT7 antagonists, and D1 agonists in the NOR test are reviewed by Rajagopal et al. [6]. The contributors are all distinguished scientists, and issues discussed in the articles are timely and of great importance for the advancement of effective schizophrenia treatment strategies. Therefore, this special issue will hopefully be well received and appreciated in the scientific community dealing with these issues.

Attentional set-shifting tasks have been used as a measure of human fronto-executive function for over 60 years. The major contribution these tasks have made has been the quantification of cognitive deficits associated with human pathologies such as schizophrenia, attention deficit/hyperactivity disorder and dementias related to Parkinson’s, Huntington’s and Alzheimer’s diseases. Thirteen years ago an intradimensional/extradimensional attentional set-shifting task was developed for rats. Since then, there have been over 70 publications detailing the effects of various manipulations on task performance in rats, and 17 publications describing adaptations of the task for mice. Much of this literature has focused on animal models of neuropathology and cognitive deficits associated with schizophrenia and other human conditions. Altogether, these results have elucidated the roles of multiple neurotransmitters in the manifestation of cognitive deficits, and their subsequent amelioration, including dopamine, serotonin, acetylcholine and noradrenaline. However, the fundamental promise of the attentional set-shifting task, to measure cognitive flexibility in humans and rodents in a formally analogous way, has often been under investigated and over simplified. This review explores the research that led to the development of the rat attentional set-shifting task, and how subsequent use of the task has expanded our understanding of the psychological and neurological underpinnings of discrimination and reversal learning, as well as the formation, maintenance and shifting of attentional set.

Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected preclinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional setshifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise.

Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.

Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to selfmedicate certain symptoms associated with the illness. Concurrently there is evidence that nicotinic receptors that have lower affinity for nicotine are more important in cognition. Therefore, a number of medications that target nicotinic acetylcholine receptors (nAChRs) have been tested or are in development. In this article we summarize the clinical evidence of nAChRs dysfunction in schizophrenia and review clinical studies testing either nicotine or nicotinic medications for the treatment of cognitive impairment in schizophrenia. Some evidence suggests beneficial effects of nAChRs based treatments for the attentional deficits associated with schizophrenia. Standardized cognitive test batteries have failed to capture consistent improvements from drugs acting at nAChRs. However, more proximal measures of brain function, such as ERPs relevant to information processing impairments in schizophrenia, have shown some benefit. Further work is necessary to conclude that nAChRs based treatments are of clinical utility in the treatment of cognitive deficits of schizophrenia.

Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world’s population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenic patients and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of the schizophrenic brain. While current antipsychotic medications—typically dopamine D2 antagonists—adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function in schizophrenic patients. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core symptoms associated with schizophrenia, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of a number of intracellular targets, including cyclic nucleotide phosphodiestereases, and non-phosphodiesterase approaches such as ITI-007, which have been proposed to regulate hyperdopaminergic function, hypoglutamatergic function and/or the delicate balance of the two associated with cognitive deficits in schizophrenia. We also discuss the challenge facing those developing drugs to target specific pathways involved in psychopathology without involving other systems that produce concomitant side effects.

Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1 partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.