Journal of Psychopharmacology

Over 100 loci are now associated with schizophrenia risk as identified by single nucleotide polymorphisms (SNPs) in genome-wide association studies. These findings mean that ‘genes for schizophrenia’ have unquestionably been found. However, many questions remain unanswered, including several which affect their therapeutic significance. The SNPs individually have minor effects, and even cumulatively explain only a modest fraction of the genetic predisposition. The remainder likely results from many more loci, from rare variants, and from gene–gene and gene–environment interactions. The risk SNPs are almost all non-coding, meaning that their biological significance is unclear; probably their effects are mediated via an influence on gene regulation, and emerging evidence suggests that some key molecular events occur during early brain development. The loci include novel genes of unknown function as well as genes and pathways previously implicated in the pathophysiology of schizophrenia, e.g. NMDA receptor signalling. Genes in the latter category have the clearer therapeutic potential, although even this will be a challenging process because of the many complexities concerning the genetic architecture and mediating mechanisms. This review summarises recent schizophrenia genetic findings and some key issues they raise, particularly with regard to their implications for identifying and validating novel drug targets.

The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.

Among the constellation of symptoms that characterize schizophrenia, negative symptoms have emerged as a critical feature linked to the functional impairment experienced by affected individuals. Despite advances in our understanding of the role of negative symptoms in the illness, effective treatments for these debilitating symptoms have remained elusive. In this review we explore the contemporary conceptualization of negative symptoms in schizophrenia, including the identification of two key subdomains of diminished expression and amotivation, and clarifications around hedonic capacity. We then explore strategies for clinical assessments of negative symptoms, followed by findings using objective paradigms for evaluating discrete aspects of these negative symptoms in clinical populations and animal models, both for symptoms of diminished expression and within the multifaceted motivation system. We conclude with a consideration of current strategies for drug development for these negative symptoms, the role of heterogeneity in the clinical presentation of symptoms in schizophrenia and opportunities for personalized assessment and treatment approaches, as well as a commentary on current clinical drug trial design and the role of environmental opportunities for novel treatments to effect change and improve outcomes for affected individuals.

The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction.

While schizophrenia and mental health are qualitatively distinct at the level of clinical presentation, the specific molecular signatures that underlie, or associate with, illness are not. Biomarker identification in schizophrenia is intended to offer a number of important benefits to patient well-being including prediction of future illness, diagnostic clarity and a level of disease description that would guide treatment choice. However, the choice of sample and form of analysis used to produce useful biomarkers is still uncertain. In this review, advances from recent studies spanning the technical spectrum are presented together with comment on their comparative strengths and weaknesses. To date, these studies have aided our understanding of the pathological processes associated with illness much more than they have provided robust biomarkers. A number of reasons for this observation are suggested, as are new strategies for the extraction of biomarkers from large ‘-omics’ datasets.

There is a growing consensus that a symptomatology as complex and heterogeneous as schizophrenia is likely to be produced by widespread perturbations of brain structure, as opposed to isolated deficits in specific brain regions. Structural brain-imaging studies have shown that several features of the brain, such as grey matter, white matter integrity and the morphology of the cortex differ in individuals at high risk of the disorder compared to controls, but to a lesser extent than in patients, suggesting that structural abnormalities may form markers of vulnerability to the disorder. Research has had some success in delineating abnormalities specific to those individuals that transition to psychosis, compared to those at high risk that do not, suggesting that a general risk for the disorder can be distinguished from alterations specific to frank psychosis. In this paper, we review cross-sectional and longitudinal studies of individuals at familial or clinical high risk of the disorder. We conclude that the search for reliable markers of schizophrenia is likely to be enhanced by methods which amalgamate structural neuroimaging data into a coherent framework that takes into account the widespread distribution of brain alterations, and relates this to leading hypotheses of schizophrenia.

Neural oscillations have received recently a great deal of interest in schizophrenia research because of the possibility to integrate findings from non-invasive electro/magnetoencephalographical recordings with pre-clinical research, which could potentially lead to the identification of pathophysiological mechanisms and novel treatment targets. In the current paper, we review the potential as well as the challenges of this approach by summarizing findings on alterations in rhythmic activity from both animal models and human data which have implicated dysfunctional neural oscillations in the explanation of cognitive deficits and certain clinical symptoms of schizophrenia. Specifically, we will focus on findings that have examined neural oscillations during 1) perceptual processing, 2) working memory and executive processes and 3) spontaneous activity. The importance of the development of paradigms suitable for human and animal models is discussed as well as the search for mechanistic explanation for oscillatory dysfunctions.

While our knowledge of the pathophysiology of schizophrenia has increased dramatically, this has not translated into the development of new and improved drugs to treat this disorder. Human brain imaging and electrophysiological studies have provided dramatic new insight into the mechanisms of brain dysfunction in the disease, with a swathe of recent studies highlighting the differences in functional brain network and neural system connectivity present in the disorder. Only recently has the value of applying these approaches in preclinical rodent models relevant to the disorder started to be recognised. Here we highlight recent findings of altered functional brain connectivity in preclinical rodent models and consider their relevance to those alterations seen in the brains of schizophrenia patients. Furthermore, we highlight the potential translational value of using the paradigm of functional brain connectivity phenotypes in the context of preclinical schizophrenia drug discovery, as a means both to understand the mechanisms of brain dysfunction in the disorder and to reduce the current high attrition rate in schizophrenia drug discovery.

Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition.

Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4β2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training.

Social cognition, including emotion processing, is a recognised deficit observed in patients with schizophrenia. It is one cognitive domain which has been emphasised as requiring further investigation, with the efficacy of antipsychotic treatment on this deficit remaining unclear. Nine studies met our criteria for entry into a meta-analysis of the effects of medication on facial affect processing, including data from 1162 patients and six antipsychotics. Overall we found a small, positive effect (Hedge’s g = 0.13, 95% CI 0.05 to 0.21, p = 0.002). In a subgroup analysis this was statistically significant for atypical, but not typical, antipsychotics. It should be noted that the pooled sample size of the typical subgroup was significantly lower than the atypical. Meta-regression analyses revealed that age, gender and changes in symptom severity were not moderating factors. For the small, positive effect on facial affect processing, the clinical significance is questionable in terms of treating deficits in emotion identification in schizophrenia. We show that antipsychotic medications are poor at improving facial affect processing compared to reducing symptoms. This highlights the need for further investigation into the neuropharmacological mechanisms associated with accurate emotion processing, to inform treatment options for these deficits in schizophrenia.

Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.