Current Pharmaceutical Design - Volume 18, Issue 4, 2012

The onset of schizophrenia is usually preceded by a prodromal phase characterized by functional decline and subtle symptoms, which include attenuated psychotic phenomena, cognitive impairments and a decline in socio-occupational function. Research into the early phases of psychosis promises to provide important clues to the mechanisms underlying schizophrenia and psychotic disorders. Investigation of subjects at the beginning of illness allows researchers to minimize confounders such as neurodegenerative progress of disease, institutionalization and long-term treatment, particularly with antipsychotics. In addition, there is evidence indicating that preventative interventions in psychosis are feasible and of great clinical benefits. There are, at least, three possible mechanisms for improving the course of the disease by active interventions before onset of psychosis. First, it might be possible to prevent psychosis by intervening in a crucial phase of beginning symptoms. Second, it might be possible to improve the course of the disease by improving the mental state in the prodromal phase or by postponing the first psychotic episode. Finally, the first psychotic episode might have a more favorable course after intervention in the prodromal phase, because the patient is already enrolled in a mental health treatment program: psychosis will be discovered soon after onset, and the patient might be more willing to accept treatment, thus shortening the duration of untreated psychosis. Interest in this area has grown to the extent that there is an ongoing debate about including a new high risk diagnostic category in DSM-5 (i.e. Attenuated Psychosis Syndrome). We present here a comprehensive issue addressing the core issues in the filed. In the first part of this issue we will focus on the diagnosis of the high risk state for psychosis. We will first review the psychopatholigical available criteria employed to define the prodromal psychotic phases. Then we will address the potential role of neuroimaging techniques such as structural neuroimaging, functional neuroimaging and neurochemical imaging to study core neurobiological markers linked to the pathophysiological mechanisms underlying the pre-psychotic phases. We will thus link the neurobiological findings to neurocognitive and environmental markers of an impending psychosis. In the second part of the issue we will focus on available treatments for people presenting with prodromal signs and symptoms of psychosis including psychopharmacological, psychoeducational and psychotherapeutical interventions. Such active treatments will be presented in the light of the implementation of specialized services devoted to young people presenting with prodromal signs and symptoms of psychosis. Finally we will discuss potential conceptual, ethical and methodological limitations in prodromal psychosis research. The issue largely benefits from leading worldwide authors with a very strong track of publications in the field of pre-psychotic phases and I would greatly thank all of them for their great contributions. Overall I feel this issue will provide a state-of-the-art-review on the diagnosis and treatment of the pre-psychotic phases and I'm sure it will definitely sustain future preventative interventions in psychiatry.

Early psychopathological attempts to characterize the vulnerability to schizophrenia were based on the phenomenological method. From the beginning, phenomenologically-oriented psychopathologists have searched the basic vulnerability underlying schizophrenic phenomena in two main domains: depersonalization and derealisation/desocialization. Schizophrenic persons undergo a special kind of depersonalisation: the living body becomes a functioning body, a thing-like mechanism in which feelings, perceptions, and actions take place as if they happened in an outer space. They also endure a special kind of derealisation/de-socialization: the interpersonal scene becomes like a theatre stage, pervaded with a sense of unreality, on which the main actor is unaware of the plot, out of touch with the role he is acting and unable to make sense of the objects he encounters and of what the other people are doing. Many years later, the mainstream research paradigms employed to investigate the vulnerability concept in schizophrenic psychosis have included genetic studies, birth cohort studies, psychosis proneness, and clinical high risk. We will review these studies and conclude with an outline of future research directions focusing on three main features of the psychopathology of early schizophrenia: anomalies of the pre-reflexive self and of the social self (intersubjectivity), and existential re-orientation.

Although prodromal symptoms of psychosis have long been recognized, the clinical management of psychotic disorders conventionally begins at the first episode of frank psychosis, and, until recently, the period immediately preceding the first episode received relatively little attention. Over the last fifteen years, there has been increasing academic and clinical interest in people presenting with potentially prodromal symptoms. This clinical syndrome has been termed an “At Risk Mental State”, and operationalised criteria, the “Ultra High Risk (UHR)”, or “Clinical High Risk” criteria, have been developed to identify the syndrome. We will review here the mainstreams of the UHR paradigms focusing on the conceptual basis, potentials and limtations in current psychiatric research.

Recent focus on early detection and intervention in psychosis has renewed interest in subtle psychopathology beyond positive and negative symptoms. Such self-experienced sub-clinical disturbances are described in detail by the basic symptom concept. This review will give an introduction into the concept of basic symptoms and describe the development of the current instruments for their assessment, the Schizophrenia Proneness Instrument, Adult (SPI-A) and Child and Youth version (SPI-CY), as well as of the two at-risk criteria: the at-risk criterion Cognitive-Perceptive Basic Symptoms (COPER) and the high-risk criterion Cognitive Disturbances (COGDIS). Further, an overview of prospective studies using both or either basic symptom criteria and transition rates related to these will be given, and the potential benefit of combining ultra-high risk criteria, particularly attenuated psychotic symptoms, and basic symptom criteria will be discussed. Finally, their prevalence in psychosis patients, i.e. the sensitivity, as well as in general population samples will be described. It is concluded that both COPER and COGDIS are able to identify subjects at a high risk of developing psychosis. Further, they appear to be sufficiently frequent prior to onset of the first psychotic episode as well as sufficiently rare in persons of general population to be considered as valuable for an early detection of psychosis.

Bipolar affective disorder (BD) is a severe, recurrent and disabling disorder with devastating consequences for individuals, families and society. Although these hazards and costs provide a compelling rationale for development of early detection and early intervention strategies in BD, the development of at-risk criteria for first episode mania is still in an early stage of development. In this paper we review the literature with respect to the clinical, neuroantomical and neuropsychological data, which support this goal. We also describe our recently developed bipolar at-risk criteria (BAR). This criteria comprises the peak age range of the first onset of bipolar disorder, genetic risk, presenting with sub-threshold mania, cyclothymic features or depressive symptoms. An initial pilot evaluation of the BAR criteria in 22 subjects indicated conversion rates to proxies of first-episode mania of 23% within 265 days on average, and high specificity and sensitivity of the criteria. If prospective studies confirm the validity of the BAR criteria, then the criteria would have the potential to open up new avenues of research for indicated prevention in BD and might therefore offer opportunities to ameliorate the severity of, or even prevent BD.

The continuum model of psychosis posits that psychotic symptoms are distributed throughout the population, with diagnosable clinical disorder existing at a certain point along this continuum. The total continuum is made up mainly of non-clinical cases with clinical cases of psychosis representing only a small proportion of the total extended psychosis phenotype. This paper is a narrative review of studies of psychotic experiences in the general population. The evidence indicates reasonably high prevalence rates of psychotic experiences in the general population, substantially higher than the prevalence of psychotic disorders, and that they are associated with increased risk of future onset of diagnosable disorder, particularly when the experiences are persistent. Psychotic experiences in the general population share an extensive range of risk factors with schizophrenia and therefore provide a useful phenotype in which to study the aetiology of clinical psychosis. Some types of psychotic experiences, such as paranoid ideas, bizarre thinking and perceptual abnormalities, may indicate a greater level of risk for psychotic disorder than other psychotic experiences, such as magical thinking. There is a need for research that further explores the interplay between psychotic experiences and other risk factors (including psychological, environmental, neurocognitive and genetic factors) in the evolution of psychotic disorder, the types of psychotic experiences that are most associated with risk for clinical disorder, the specificity of risk associated with psychotic experiences, and the possible adaptive advantages of these experiences.

The Comprehensive Assessment of the At Risk Mental State (CAARMS) is a semi-structured interview designed to assess attenuated psychotic symptoms in people at ultra high risk of developing psychosis (UHR). It is widely used worldwide but no studies have ever assessed its psychometric properties in the Italian population. Here we tested the reliability and validity of the Italian version of the CAARMS (CAARMS-I). Psychometric properties (inter-rater reliability, internal coherence, construct validity, concurrent validity and predictive validity) were assessed in an Italian sample of ARMS subjects, first-episode subjects and matched controls. We found that the CAARMS-I demonstrates adequate validity and reliability and appears to be helpful in the diagnosis of the ARMS and prediction of psychosis transition.

The purpose of this study is to answer the following question: What are the typical features of abnormal bodily experiences (ABEs) in persons affected by acute first-episode schizophrenia? Our overall objective is to contribute to enhance early diagnosis of schizophrenia, and providing supplementary diagnostic criteria especially for ultra-high risk patients. In a group of 39 patients with firstepisode schizophrenia selected from a sample of 393 psychotic patients, 30 (76.9 %) reported ABEs. By means of a phenomenologicallybased qualitative method of inquiry, we recognized four subtypes of ABEs whose main characteristics are dynamization of bodily boundaries and construction, morbid objectivization/devitalization, dysmorphic experiences and pain-like experiences. These four typologies of ABEs are documented through the patients' first-person self-descriptions, and then operationally defined. Two main properties emerge as tentative eidetic (defining) cores of ABEs in early schizophrenia: dynamization of bodily boundaries and construction, and morbid objectivization/devitalization. Sharpening the diagnostic sensibility for typically schizophrenic ABEs can help improve differential diagnosis between schizophrenia and other disorders entailing other types of anomalies of lived corporeality. Also, studying possible transitions from schizophrenic cenesthopathies to bodily delusions in persons with schizophrenia may refine the concept of bizarre delusions by improving its validity. Furthermore, our knowledge about the pathogenesis of schizophrenia may profit from an in-depth assessment of ABEs and their relationship with an abnormal sense of selfhood, especially in early schizophrenia.

Cognitive dysfunction is a hallmark feature of schizophrenia and is evident across all phases of the illness. While prior metaanalyses have elucidated the level and pattern of cognitive deficits in the premorbid and post-onset periods of psychosis, no metaanalyses of studies of the putative prodromal period have been published. Our primary aim is to provide a meta-analysis of neurocognitive findings from 14 studies of psychosis risk syndrome (PRS) individuals published through February 2011, and compare the resulting profile with that synthesized by meta-analyses from other periods of the disorder. Meta-analysis of 1215 PRS individuals with a mean age of 19.2 (± 3.3) and 851 healthy control subjects yielded small-to-medium impairments across nine of 10 neurocognitive domains (Cohen's d = -0.26 to -0.67). Seven studies reported on PRS individuals who later developed psychosis (n = 175) and their baseline performance level generally yielded moderate-to-large ESs (d = -0.35 to -0.84). Mild cognitive deficits are reliably and broadly present in PRS individuals, falling at a level that is intermediate between healthy individuals and those diagnosed with schizophrenia, and at a level that is comparable to those at familial (“genetic”) risk and with premorbid data. Moreover, baseline neurocognition in PRS individuals who converted to psychosis showed more severe deficits than non-converters in nearly all domains. However, considerable heterogeneity of ESs across studies in many domains underscores variability in phenotypic expression and/or measurement sensitivity, and a critical need for improved reporting of sample characteristics to support moderator variable analyses.

Over the past decade, vulnerability- and psychosis-associated structural and functional brain abnormalities in a population at high clinical risk to develop psychosis were intensively studied. We reviewed the results from studies comparing at-risk mental state (ARMS) individuals with and without subsequent transition to psychosis. Additionally, we introduced a new concept of splitting ARMS population according to the duration of the psychosis risk syndrome and their probability to develop psychosis. Studying the ARMS individuals still vulnerable to psychosis but with lower risk to transit can disclose the possible protective - resilience factors or characteristics. Resilience, understood as ability to recover from change, can be thus applied in the early intervention for high clinical risk for psychosis individuals.

Schizophrenia is a disorder with a pronounced developmental component. Accordingly, there is a growing interest in characterizing developmental changes in the period leading up to disease onset, in an effort to develop effective preventative interventions. One of the ongoing neurodevelopmental changes known to occur in the late adolescent period that often overlaps with the prodromal phase and time of onset is white matter development and myelination. In this critical review, a disruption in the normal trajectory of white matter development could potentially play an important role in the onset of psychosis. We seek to summarize the existing state of research on white matter development in prodromal subjects, with a particular focus on diffusion tensor imaging (DTI) measures. First, we describe the physiological basis of developmental white matter changes and myelination. Next, we characterize the pattern of white matter changes associated with typical development across adolescence as measured with DTI. Then, we discuss white matter changes observed in adult patients with schizophrenia and in individuals seen in genetic and clinical high risk states. Finally, we discuss the implications of these findings for future research directions and for potential therapeutic interventions.

Measures of cortical folding (‘gyrification’) and connectivity are both reported to be disrupted in schizophrenia. There are also reports that increases in prefrontal gyrification may be predictive of subsequent illness in individuals at familial risk of the disorder. Such measures therefore have important potential clinical relevance. The nature of the relationship between cortical morphology and underlying connectivity is however unclear. In the current study we sought to explore the relationship between measures of gyrification and functional connectivity in a cohort of individuals at high genetic risk for the disorder. The theoretical background is based on the hypothesis that increased gyrification index (GI) in the prefrontal cortex may reflect increased short range regional connectivity. The cohort comprised 68 young unaffected relatives of schizophrenia patients and 21 healthy controls. Cortical folding was assessed using an automated Gyrification Index method (A-GI). Participants performed the Hayling sentence completion paradigm in the scanner and measures of functional connectivity were assessed using a correlation based approach. In the high risk subjects significant positive associations were found between prefrontal GI and prefrontal lateral-medial connectivity, while a negative correlation was found between prefrontal GI and prefrontal-thalamic connectivity. These associations indicate that measures describing morphological features of the brain surface relate to measures of underlying functional connectivity in the high risk subjects. Correlations in high risk people were more pronounced than in control subjects. We suggest our previous finding of increased prefrontal gyrification may therefore relate to increased local short range prefrontal connectivity and reduced long range connectivity.

Cognitive impairment is one of the key features of schizophrenia, with the largest effect sizes identified for verbal learning and memory, however little is known about its features in the time that precedes psychosis onset. Here we review a total of thirty-two studies that examined memory and learning in populations at clinical and genetic high-risk for psychosis. These studies can be divided into three different categories based on their design. Some were cross-sectional and examined neuropsychological differences between high-risk individuals and healthy controls. A second type of studies included a clinical follow-up that permitted dividing participants based on their outcome to examine abnormalities specific of subsequent transition to psychosis as well as the inclusion of cognitive data in regression models for psychosis prediction. A third type of studies had a longitudinal design with measures repeated at two or more time points in order to examine the course of cognitive functions over time. We also reviewed all neurofuncitonal studies investigating subjects at risk for psychosis and focused on brain alterations associated with the above neuropsychological impairments. Results of cross-sectional studies revealed impairments in verbal learning and memory as well as executive function/working memory, attention and processing speed; in most of these studies, performance of individuals at clinical or genetic high-risk was intermediate between that of healthy controls and first episode patients. Neurofunctional investigations revealed altered brain functioning in the neural circuits underlying memory and learning processes. Results are less consistent in terms of clearly identifying cognitive differences and their progression over time between individuals subsequently developing psychosis and those remaining non-psychotic. However, studies that included cognitive variables in regression models or prediction algorithms suggest that some areas of cognition, particularly verbal memory, can increase the accuracy obtained in the identification of individuals developing psychosis beyond that based purely on psychopathological measures, suggesting that the inclusion of neurocognitive tests of domains for which there is evidence of prediction potential could be useful in a stepwise assessment of risk.

Schizophrenia is a chronic psychotic disorder that remains a considerable cause of global disease burden. Cognitive impairments are common and contribute significantly to the morbidity of the disorder. Over the last two decades or so molecular imaging studies have refined understanding of the pathophysiology underlying the development of psychosis and cognitive impairments. Firstly they have consistently implicated presynaptic dopaminergic dysfunction in the disorder, finding that dopamine synthesis capacity, dopamine release and baseline dopamine levels are increased in the illness. Secondly recent findings show that dopamine synthesis capacity is elevated in those that go on to develop psychosis in the following year, but not in those that do not, and appears to increase further with the development of psychosis. Thirdly evidence links greater dopamine synthesis capacity to poorer cognitive performance and altered frontal cortical function measured using functional imaging during cognitive tasks. Finally they have provided data on the nature of other neurofunctional alterations in the disorder, in particular in the serotonergic system and neuroinflammation. We review these findings and discuss their implications for understanding the neurobiology of psychosis and cognitive impairments in schizophrenia.

Increasing evidence suggests that abnormalities in glutamatergic transmission may be associated with psychosis risk. Genetic polymorphisms associated with schizophrenia converge on NMDA receptor signalling pathways, and transgenic animal models and human neuroimaging studies have shown the functional impact of these risk alleles. Animal models have also shown that environmental risk factors, such as stress, cannabis use and maternal infection can result in glutamatergic dysfunction, and in vivo magnetic resonance spectroscopy (MRS) studies have detected glutamatergic abnormalities in individuals at clinical or genetic risk of psychosis. Glutamatergic dysfunction may impact on dopaminergic transmission, and ultimately lead to the emergence of psychosis. In this review, the evidence that genetic and environmental risk factors for psychosis impact on glutamatergic transmission is discussed. If glutamatergic abnormalities are present early in the disorder, this suggests that glutamatergic therapies may be useful in psychosis prevention.

Electroencephalography and Magnetoencephalography have provided valuable information about the brain functioning in psychosis. In the last few years, authors have demonstrated that there are neurophysiological alterations already in the prodromal period, before the development of psychosis. This makes them promising tools for predicting a future transition to psychosis. In this paper we review the latest studies using event-related potentials (ERP) in subjects clinically at high-risk of developing psychosis. We particularly focus in the P300, Mismatch-Negativity (MMN) and P50 paradigms, discussing the main findings, but also the limitations and challenges in electrophysiological studies in this population.

A number of structural brain imaging studies and meta-analytic reviews have shown that multiple subtle brain abnormalities are consistently found in schizophrenia and bipolar disorder. Several studies suggest that schizophrenia and affective psychoses share a largely common pattern of brain abnormalities. Aim of the present study was to compare, by means of a meta-analytic approach, brain structural abnormalities, as detected by Magnetic Resonance Imaging (MRI), found at the onset of schizophrenia and bipolar disorder in order to address the question of the specificity of brain abnormalities across diagnostic groups. Forty-five studies were identified as suitable for analysis. In both schizophrenic and bipolar patients significant overall effect sizes were demonstrated for intracranial, whole brain, total grey and white matter volume reduction as well as for an increase of lateral ventricular volume at disease onset. Thus, the available literature data strongly indicate that some brain abnormalities are already present in first-episode schizophrenia or bipolar disorder and that there is a significant overlap of brain abnormalities in affective and non-affective psychotic disorders at the onset of the disease. However, whole grey matter volume deficits and lateral ventricular enlargement appear to be more prominent in first-episode schizophrenia whereas white matter volume reduction seems more prominent in bipolar disorder. The common vs specific trajectories of brain pathomorphology in schizophrenia and bipolar disorder are discussed.

Background Neuroanatomical abnormalities, including cingulate cortex volume abnormalities, are a common feature in psychosis. However, the extent to which these are related to a vulnerability to psychosis, as opposed to the disorder per se, is less certain. Aim und Hypotheses The aim of the present study is to compare cingulate gray matter volumes in different stages of psychosis. We reviewed previous studies of subjects in a prodromal stage of psychosis and tested cingulate volume changes during the transition to psychosis. Methods A cross-sectional MRI study of manually traced cingulate gray-matter volumes in 37 individuals with an at risk mental state (ARMS) for psychosis, 23 individuals with a first-episode psychosis (FEP), and 22 healthy controls (HC) was performed using a 1.5 T MRI-scanner. 16 of 37 ARMS individuals (43 %) developed psychosis during follow up (ARMS-T), whereas 21 did not (ARMS-NT). The mean duration of follow up in ARMS was 25.1 months. 8 cingulate subregions were analysed in a region-of-interest analysis. Results Compared to HC, subjects with an ARMS had significantly reduced left caudal anterior cingulate cortex volume (p<0.027). This finding was also evident at a trend level (p: 0.069) in FEP patients. Within ARMS, the ARMS-T group showed a significantly reduced whole right cingulate cortex (p: 0.036), right subgenual cingulate cortex (p: 0.036) and right posterior cingulate cortex (p: 0.012) compared to ARMS-NT. Discussion These results suggest that the at risk mental state is associated with cingulate volume reductions, in particular in the left caudal anterior cingulate cortex (CACC). These abnormalities do not only seem to occur with transition to psychosis, but may be a correlate of an increased vulnerability to psychosis.

Recent years have witnessed numerous attempts at identifying the biological correlates of impending psychosis. Biochemical markers may theoretically provide a powerful approach to identify at-risk individuals, potentially leading to more effective intervention strategies to treat them. Hopefully, future developments in the field of research biochemistry in patients with at risk mental states or prodromal symptoms will make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different biochemical markers which have been recently demonstrated to be altered in the biological fluids of patients with impending psychosis. We will also examine the practical issues that seem to be limiting the effective integration of biomarkers into clinical development.

Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p<0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.