Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC.

BACKGROUND: Cannabis and its main psychoactive ingredient δ-9-tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear. METHODS: We investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22). RESULTS: Under placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's ρ = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC. CONCLUSIONS: These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. METHOD: This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 µg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. RESULTS: SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. CONCLUSIONS: Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications.

RATIONALE: Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. OBJECTIVES: We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. RESULTS: The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. CONCLUSIONS: An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.

Which psychotic experiences are associated with a need for clinical care?

BACKGROUND: The aims of this study were to identify (1) the factor structure of anomalous experiences across the psychosis continuum; (2) qualitative and quantitative differences in psychotic experiences (PEs) between "non need-for-care" and two clinical groups: psychosis patients and individuals at ultra high risk (UHR) of psychosis. We aimed to distinguish which types of experiences would be related to malign (need-for-care and/or help-seeking) versus benign outcomes. METHODS: Component scores obtained from a Principal Components Analysis of PEs from lifetime scores on the Appraisals of Anomalous Experience Inventory (Brett et al., 2007) were compared across 96 participants: patients diagnosed with a psychotic disorder (n=37), help-seeking UHR people (n=21), and non-clinical individuals presenting with enduring PEs (n=38). RESULTS: A five-component structure provided the best solution, comprising dissociative-type experiences, subjective cognitive deficits, and three separate components relating to "positive" symptoms. All groups reported "positive" experiences, such as ideas of reference and hallucinations, with the non-clinical group displaying more PEs in the Paranormal/Hallucinatory component than both clinical groups. "Cognitive/Attentional anomalies" was the only component where the clinical groups reported significantly more anomalies than the non-clinical group. However psychosis patients reported more frequent first-rank type symptoms and "hypomanic" type PEs than the other groups. DISCUSSION: "Positive" PEs were common across the psychosis spectrum, although first-rank type symptoms were particularly marked in participants diagnosed with a psychotic disorder. Help-seeking and need-for-care were associated with the presence of subjective cognitive disturbances. These findings suggest that anomalies of cognition and attention may be more relevant to poorer outcomes than the presence of anomalous experiences.

Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis.

Cannabis use can induce acute psychotic symptoms and increase the risk of schizophrenia. Impairments in inhibitory control and processing are known to occur both under the influence of cannabis and in schizophrenia. Whether cannabis-induced impairment in inhibitory processing is related to the acute induction of psychotic symptoms under its influence is unclear. We investigated the effects of acute oral administration of 10mg of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on inhibitory control and regional brain activation during inhibitory processing in humans and examined whether these effects are related to the induction of psychotic symptoms under its influence using a repeated-measures, placebo-controlled, double-blind, within-subject design. We studied thirty-six healthy, English-speaking, right-handed men with minimal previous exposure to cannabis and other illicit drugs twice using functional magnetic resonance imaging (fMRI) while they performed a response inhibition (Go/No-Go) task. Relative to placebo, delta-9-THC caused transient psychotic symptoms, anxiety, intoxication and sedation, inhibition errors and impaired inhibition efficiency. Severity of psychotic symptoms was directly correlated with inhibition error frequency and inversely with inhibition efficiency under the influence of delta-9-THC. Delta-9-THC attenuated left inferior frontal activation which was inversely correlated with the frequency of inhibition errors and severity of psychotic symptoms and positively with inhibition efficiency under its influence. These results provide experimental evidence that impairments in cognitive processes involved in the inhibitory control of thoughts and actions and inferior frontal function under the influence of cannabis may have a role in the emergence of transient psychotic symptoms under its influence.

Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.

BACKGROUND: What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide? METHOD: Employing a double-blind, repeated-measures design, we investigated the genetic and neural basis of variable sensitivity to cannabis-induced behavioural dyscontrol in healthy occasional cannabis users. Acute oral challenge with placebo or Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was combined with functional magnetic resonance imaging, while participants performed a response inhibition task that involved inhibiting a pre-potent motor response. They were genotyped for rs1130233 single nucleotide polymorphisms (SNPs) of the protein kinase B (AKT1) gene. RESULTS: Errors of inhibition were significantly (p = 0.008) increased following administration of THC in carriers of the A allele, but not in G allele homozygotes of the AKT1 rs1130233 SNP. The A allele carriers also displayed attenuation of left inferior frontal response with THC evident in the sample as a whole, while there was a modest enhancement of inferior frontal activation in the G homozygotes. There was a direct relationship (r = -0.327, p = 0.045) between the behavioural effect of THC and its physiological effect in the inferior frontal gyrus, where AKT1 genotype modulated the effect of THC. CONCLUSIONS: These results require independent replication and show that differing vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that influences dopamine function, and is mediated through modulation of the effect of cannabis on the inferior frontal cortex, that is rich in dopaminergic innervation and critical for psychomotor control.

Cannabis use and transition to psychosis in people at ultra-high risk.

BACKGROUND: Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder. METHOD: Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes. RESULTS: Lifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n=98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ(2)1=10.971, p=0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ(2)1=1.061, p=0.303). CONCLUSIONS: In people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review.

BACKGROUND: In recent years, growing concerns about the effects of cannabis use on mental health have renewed interest in cannabis research. In particular, there has been a marked increase in the number of neuroimaging studies of the effects of cannabinoids. We conducted a systematic review to assess the impact of acute cannabis exposure on brain function in humans and in experimental animals. METHODS: Papers published until June 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only pharmacological challenge studies involving the acute experimental administration of cannabinoids in occasional or naïve cannabis users, and naïve animals were considered. RESULTS: Two hundred and twenty-four studies were identified, of which 45 met our inclusion criteria. Twenty-four studies were in humans and 21 in animals. Most comprised studies of the acute effects of cannabinoids on brain functioning in the context of either resting state activity or activation during cognitive paradigms. In general, THC and CBD had opposite neurophysiological effects. There were also a smaller number of neurochemical imaging studies: overall, these did not support a central role for increased dopaminergic activity in THC-induced psychosis. There was a considerable degree of methodological heterogeneity in the imaging literature reviewed. CONCLUSION: Functional neuroimaging studies have provided extensive evidence for the acute modulation of brain function by cannabinoids, but further studies are needed in order to understand the neural mechanisms underlying these effects. Future studies should also consider the need for more standardised methodology and the replication of findings.

Negative psychotic symptoms and impaired role functioning predict transition outcomes in the at-risk mental state: a latent class cluster analysis study.

BACKGROUND: Many research groups have attempted to predict which individuals with an at-risk mental state (ARMS) for psychosis will later develop a psychotic disorder. However, it is difficult to predict the course and outcome based on individual symptoms scores. METHOD: Data from 318 ARMS individuals from two specialized services for ARMS subjects were analysed using latent class cluster analysis (LCCA). The score on the Comprehensive Assessment of At-Risk Mental States (CAARMS) was used to explore the number, size and symptom profiles of latent classes. RESULTS: LCCA produced four high-risk classes, censored after 2 years of follow-up: class 1 (mild) had the lowest transition risk (4.9%). Subjects in this group had the lowest scores on all the CAARMS items, they were younger, more likely to be students and had the highest Global Assessment of Functioning (GAF) score. Subjects in class 2 (moderate) had a transition risk of 10.9%, scored moderately on all CAARMS items and were more likely to be in employment. Those in class 3 (moderate-severe) had a transition risk of 11.4% and scored moderately severe on the CAARMS. Subjects in class 4 (severe) had the highest transition risk (41.2%), they scored highest on the CAARMS, had the lowest GAF score and were more likely to be unemployed. Overall, class 4 was best distinguished from the other classes on the alogia, avolition/apathy, anhedonia, social isolation and impaired role functioning. CONCLUSIONS: The different classes of symptoms were associated with significant differences in the risk of transition at 2 years of follow-up. Symptomatic clustering predicts prognosis better than individual symptoms.

Outreach and support in south London (OASIS), 2001-2011: ten years of early diagnosis and treatment for young individuals at high clinical risk for psychosis.

INTRODUCTION: Prevention of psychosis has become a major objective of modern clinical psychiatry. An increasing number of new services have been established in Europe and in the world. The OASIS team has become an established model where clinical practice and research are fully integrated in the field of preventative interventions in psychosis. METHOD: Comprehensive analysis of different clinical and service measures describing the 2001-2011 implementation of the OASIS team. RESULTS: Over the last decade, the OASIS team has received a total of 1102 referrals, mostly young males from ethnic minorities. After the assessment, 35% were diagnosed with an At Risk Mental State (ARMS) while 32% were already psychotic. Within the ARMS, 70% met the inclusion criteria for the attenuated psychotic symptoms subgroup, 1% met the inclusion criteria for the genetic deterioration syndrome, 9% met inclusion criteria for a brief and self-limited intermittent psychotic episode and the others met inclusion criteria for more than one subgroup. Most of them had at least one comorbid diagnosis, mainly relating to anxiety and depressive domains. The majority of the OASIS clients received cognitive behavioural therapy alone or in combination with antidepressants/antipsychotics. Over the 2-year follow-up time, 44 subjects (15.2%) developed a frank psychotic episode. CONCLUSIONS: The OASIS service represents one of the largest and most established prodromal services in the world. The burden of research evidence and the translational impact produced on the clinical practice support the OASIS as a model for the development of similar services.

Faulty suppression of irrelevant material in patients with thought disorder linked to attenuated frontotemporal activation.

Formal thought disorder is a feature schizophrenia that manifests as disorganized, incoherent speech, and is associated with a poor clinical outcome. The neurocognitive basis of this symptom is unclear but it is thought to involve an impairment in semantic processing classically described as a loosening of meaningful associations. Using a paradigm derived from the n400 event-related, potential, we examined the extent to which regional activation during semantic processing is altered in schizophrenic patients with formal thought disorder. Ten healthy control and 18 schizophrenic participants (9 with and 9 without formal thought disorder) performed a semantic decision sentence task during an event-related functional magnetic resonance imaging experiment. We employed analysis of variance to estimate the main effects of semantic congruency and groups on activation and specific effects of formal thought disorder were addressed using post-hoc comparisons. We found that the frontotemporal network, normally engaged by a semantic decision task, was underactivated in schizophrenia, particularly in patients with FTD. This network is implicated in the inhibition of automatically primed stimuli and impairment of its function interferes with language processing and contributes to the production of incoherent speech.

Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication.

Structure and function in the human brain are closely related. At the onset of psychosis, brain imaging studies have identified robust changes in brain function and structure, but no data are available relating these two domains. After systematic literature searches, we included all available studies reporting whole-brain structural or cognitive functional imaging findings in first-episode (FEP) subjects in multimodal Signed Differential Mapping (SDM). Forty-three studies met the inclusion criteria. The structural database comprised 965 FEP subjects matched with 1040 controls whilst the functional cohort included 362 FEP subjects matched with 403 controls. The analysis identified conjoint structural and functional differences in the insula/superior temporal gyrus and the medial frontal/anterior cingulate cortex bilaterally. In these regions, large and robust decreases in grey matter volume were found with either reduced or enhanced activation. Meta-regression analyses indicated that grey matter volume in the anterior cingulate and left insular clusters was influenced by exposure to antipsychotics: patients receiving medication were more likely to show structural abnormalities in these regions.

Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.

RATIONALE: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied separately. OBJECTIVE: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. METHODS: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. RESULTS: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p < 0.01), an increase in heart rate (p < 0.05). There were no differences between CBD and placebo on any symptomatic, physiological variable. CONCLUSIONS: In healthy volunteers, THC has marked acute behavioural and physiological effects, whereas CBD has proven to be safe and well tolerated.

Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study.

BACKGROUND: Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). METHOD: FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. RESULTS: We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis×time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis×time interaction. CONCLUSIONS: Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis.

Interpersonal sensitivity in the at-risk mental state for psychosis.

BACKGROUND: Interpersonal sensitivity is a personality trait described as excessive awareness of both the behaviour and feelings of others. Although interpersonal sensitivity has been found to be one of the vulnerability factors to depression, there has been little interest in its relationship with the prodromal phase of psychosis. The aims of this study were to examine the level of interpersonal sensitivity in a sample of individuals with an at-risk mental state (ARMS) for psychosis and its relationship with other psychopathological features. METHOD: Sixty-two individuals with an ARMS for psychosis and 39 control participants completed a series of self-report questionnaires, including the Interpersonal Sensitivity Measure (IPSM), the Prodromal Questionnaire (PQ), the Ways of Coping Questionnaire (WCQ) and the Depression and Anxiety Stress Scale (DASS). RESULTS: Individuals with an ARMS reported higher interpersonal sensitivity compared to controls. Associations between interpersonal sensitivity, positive psychotic symptoms (i.e. paranoid ideation), avoidant coping and symptoms of depression, anxiety and stress were also found. CONCLUSIONS: This study suggests that being 'hypersensitive' to interpersonal interactions is a psychological feature of the putatively prodromal phase of psychosis. The relationship between interpersonal sensitivity, attenuated positive psychotic symptoms, avoidant coping and negative emotional states may contribute to long-term deficits in social functioning. We illustrate the importance, when assessing a young client with a possible ARMS, of examining more subtle and subjective symptoms in addition to attenuated positive symptoms.

Delusional ideation, manic symptomatology and working memory in a cohort at clinical high-risk for psychosis: a longitudinal study.

We followed up a cohort (n=35) of clients with an "At Risk Mental State" (ARMS) for almost 2 years (mean 21.3 months). At baseline, these clients had taken part in research looking at the relationship between reasoning biases, memory, personality styles and delusional ideation. During the follow-up period, clients underwent a package of intervention from a specialist early detection team. Eighty percent (n=28) of these clients were successfully re-interviewed. There was improvement across the cohort as a whole, however five participants (17.9%) had made the transition to psychosis at follow-up. Those who had become psychotic had lower levels of manic symptomatology at baseline than those who did not enter the first episode. Further, across the cohort, impaired working memory and delusional ideation at baseline combined to predict 45% of the delusional ideation at follow-up. These preliminary findings suggest that working memory impairments may be linked to the persistence of delusional ideation and that manic symptoms in someone with an ARMS may suggest that such an individual is less likely to develop a frank psychotic episode.

Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis.

CONTEXT: Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. OBJECTIVE: To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). DESIGN: Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. SETTING: Maudsley Hospital, London, England. PATIENTS AND OTHER PARTICIPANTS: A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). MAIN OUTCOME MEASURES: Regional brain activation (blood oxygen level-dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. RESULTS: During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. CONCLUSIONS: Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls.

Outreach and Support in South London (OASIS). Outcomes of non-attenders to a service for people at high risk of psychosis: the case for a more assertive approach to assessment.

BACKGROUND: International agreement dictates that clients must be help-seeking before any assessment or intervention can be implemented by an 'at-risk service'. Little is known about individuals who decline input. This study aimed to define the size of the unengaged population of an 'at-risk service', to compare this group to those who did engage in terms of sociodemographic and clinical features and to assess the clinical outcomes of those who did not engage with the service. METHOD: Groups were compared using data collected routinely as part of the service's clinical protocol. Data on service use and psychopathology since referral to Outreach and Support in South London (OASIS) were collected indirectly from clients' general practitioners (GPs) and by screening electronic patient notes held by the local Mental Health Trust. RESULTS: Over one-fifth (n=91, 21.2%) of those referred did not attend or engage with the service. Approximately half of this group subsequently received a diagnosis of mental illness. A diagnosis of psychosis was given to 22.6%. Nearly 70% presented to other mental health services. There were no demographic differences, except that those who engaged with the service were more likely to be employed. CONCLUSIONS: Over one-fifth of those referred to services for people at high risk of psychosis do not attend or engage. However, many of this group require mental health care, and a substantial proportion has, or will later develop, psychosis. A more assertive approach to assessing individuals who are at high risk of psychosis but fail to engage may be indicated.

Ketamine-induced disruption of verbal self-monitoring linked to superior temporal activation.

INTRODUCTION: Misattribution of distorted self-generated speech in patients with schizophrenia has been associated with increased lateral temporal activation. As a pharmacological model of schizophrenia, we tested whether ketamine would induce the same effects in healthy individuals. METHODS: Participants were 8 healthy male volunteers who were naïve to ketamine (mean age: 28 years). Ketamine (0.23 mg/kg bolus followed by 0.64 mg/kg/h) and placebo infusions were administered in a double-blind, randomised order, during 2 functional magnetic resonance imaging (fMRI) sessions. Each fMRI session consisted of a verbal self-monitoring task in which auditory feedback was experimentally modified. RESULTS: Ketamine was associated with psychotic and dissociative symptoms. Participants made more misattributions of distorted self-generated speech (P < 0.02) during the ketamine infusion. Ketamine led to reduced activation in the left superior temporal cortex during self-distorted speech, regardless of whether the speech was identified correctly or not, as compared to the placebo infusion. Misidentification of speech that had been distorted was not associated with any increase in brain activation in during the placebo infusion, however ketamine-induced misattributions were associated with a relative increase in left superior temporal cortex activation. DISCUSSION: These data are consistent with the notion that self-monitoring impairments underlie psychotic symptoms and suggest that N-methyl-D-aspartate (NMDA) receptor dysfunction may mediate self-monitoring deficits and psychotic phenomena in schizophrenia.