Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Altered relationship between cortisol response to social stress and mediotemporal function during fear processing in people at clinical high risk for psychosis: a preliminary report.

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine-neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.

Human Striatal Response to Reward Anticipation Linked to Hippocampal Glutamate Levels.

Background: Dysfunctional reward processing is associated with a number of psychiatric disorders, such as addiction and schizophrenia. It is thought that reward is regulated mainly by dopamine transmission in the ventral striatum. Contemporary animal models suggest that striatal dopamine concentrations and associated behaviors are related to glutamatergic functioning in the ventral hippocampus. However, in humans the association between reward-related ventral striatal response and hippocampal glutamate levels is unclear. Methods: Nineteen healthy participants were studied using proton magnetic resonance spectroscopy to measure hippocampal glutamate levels, and functional magnetic resonance imaging to assess striatal activation and functional connectivity during performance of a monetary incentive delay task. Results: We found that ventral striatal activation related to reward processing was correlated with hippocampal glutamate levels. In addition, context-dependent functional coupling was demonstrated between the ventral striatum and both the lingual gyrus and hippocampus during reward anticipation. Elevated hippocampal glutamate levels were inversely related to context-dependent functional connectivity between the ventral striatum and the anterior hippocampus while anticipating reward. Conclusions: These findings indicate that human striatal responses to reward are influenced by hippocampal glutamate levels. This may be relevant for psychiatric disorders associated with abnormal reward processing such as addiction and schizophrenia.

Anxiety and negative self-schemas mediate the association between childhood maltreatment and paranoia.

This study examined affective and psychological routes from childhood maltreatment to increased paranoia in adulthood. Recent anxiety and negative beliefs about the self partially accounted for the associations between emotional or physical abuse and paranoia. However, as full mediation did not occur, other psychological, social and biological pathways require exploration.

Prevalence of mental disorders in defendants at criminal court.

BACKGROUND: Psychiatric morbidity in prisons and police custody is well established, but little is known about individuals attending criminal court. There is international concern that vulnerable defendants are not identified, undermining their right to a fair trial. AIMS: To explore the prevalence of a wide range of mental disorders in criminal defendants and estimate the proportion likely to be unfit to plead. METHOD: We employed two-stage screening methodology to estimate the prevalence of mental illness, neurodevelopmental disorders and unfitness to plead, in 3322 criminal defendants in South London. Sampling was stratified according to whether defendants attended court from the community or custody. Face-to-face interviews, using diagnostic instruments and assessments of fitness to plead, were administered (n = 503). Post-stratification probability weighting provided estimates of the overall prevalence of mental disorders and unfitness to plead. RESULTS: Mental disorder was more common in those attending court from custody, with 48.5% having at least one psychiatric diagnosis compared with 20.3% from the community. Suicidality was frequently reported (weighted prevalence 71.2%; 95% CI 64.2-77.3). Only 16.7% of participants from custody and 4.6% from the community were referred to the liaison and diversion team; 2.1% (1.1-4.0) of defendants were estimated to be unfit to plead, with a further 3.2% (1.9-5.3) deemed 'borderline unfit'. CONCLUSIONS: The prevalence of mental illness and neurodevelopmental disorders in defendants is high. Many are at risk of being unfit to plead and require additional support at court, yet are not identified by existing services. Our evidence challenges policy makers and healthcare providers to ensure that vulnerable defendants are adequately supported at court.

Imaginator: A Proof-of-Concept Feasibility Trial of a Brief Imagery-Based Psychological Intervention for Young People Who Self-Harm.

OBJECTIVES: The Imaginator study tested the feasibility of a short mental imagery-based psychological intervention for young people who self-harm and used a stepped-wedge design to investigate effects on self-harm frequency reduction at 3 and 6 months. METHOD: A total of 38 participants aged 16-25 were recruited via community self-referral and mental health services. Participants were randomized to immediate delivery of Functional Imagery Training (FIT) or usual care followed by delayed delivery after 3 months. FIT comprised two face-to-face sessions, five phone sessions, and use of a smartphone app. Outcomes' assessment was blind to allocation. RESULTS: Three quarters of those who began treatment completed face-to-face sessions, and 57% completed five or more sessions in total. Self-harm frequency data were obtained on 76% of the sample at 3 months (primary outcome) and 63% at 6 months. FIT produced moderate reductions in self-harm frequency at 3 months after immediate (d = 0.65) and delayed delivery (d = 0.75). The Immediate FIT group maintained improvements from 3 to 6 months (d = 0.05). Participants receiving usual care also reduced self-harm (d = 0.47). CONCLUSIONS: A brief mental imagery-based psychological intervention targeting self-harm in young people is feasible and may comprise a novel transdiagnostic treatment for self-harm.

A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis.

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.

Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis.

Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear. We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls. We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition. We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions. CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.

Fitness to plead: Development and validation of a standardised assessment instrument.

The ability of an individual to participate in courtroom proceedings is assessed by clinicians using legal 'fitness to plead' criteria. Findings of 'unfitness' are so rare that there is considerable professional unease concerning the utility of the current subjective assessment process. As a result, mentally disordered defendants may be subjected unfairly to criminal trials. The Law Commission in England and Wales has proposed legal reform, as well as the utilisation of a defined psychiatric instrument to assist in fitness to plead assessments. Similar legal reforms are occurring in other jurisdictions. Our objective was to produce and validate a standardised assessment instrument of fitness to plead employing a filmed vignette of criminal proceedings. The instrument was developed in consultation with legal and clinical professionals, and was refined using standard item reduction methods in two initial rounds of testing (n = 212). The factorial structure, test-retest reliability and convergent validity of the resultant instrument were assessed in a further round (n = 160). As a result of this iterative process a 25-item scale was produced, with an underlying two-factor structure representing the foundational and decision-making abilities underpinning fitness to plead. The sub-scales demonstrate good internal consistency (factor 1: 0·76; factor 2: 0·65) and test-retest stability (0·7) as well as excellent convergent validity with scores of intelligence, executive function and mentalising abilities (p≤0·01 in all domains). Overall the standardised Fitness to Plead Assessment instrument has good psychometric properties. It has the potential to ensure that the significant numbers of mentally ill and cognitively impaired individuals who face trial are objectively assessed, and the courtroom process critically informed.

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

Importance: Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear. Objective: To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis. Design, Setting, and Participants: In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017. Interventions: A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task. Main Outcomes and Measures: Brain activation during verbal encoding and recall, indexed using the blood oxygen level-dependent hemodynamic response fMRI signal. Results: Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level-dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, -0.016 to 0.010; control: median, 0.035; IQR, 0.015 to 0.039; P < .001). Within these 3 regions, activation in the CBD group was greater than in the placebo group but lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, -0.013; IQR, -0.027 to 0.002; placebo: median, -0.007; IQR, -0.019 to 0.008; control: median, 0.034; IQR, 0.005 to 0.059); the level of activation in the CBD group was thus intermediate to that in the other 2 groups. There were no significant group differences in task performance. Conclusions and Relevance: Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state. As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms. Trial Registration: isrctn.org Identifier: ISRCTN46322781.