Bill Deakin

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

Minocycline benefits negative symptoms in early schizophrenia : a randomised double-blind placebo-controlled clinical trial in patients on standard treatment

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such ‘negative’ symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls

BACKGROUND Previous studies reporting cortisol hyposecretion in chronic fatigue syndrome may have been confounded by venepuncture, fasting and hospitalisation. METHODS Morning and evening salivary cortisol were obtained on consecutive days in the first 3 days of the menstrual cycle and compared in three samples of women taking no medication and matched for age: 14 patients with chronic fatigue syndrome, 26 community cases of ICD-10 current depressive episodes and 131 healthy community controls. RESULTS The mean evening cortisol was significantly lower in the chronic fatigue syndrome patients compared to controls with depression (P = 0.02) and healthy controls (P = 0.005). Chronic fatigue syndrome patients without psychiatric disorder had significantly lower morning salivary cortisols compared to controls (P = 0.009). CONCLUSION Chronic fatigue syndrome patients display cortisol hyposecretion in saliva as well as plasma compared to patients with depression and healthy controls. LIMITATIONS Small samples of female patients with cortisol estimated at only two time points in the day. Cortisol secretion may be secondary to other neurotransmitter abnormalities or other physiological or lifestyle factors in chronic fatigue syndrome patients. CLINICAL RELEVANCE Chronic fatigue syndrome is biochemically distinct from community depression.

Role of the orbitofrontal cortex in reinforcement processing and inhibitory control: evidence from functional magnetic resonance imaging studies in healthy human subjects.

Publisher Summary This chapter reviews the studies, suggesting that the orbitofrontal cortex (OFC) is involved in choosing responses and making decisions based on motivationally salient information. To do this effectively, the OFC must code current incentive value of external reinforcing cues and be able to respond rapidly to changes in contingencies and values. Motivationally salient information can be uncertain and unpredictable; therefore, the OFC must be able to process uncertainty and respond in anticipation of expected outcome, as well as be able to change response quickly in the face of unexpected negative outcomes. The social interactions and behaviors that are fundamental to everyday life depend on effectively and flexibly making decisions based on unpredictable and potentially changeable motivationally salient information, and therefore patients with OFC damage show impaired social behavior and decision making, although many cognitive components of complex behaviors may remain intact. The prefrontal cortex generally is considered to play a role in keeping relevant information in mind and in monitoring whether outcomes match expectations. The suggestion is that the OFC applies these functions of holding in mind and monitoring specifically to reinforcing and motivationally salient information.

Neuronal correlates of reward and loss in Cluster B personality disorders: A functional magnetic resonance imaging study

Decision making is guided by the likely consequences of behavioural choices. Neuronal correlates of financial reward have been described in a number of functional imaging studies in humans. Areas implicated in reward include ventral striatum, dopaminergic midbrain, amygdala and orbitofrontal cortex. Response to loss has not been as extensively studied but may involve prefrontal and medial temporal cortices. It has been proposed that increased sensitivity to reward and reduced sensitivity to punishment underlie some of the psychopathology in impulsive personality disordered individuals. However, few imaging studies using reinforcement tasks have been conducted in this group. In this fMRI study, we investigate the effects of positive (monetary reward) and negative (monetary loss) outcomes on BOLD responses in two target selection tasks. The experimental group comprised eight people with Cluster B (antisocial and borderline) personality disorder, whilst the control group contained fourteen healthy participants. A key finding was the absence of prefrontal responses and reduced BOLD signal in the subcortical reward system in the PD group during positive reinforcement. Impulsivity scores correlated negatively with prefrontal responses in the PD but not the control group during both, reward and loss. Our results suggest dysfunctional responses to rewarding and aversive stimuli in Cluster B personality disordered individuals but do not support the notion of hypersensitivity to reward and hyposensitivity to loss.

Neuronal correlates and serotonergic modulation of behavioural inhibition and reward in healthy and antisocial individuals

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT(2C)-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.

Power Calculations for Multicenter Imaging Studies Controlled by the False Discovery Rate

Magnetic resonance imaging (MRI) is widely used in brain imaging research (neuroimaging) to explore structural and functional changes across dispersed neural networks visible only via multisubject experiments. Multicenter investigations are an effective way to increase recruitment rates. This article describes image‐based power calculations for a two‐group, cross‐sectional design specified by the mean effect size and its standard error, sample size, false discovery rate (FDR), and size of the network (i.e., proportion of image locations) that truly demonstrates an effect. Minimum sample size (for fixed effect size) and the minimum effect size (for fixed sample size) are calculated by specifying the acceptable power threshold. Within‐center variance was estimated in five participating centers by repeat MRI scanning of 12 healthy participants from whom distributions of gray matter were estimated. The effect on outcome measures when varying FDR and the proportion of true positives is presented. Their spatial patterns reflect within‐center variance, which is consistent across centers. Sample sizes 3–6 times larger are needed when detecting effects in subcortical regions compared to the neocortex. Hypothesized multicenter studies of patients with first episode psychosis and control participants were simulated with varying proportions of the cohort recruited at each center. There is little penalty to sample size for recruitment at five centers compared to the center with the lowest variance alone. At 80% power 80 participants per group are required to observe differences in gray matter in high variance regions. Hum Brain Mapp, 2010.

The Neuro/PsyGRID Calibration Experiment: Identifying Sources of Variance and Bias in Multicenter MRI Studies

Calibration experiments precede multicenter trials to identify potential sources of variance and bias. In support of future imaging studies of mental health disorders and their treatment, the Neuro/PsyGRID consortium commissioned a calibration experiment to acquire functional and structural MRI from twelve healthy volunteers attending five centers on two occasions. Measures were derived of task activation from a working memory paradigm, fractal scaling (Hurst exponent) from resting fMRI, and grey matter distributions from T1‐weighted sequences. At each intracerebral voxel a fixed‐effects analysis of variance estimated components of variance corresponding to factors of center, subject, occasion, and within‐occasion order, and interactions of center‐by‐occasion, subject‐by‐occasion, and center‐by‐subject, the latter (since there is no intervention) a surrogate of the expected variance of the treatment effect standard error across centers. A rank order test of between‐center differences was indicative of crossover or noncrossover subject‐by‐center interactions. In general, factors of center, subject and error variance constituted >90% of the total variance, whereas occasion, order, and all interactions were generally <5%. Subject was the primary source of variance (70%–80%) for grey‐matter, with error variance the dominant component for fMRI‐derived measures. Spatially, variance was broadly homogenous with the exception of fractal scaling measures which delineated white matter, related to the flip angle of the EPI sequence. Maps of P values for the associated F‐tests were also derived. Rank tests were highly significant indicating the order of measures across centers was preserved. In summary, center effects should be modeled at the voxel‐level using existing and long‐standing statistical recommendations. Hum Brain Mapp, 2012.

Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia

Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.

Drug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients

Background: An association between abnormal involuntary movements and psychotic relapse was previously reported in a group of patients compliant with antipsychotic medication (Fallon and Dursun 2011). This was interpreted as the presence of an antipsychotic medication-induced supersensitivity psychosis. Method: From the results of that study and the Chouinard diagnostic criteria for supersensitivity psychosis an abbreviated diagnostic checklist was developed to identify the phenomenon. In the present study the checklist was used on a larger sample of medication-compliant individuals experiencing a psychotic relapse. Results: The checklist demonstrated its utility by identifying a cause of relapse in 70% (29/41) of patients. Furthermore, it identified the presence of supersensitivity psychosis in 39% (16/41) of patients. This study also replicated a number of findings from the previous paper supporting the idea that supersensitivity psychosis is one cause of relapse in psychosis. Discussion: These results suggested that clinicians should exercise caution in prescribing and may have to augment treatment with other agents or switch to low dopamine-affinity antipsychotics.