Refining our understanding of depressive states and state transitions in response to cognitive behavioural therapy using latent Markov modelling.

BACKGROUND: It is increasingly recognized that existing diagnostic approaches do not capture the underlying heterogeneity and complexity of psychiatric disorders such as depression. This study uses a data-driven approach to define fluid depressive states and explore how patients transition between these states in response to cognitive behavioural therapy (CBT). METHODS: Item-level Patient Health Questionnaire (PHQ-9) data were collected from 9891 patients with a diagnosis of depression, at each CBT treatment session. Latent Markov modelling was used on these data to define depressive states and explore transition probabilities between states. Clinical outcomes and patient demographics were compared between patients starting at different depressive states. RESULTS: A model with seven depressive states emerged as the best compromise between optimal fit and interpretability. States loading preferentially on cognitive/affective v. somatic symptoms of depression were identified. Analysis of transition probabilities revealed that patients in cognitive/affective states do not typically transition towards somatic states and vice-versa. Post-hoc analyses also showed that patients who start in a somatic depressive state are less likely to engage with or improve with therapy. These patients are also more likely to be female, suffer from a comorbid long-term physical condition and be taking psychotropic medication. CONCLUSIONS: This study presents a novel approach for depression sub-typing, defining fluid depressive states and exploring transitions between states in response to CBT. Understanding how different symptom profiles respond to therapy will inform the development and delivery of stratified treatment protocols, improving clinical outcomes and cost-effectiveness of psychological therapies for patients with depression.

Quantifying the Association Between Psychotherapy Content and Clinical Outcomes Using Deep Learning.

Importance: Compared with the treatment of physical conditions, the quality of care of mental health disorders remains poor and the rate of improvement in treatment is slow, a primary reason being the lack of objective and systematic methods for measuring the delivery of psychotherapy. Objective: To use a deep learning model applied to a large-scale clinical data set of cognitive behavioral therapy (CBT) session transcripts to generate a quantifiable measure of treatment delivered and to determine the association between the quantity of each aspect of therapy delivered and clinical outcomes. Design, Setting, and Participants: All data were obtained from patients receiving internet-enabled CBT for the treatment of a mental health disorder between June 2012 and March 2018 in England. Cognitive behavioral therapy was delivered in a secure online therapy room via instant synchronous messaging. The initial sample comprised a total of 17 572 patients (90 934 therapy session transcripts). Patients self-referred or were referred by a primary health care worker directly to the service. Exposures: All patients received National Institute for Heath and Care Excellence-approved disorder-specific CBT treatment protocols delivered by a qualified CBT therapist. Main Outcomes and Measures: Clinical outcomes were measured in terms of reliable improvement in patient symptoms and treatment engagement. Reliable improvement was calculated based on 2 severity measures: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder 7-item scale (GAD-7), corresponding to depressive and anxiety symptoms respectively, completed by the patient at initial assessment and before every therapy session (see eMethods in the Supplement for details). Results: Treatment sessions from a total of 14 899 patients (10 882 women) aged between 18 and 94 years (median age, 34.8 years) were included in the final analysis. We trained a deep learning model to automatically categorize therapist utterances into 1 or more of 24 feature categories. The trained model was applied to our data set to obtain quantifiable measures of each feature of treatment delivered. A logistic regression revealed that increased quantities of a number of session features, including change methods (cognitive and behavioral techniques used in CBT), were associated with greater odds of reliable improvement in patient symptoms (odds ratio, 1.11; 95% CI, 1.06-1.17) and patient engagement (odds ratio, 1.20, 95% CI, 1.12-1.27). The quantity of nontherapy-related content was associated with reduced odds of symptom improvement (odds ratio, 0.89; 95% CI, 0.85-0.92) and patient engagement (odds ratio, 0.88, 95% CI, 0.84-0.92). Conclusions and Relevance: This work demonstrates an association between clinical outcomes in psychotherapy and the content of therapist utterances. These findings support the principle that CBT change methods help produce improvements in patients' presenting symptoms. The application of deep learning to large clinical data sets can provide valuable insights into psychotherapy, informing the development of new treatments and helping standardize clinical practice.

Demographic and clinical predictors of response to internet-enabled cognitive-behavioural therapy for depression and anxiety.

BACKGROUND: Common mental health problems affect a quarter of the population. Online cognitive-behavioural therapy (CBT) is increasingly used, but the factors modulating response to this treatment modality remain unclear. AIMS: This study aims to explore the demographic and clinical predictors of response to one-to-one CBT delivered via the internet. METHOD: Real-world clinical outcomes data were collected from 2211 NHS England patients completing a course of CBT delivered by a trained clinician via the internet. Logistic regression analyses were performed using patient and service variables to identify significant predictors of response to treatment. RESULTS: Multiple patient variables were significantly associated with positive response to treatment including older age, absence of long-term physical comorbidities and lower symptom severity at start of treatment. Service variables associated with positive response to treatment included shorter waiting times for initial assessment and longer treatment durations in terms of the number of sessions. CONCLUSIONS: Knowledge of which patient and service variables are associated with good clinical outcomes can be used to develop personalised treatment programmes, as part of a quality improvement cycle aiming to drive up standards in mental healthcare. This study exemplifies translational research put into practice and deployed at scale in the National Health Service, demonstrating the value of technology-enabled treatment delivery not only in facilitating access to care, but in enabling accelerated data capture for clinical research purposes. DECLARATION OF INTEREST: A.C., S.B., V.T., K.I., S.F., A.R., A.H. and A.D.B. are employees or board members of the sponsor. S.R.C. consults for Cambridge Cognition and Shire. Keywords: Anxiety disorders; cognitive behavioural therapies; depressive disorders; individual psychotherapy.

Memory Correlates of Alzheimer's Disease Cerebrospinal Fluid Markers: A Longitudinal Cohort Study.

BACKGROUND: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression. OBJECTIVE: To examine the association between amyloid-ß 1-42 (Aß42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline. METHODS: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aß42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline. RESULTS: At baseline, decreased CSF Aß42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aß42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis. CONCLUSION: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.

Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a 'cost' of set-shifting - the ED stage was completed in fewer trials than the ID stage - and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

The Paired Associates Learning (PAL) Test: 30 Years of CANTAB Translational Neuroscience from Laboratory to Bedside in Dementia Research.

The origins and rationale of the Cambridge Neuropsychological Test Automated Battery (CANTAB) as a cross-species translational instrument suitable for use in human neuropsychopharmacological studies are reviewed. We focus on its use for the early assessment and detection of Alzheimer's disease, in particular the Paired Associates Learning (PAL) test. We consider its psychometric properties, neural validation, and utility, including studies on large samples of healthy volunteers, patients with mild cognitive impairment (MCI), and Alzheimer's disease. We demonstrate how it can be applied in cross-species studies using experimental animals to bridge the cross-species translational 'gap'. We also show how the CANTAB PAL has bridged a second translational 'gap' through its application to the early detection of memory problems in primary care clinics, using iPad technology.

Assessment of cognitive safety in clinical drug development.

Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks.

Early intervention in Alzheimer's disease: a health economic study of the effects of diagnostic timing.

BACKGROUND: Intervention and treatment in Alzheimer's disease dementia (AD-dementia) can be cost effective but the majority of patients are not diagnosed in a timely manner. Technology is now available that can enable the earlier detection of cognitive loss associated with incipient dementia, offering the potential for earlier intervention in the UK health care system. This study aimed to determine to what extent the timing of an intervention affects its cost-effectiveness. METHODS: Using published data describing cognitive decline in the years prior to an AD diagnosis, we modelled the effects on healthcare costs and quality-adjusted life years of hypothetical symptomatic and disease-modifying interventions. Early and standard interventions were assumed to have equal clinical effects, but the early intervention could be applied up to eight years prior to standard diagnosis. RESULTS: A symptomatic treatment which immediately improved cognition by one MMSE point and reduced in efficacy over three years, would produce a maximum net benefit when applied at the earliest timepoint considered, i.e. eight years prior to standard diagnosis. In this scenario, the net benefit was reduced by around 17% for every year that intervention was delayed. In contrast, for a disease-modifying intervention which halted cognitive decline for one year, economic benefits would peak when treatment effects were applied two years prior to standard diagnosis. In these models, the maximum net benefit of the disease modifying intervention was fifteen times larger than that of the symptomatic treatment. CONCLUSION: Timeliness of intervention is likely to have an important impact on the cost-effectiveness of both current and future treatments. Healthcare policy should aim to optimise the timing of AD-dementia diagnosis, which is likely to necessitate detecting and treating patients several years prior to current clinical practice.

Cognitive health begins at conception: addressing dementia as a lifelong and preventable condition.

BACKGROUND: Dementia is a major public health problem that poses an increasing burden on the health and wealth of societies worldwide. Because the efficacy of current treatments is limited, increasing efforts are required to prevent the diseases that cause dementia. DISCUSSION: We consider the evidence that lifelong prevention strategies may be an effective way to tackle the national burden of dementia in the absence of a cure. The links between lifestyle and cardiovascular disease are widely understood and accepted, but health professionals and patients remain unconvinced about the extent to which risk for dementia can be modified. However, there is strong evidence that at least half of risk for dementia is attributable to lifestyle factors such as diet, exercise and smoking. Moreover, the disease processes that result in dementia develop over several decades, implying that attempts to ameliorate them need to start early in life. Some modifiable risk factors for dementia act from the earliest stages of life, including in utero. SUMMARY: Rebalancing efforts from the development of treatments to increased emphasis on prevention may be an alternative means to reducing the impact of dementia on society.

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

BACKGROUND/AIMS: AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. METHODS: A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. RESULTS: AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. CONCLUSION: These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease.

Differential cognitive deterioration in dementia: a two year longitudinal study.

The ability to predict cognitive deterioration in patients with dementia holds valuable potential for clinical trials and early intervention. This study identified cognitive domains deteriorating differentially over time as well as baseline predictors of subsequent cognitive decline in patients referred to a memory clinic. Twenty-six subjects with Alzheimer's disease (AD) and 43 subjects with Subjective Memory Impairment (SMI) were entered into a longitudinal study in which cognitive function was assessed at baseline and at 8-monthly intervals for 2 years, using a range of well-validated measures. Thirty-seven patients with depression and 39 healthy controls were also longitudinally assessed. AD was associated with disproportionate deterioration over time on general measures of cognitive function, multiple measures of mnemonic processing, mental fluency (letter and category), and aspects of motor speed. SMI showed restricted relative cognitive deterioration on general measures of cognitive function, on a subset of memory measures, and on letter but not category fluency. Secondary analysis showed that earliest detectable ADAS-cog and MMSE decline in AD was at 16 months, while several specific neuropsychological indices were sensitive as early as 8 months (graded naming test, semantic naming, and the category/letter fluency tests). In combination, baseline/early changes in cognitive performance, alongside clinical measures, predicted 48% of disease progression over two years in memory impaired patients as a whole. These findings have implications for identifying patients likely to benefit from disease modifying agents, and for designing, powering, enriching, and implementing future clinical trials. Follow-up studies in independent populations are needed to validate predictive algorithms identified.

Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent condition associated with cognitive dysfunction. The Cambridge Neuropsychological Test Automated Battery is a computerized set of tests that has been widely used in ADHD and in translation/back-translation. Following a survey of translational research relevant to ADHD in experimental animals, a comprehensive literature review was conducted of studies that had used core Cambridge Neuropsychological Test Automated Battery tests 1) to evaluate cognitive dysfunction in ADHD and 2) to evaluate effects of salient drugs in patients and in volunteers. Meta-analysis was conducted where four or more independent datasets were available. Meta-analysis revealed medium-large decrements in ADHD for response inhibition (d = .790, p < .001), working memory (d = .883, p < .001), executive planning (d = .491, p < .001), and a small decrement in attentional set shifting (d = .160, p = .040). Qualitative review of the literature showed some consistent patterns. In ADHD, methylphenidate improved working memory, modafinil improved planning, and methylphenidate, modafinil, and atomoxetine improved inhibition. Meta-analysis of modafinil healthy volunteer studies showed no effects on sustained attention or set shifting. Results were paralleled by findings in experimental animals on comparable tests, enabling further analysis of drug mechanisms. Substantial cognitive deficits are present in ADHD, which can be remediated somewhat with current medications and which can readily be modeled in experimental animals using back-translational methodology. The findings suggest overlapping but also distinct early cognitive effects of ADHD medications and have important implications for understanding the pathophysiology of ADHD and for future trials.

European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline.

BACKGROUND: Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimer's disease. Higher DHA intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in age-related cognitive decline (ARCD) have not been fully examined. OBJECTIVE: Determine effects of DHA administration on improving cognitive functions in healthy older adults with ARCD. METHODS: Randomized, double-blind, placebo-controlled, clinical study was conducted at 19 U.S. clinical sites. A total of 485 healthy subjects, aged ≥55 with Mini-Mental State Examination >26 and a Logical Memory (Wechsler Memory Scale III) baseline score ≥1 standard deviation below younger adults, were randomly assigned to 900 mg/d of DHA orally or matching placebo for 24 weeks. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. RESULTS: Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, -1.63 ± 0.76 [-3.1, -0.14, 95% CI], P = .03). DHA supplementation was also associated with improved immediate and delayed Verbal Recognition Memory scores (P < .02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores (P < .02) in the DHA group. DHA was well tolerated with no reported treatment-related serious adverse events. CONCLUSIONS: Twenty-four week supplementation with 900 mg/d DHA improved learning and memory function in ARCD and is a beneficial supplement that supports cognitive health with aging. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT0027813.

Assessing cognitive function in clinical trials of schizophrenia.

Cognitive dysfunction in schizophrenia is an important target for novel therapies. Effectively measuring the cognitive effects of compounds in clinical trials of schizophrenia could be a major barrier to drug development. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) programme produced a consensus cognitive battery which is now widely used, however alternative assessments have advantages and disadvantages when compared with MATRICS. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computerised assessment developed from animal behaviour paradigms and human neuropsychology. We review the utility of CANTAB according to MATRICS and CNTRICS recommendations. CANTAB tests have been used in more than 60 studies of psychotic disorders. Their neural bases are well understood through patient and neuroimaging studies and directly equivalent tests in rodents and non-human primates. The tests' sensitivity to pharmacological manipulation is well established. Future studies should collect more data regarding psychometric properties in patients over short time periods, and should continue to study the tests' relationships to functional outcomes. Computerised cognitive assessment may optimise the statistical power of cognitive trials by reducing measurement error and between-site variability and decreasing patient attrition through increased tolerability.

Early risk assessment for Alzheimer's disease.

The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Methylphenidate improves response inhibition but not reflection-impulsivity in children with attention deficit hyperactivity disorder (ADHD).

RATIONALE: Impulsivity is a cardinal feature of attention deficit hyperactivity disorder (ADHD), which is thought to underlie many of the cognitive and behavioural symptoms associated with the disorder. Impairments on some measures of impulsivity have been shown to be responsive to pharmacotherapy. However, impulsivity is a multi-factorial construct and the degree to which different forms of impulsivity contribute to impairments in ADHD or respond to pharmacological treatments remains unclear. OBJECTIVES: The aims of the study were to assess the effects of methylphenidate (MPH) on the performance of children with ADHD on measures of reflection-impulsivity and response inhibition and to compare with the performance of healthy volunteers. METHODS: Twenty-one boys (aged 7-13 years) diagnosed with ADHD underwent a double-blind, placebo-controlled trial of MPH (0.5 mg/kg) during which they performed the Information Sampling Task (IST) and the Stop Signal Task. A healthy age- and education-matched control group was tested on the same measures without medication. RESULTS: Children with ADHD were impaired on measures of response inhibition, but did not demonstrate reflection-impulsivity on the IST. However, despite sampling a similar amount of information as their peers, the ADHD group made more poor decisions. MPH improved performance on measures of response inhibition and variability of response, but did not affect measures of reflection-impulsivity or quality of decision-making. CONCLUSIONS: MPH differentially affected two forms of impulsivity in children with ADHD and failed to ameliorate their poor decision-making on the information sampling test.

The effects of modafinil on mood and cognition in Huntington's disease.

RATIONALE: The wake-promoting agent modafinil selectively improves neuropsychological task performance in healthy volunteers, in adults with attention deficit hyperactivity disorder (ADHD) and in schizophrenia. We examined whether modafinil induced similar effects in individuals with Huntington's disease (HD). MATERIALS AND METHODS: Twenty patients with genetically proven, mild HD participated in a double-blind, randomised, placebo-controlled cross-over study using a single 200 mg dose of modafinil. Patients undertook a battery of neuropsychological tests including measures of cognition and mood. RESULTS: Modafinil increased alertness as indexed by visual analogue scales. Modafinil did not elicit any significant improvements in cognitive function or mood. Modafinil had a deleterious effect on visual recognition and working memory. CONCLUSIONS: Two hundred milligrams acute modafinil administration did improve alertness but did not improve cognition or mood in patients with mild HD. A multiple dose, chronic administration study is needed before the potential clinical utility of modafinil in HD is discounted.

The effects of methylphenidate on decision making in attention-deficit/hyperactivity disorder.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) frequently display poor judgment and risk taking in their everyday behavior, but there are little empirical data on decision-making cognition in this disorder. The objectives of the study were to assess the effects of stimulant medication on decision making in ADHD and compare performance on the Cambridge Gamble Task between boys with and without ADHD. METHODS: Twenty-one boys (aged 7-13) diagnosed with ADHD underwent a double-blind, placebo-controlled trial of methylphenidate (.5 mg/kg) during which they performed the Cambridge Gamble Task (CGT). A healthy age-matched control group was tested on two occasions off drug. RESULTS: The ADHD group bet more conservatively on the methylphenidate session than on the placebo session. In comparison with healthy control subjects, the ADHD group made more poor decisions, placed their bets more impulsively, and adjusted their bets less according to the chances of winning. Poor decision making was correlated with parent-reported symptoms and disruptive behavior in the ADHD group. CONCLUSIONS: Methylphenidate reduced risk-prone betting behavior on the CGT. Compared with control subjects, children with ADHD display a number of decision-making deficits on the task, and the measure of rational decision making may serve as an ecologically valid neuropsychological marker of impairment.

Incentive motivation in first-episode psychosis: a behavioural study.

BACKGROUND: It has been proposed that there are abnormalities in incentive motivational processing in psychosis, possibly secondary to subcortical dopamine abnormalities, but few empirical studies have addressed this issue. METHODS: We studied incentive motivation in 18 first-episode psychosis patients from the Cambridge early psychosis service CAMEO and 19 control participants using the Cued Reinforcement Reaction Time Task, which measures motivationally driven behaviour. We also gathered information on participants' attentional, executive and spatial working memory function in order to determine whether any incentive motivation deficits were secondary to generalised cognitive impairment. RESULTS: We demonstrated the anticipated "reinforcement-related speeding" effect in controls (17 out of 19 control participants responded faster during an "odd-one-out" task in response to a cue that indicated a high likelihood of a large points reward). Only 4 out of 18 patients showed this effect and there was a significant interaction effect between reinforcement probability and diagnosis on reaction time (F1,35 = 14.2, p = 0.001). This deficit was present in spite of preserved executive and attentional function in patients, and persisted even in antipsychotic medication free patients. CONCLUSION: There are incentive motivation processing abnormalities in first-episode psychosis; these may be secondary to dopamine dysfunction and are not attributable to generalised cognitive impairment.