Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the 'responsivity' of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E-I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal 'Inhibitory Index'-the GABA fraction within the pool of glutamate plus GABA metabolites-post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E-I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E-I flux can be 'shifted' with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be 'normalised' by targeting E-I, even in adults.

Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire.

BACKGROUND: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear. METHOD: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments. RESULTS: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were 'false negatives' who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may 'mimic' ASD and inflate AQ scores, leading to false positives. CONCLUSIONS: The AQ's utility for screening referrals was limited in this sample. Recommendations supporting the AQ's role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.

Is there an excess of significant findings in published studies of psychotherapy for depression?

BACKGROUND: Many studies have examined the efficacy of psychotherapy for major depressive disorder (MDD) but publication bias against null results may exist in this literature. However, to date, the presence of an excess of significant findings in this literature has not been explicitly tested. METHOD: We used a database of 1344 articles on the psychological treatment of depression, identified through systematic search in PubMed, PsycINFO, EMBASE and the Cochrane database of randomized trials. From these we identified 149 studies eligible for inclusion that provided 212 comparisons. We tested for an excess of significant findings using the method developed by Ioannidis and Trikalinos (2007), and compared the distribution of p values in this literature with the distribution in the antidepressant literature, where publication bias is known to be operating. RESULTS: The average statistical power to detect the effect size indicated by the meta-analysis was 49%. A total of 123 comparisons (58%) reported a statistically significant difference between treatment and control groups, but on the basis of the average power observed, we would only have expected 104 (i.e. 49%) to do so. There was therefore evidence of an excess of significance in this literature (p = 0.010). Similar results were obtained when these analyses were restricted to studies including a cognitive behavioural therapy (CBT) arm. Finally, the distribution of p values for psychotherapy studies resembled that for published antidepressant studies, where publication bias against null results has already been established. CONCLUSIONS: The small average size of individual psychotherapy studies is only sufficient to detect large effects. Our results indicate an excess of significant findings relative to what would be expected, given the average statistical power of studies of psychotherapy for major depression.

Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.

There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD-the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)-and one 'control' region-the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal 'control' region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate-glutamine levels are not explained by use of stimulant medication.

Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [¹H]MRS study.

Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the 'narrowly' defined criteria for typical autism, whereas 13 met the 'broader phenotype'. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD--the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex--as well as in a parietal cortex 'control' region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the 'narrow' and 'broader' phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development.

Early effects of mirtazapine on emotional processing.

BACKGROUND: Acute administration of selective serotonin and noradrenaline re-uptake blockers to healthy volunteers affects the processing of emotional information but it is not known if similar effects occur with antidepressants acting through other pharmacological mechanisms. Mirtazapine is a clinically established antidepressant with complex actions involving blockade of noradrenaline alpha(2)-adrenoceptors as well as a number of 5-HT receptor subtypes. The aim of the present study was to test whether, like monoamine re-uptake inhibitors, mirtazapine would also produce positive biases in emotional processing. METHODS: We studied 30 healthy volunteers who received either a single dose of mirtazapine (15 mg) or placebo in a parallel group, double-blind study. Two hours following medication administration, participants completed a battery of tasks testing various aspects of emotional processing including facial expression recognition, emotion potentiated startle, and emotional categorization and memory. RESULTS: Compared to placebo, mirtazapine significantly impaired the recognition of fearful facial expressions and reduced eye-blink responses in the emotion potentiated startle task. Participants receiving mirtazapine were also significantly quicker to respond to emotional self-relevant information in the categorization task and showed a positive bias in memory recall compared to those receiving placebo. CONCLUSIONS: Our findings indicate that mirtazapine reduces fear processing in healthy volunteers, an effect similar to that produced by repeated administration of selective serotonin re-uptake inhibitors. In addition, mirtazapine increased memory for likeable versus dislikeable self-relevant information suggesting an induction of positive bias in emotional memory. Such effects may be important for our understanding of the neuropsychological mechanisms of antidepressant action in both anxiety and depressive disorders.

Randomised controlled assessment of non-directive psychotherapy versus routine general-practitioner care.

BACKGROUND: We compared the efficacy of and patients' satisfaction with general-practice-based psychotherapists with those of general practitioners in providing treatment to people with emotional difficulties. METHODS: We carried out a prospective, randomised, controlled trial of brief, non-directive psychotherapy and routine general-practice care. Therapists adhered to a non-directive Rogerian model of psychotherapy. Between one and 12 sessions of psychotherapy were given over 12 weeks in 14 general practices in north London, UK. Of 136 patients with emotional difficulties, mainly depression, 70 patients were randomly assigned to the therapist and 66 to the general practitioner. Depression, anxiety, other mental-disorder symptoms, and social adjustment were measured by self-report at baseline, 3 months, and 9 months. Patients' satisfaction was also measured by self-report at 3 and 9 months. FINDINGS: All patients improved significantly over time. There were no significant differences between the groups receiving brief psychotherapy and routine general-practitioner care. Patients assigned brief psychotherapy were more satisfied with the help they received than those assigned to the general practitioner at both 3 and 9 months' follow-up (mean scores on satisfaction scale 50.9 [SD 7.9] vs 44.4 [9.8] and 45.6 [9.4] vs 37.1 [11.2], respectively). INTERPRETATION: General-practitioner care is as effective as brief psychotherapy for patients usually referred by doctors to practice-based psychotherapists. Patients with emotional difficulties prefer brief psychotherapy from a counsellor to care from their general practitioner.

Controlled trials in the evaluation of counselling in general practice.

In this paper the difficulties of conducting a controlled evaluation of counselling (brief psychotherapy) in general practice are discussed. Results of a pilot study indicate that patients referred by family doctors to counsellors are often seriously emotionally distressed and recovery is slow. Counsellors come from different backgrounds and use a variety of therapies. Although the results show that controlled research is feasible, in a definitive trial patients should be randomized in a stratified manner, according to severity, by the researcher after initial assessments have been made. Counsellors should have a recognized accreditation and preferably be employed for the trial to ensure uniformity of approach and avoid long waiting lists. Blind assessments of outcome are desirable but are not always feasible and reliance on patient self-report is important. Within the limitations of current knowledge, only controlled evaluations will provide a greater understanding of the efficacy of counselling in general practice.

Factors influencing the communication skills of first-year clinical medical students.

The aim of this study was to examine the factors influencing medical students' communication skills. The sample comprised all first-year clinical students. Thirty-two received teaching in communication skills during the year; the remaining 56 did not. Students' career preferences, attitudes towards communication skills and confidence in their ability to communicate with patients were assessed by questionnaire at the beginning and end of the year. At the end of the year each student was videotaped interviewing a simulated patient. Students' communication skills were assessed on the basis of this interview by raters using a standardized rating scale, and by patient questionnaires. While there was some evidence that brief communication skills training improved skills, sex of student was a more significant predictor of level of skill. Students who perceived communication skills as less relevant to medicine and those who were more confident about their own communication skills were more likely to prefer a career in hospital medicine. Students' judgements of their ability to communicate effectively were poor. In the main there was no relationship between confidence and level of skill: where they were related, the association was negative. The benefits from communication skills training might be enhanced by involving hospital doctors in the teaching, and providing students with detailed video feedback on their skills at the outset.