Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers.

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19-49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional processing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires further clarification, including with different doses of istradefylline and over different schedules of administration.

Stereotactic Radiofrequency Ablation for Treatment-Refractory Depression: A Systematic Review and Meta-Analysis.

(1) Background: Major depressive disorder (MDD) generates a large proportion of global disease burden. Stereotactic radiofrequency ablation (SRA) may be beneficial for selected patients with its most debilitating and refractory forms, but effect size is uncertain. (2) Methods: A systematic literature review and meta-analysis on SRA for MDD was carried out. Patient-level data were extracted from articles reporting validated depression measures (Beck Depression Inventory (BDI), Montgomery-Åsberg Depression Rating Scale (MADRS)), pre- and at least six months post surgery. To accommodate different outcome measures, the standardised mean difference (SMD) between both scores was used as the principal effect size. Data were synthesised using a random-effects model. (3) Results: Five distinct studies were identified, comprising 116 patients (64 included in meta-analysis). Effect size comparing post- vs. pre-operative scores was 1.66 (CI 1.25-2.07). Anterior cingulotomy (two studies, n = 22) and anterior capsulotomy (three studies, n = 42) showed similar effect sizes: 1.51 (CI 0.82-2.20) vs. 1.74 (CI 1.23-2.26). Multiple procedures were performed in 30 of 116 (25.9%) patients. Based on patient-level data, 53% (n = 47) were responders (≥50% improvement), of which 34% reached remission (MADRS ≤ 10 or BDI ≤ 11). BDI mean improvement was 16.7 (44.0%) after a second procedure (n = 19). (4) Conclusions: The results are supportive of the benefit of SRA in selected patients with refractory MDD.

Cortical dopamine reduces the impact of motivational biases governing automated behaviour.

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n = 35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomised, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans.

Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

Iatrogenic Complications of Compulsory Treatment in a Patient Presenting with an Emotionally Unstable Personality Disorder and Self-Harm.

Attempted suicide and deliberate self-harm are common and challenging presentations in the emergency department. A proportion of these patients refuse interventions and this presents the clinical, legal, and ethical dilemma as to whether treatment should be provided against their will. Multiple factors influence this decision. It is difficult to foresee the multitude and magnitude of complications that can arise once it has been decided to treat individuals who do not consent. This case illustrates a particularly complex chain of events that occurred after treating someone against their will who presented with self-harm and suicidal ideation. These consequences are contrasted with those of not intervening when similar situations arose with the same patient.

Simulating a Community Mental Health Service During the COVID-19 Pandemic: Effects of Clinician-Clinician Encounters, Clinician-Patient-Family Encounters, Symptom-Triggered Protective Behaviour, and Household Clustering.

Objectives: Face-to-face healthcare, including psychiatric provision, must continue despite reduced interpersonal contact during the COVID-19 (SARS-CoV-2 coronavirus) pandemic. Community-based services might use domiciliary visits, consultations in healthcare settings, or remote consultations. Services might also alter direct contact between clinicians. We examined the effects of appointment types and clinician-clinician encounters upon infection rates. Design: Computer simulation. Methods: We modelled a COVID-19-like disease in a hypothetical community healthcare team, their patients, and patients' household contacts (family). In one condition, clinicians met patients and briefly met family (e.g., home visit or collateral history). In another, patients attended alone (e.g., clinic visit), segregated from each other. In another, face-to-face contact was eliminated (e.g., videoconferencing). We also varied clinician-clinician contact; baseline and ongoing "external" infection rates; whether overt symptoms reduced transmission risk behaviourally (e.g., via personal protective equipment, PPE); and household clustering. Results: Service organisation had minimal effects on whole-population infection under our assumptions but materially affected clinician infection. Appointment type and inter-clinician contact had greater effects at low external infection rates and without a behavioural symptom response. Clustering magnified the effect of appointment type. We discuss infection control and other factors affecting appointment choice and team organisation. Conclusions: Distancing between clinicians can have significant effects on team infection. Loss of clinicians to infection likely has an adverse impact on care, not modelled here. Appointments must account for clinical necessity as well as infection control. Interventions to reduce transmission risk can synergize, arguing for maximal distancing and behavioural measures (e.g., PPE) consistent with safe care.

Serotonin depletion amplifies distinct human social emotions as a function of individual differences in personality.

Serotonin is involved in a wide range of mental capacities essential for navigating the social world, including emotion and impulse control. Much recent work on serotonin and social functioning has focused on decision-making. Here we investigated the influence of serotonin on human emotional reactions to social conflict. We used a novel computerised task that required mentally simulating social situations involving unjust harm and found that depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-enhanced emotional responses to the scenarios in a large sample of healthy volunteers (n = 73), and interacted with individual differences in trait personality to produce distinctive human emotions. Whereas guilt was preferentially elevated in highly empathic participants, annoyance was potentiated in those high in trait psychopathy, with medium to large effect sizes. Our findings show how individual differences in personality, when combined with fluctuations of serotonin, may produce diverse emotional phenotypes. This has implications for understanding vulnerability to psychopathology, determining who may be more sensitive to serotonin-modulating treatments, and casts new light on the functions of serotonin in emotional processing.

Effect of Tryptophan Depletion on Conditioned Threat Memory Expression: Role of Intolerance of Uncertainty.

BACKGROUND: Responding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occur in many psychiatric disorders, including posttraumatic stress disorder, obsessive-compulsive disorder, and schizophrenia, in which emotional responses can persist pathologically. While there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does lowering serotonin affect memory retention of conditioned threat and safety memory? METHODS: Forty-seven healthy participants underwent conditioning to two stimuli predictive of threat on day 1. One stimulus but not the other was subsequently presented in an extinction session. Emotional responding was assessed by the skin conductance response. On day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind, placebo-controlled, randomized between-groups design. We then tested for the retention of conditioned threat and extinction memory. We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression. RESULTS: The expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion. CONCLUSIONS: These results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.

Probabilistic reversal learning under acute tryptophan depletion in healthy humans: a conventional analysis.

The involvement of serotonin in responses to negative feedback is well established. Acute serotonin reuptake inhibition has enhanced sensitivity to negative feedback (SNF), modelled by behaviour in probabilistic reversal learning (PRL) paradigms. Whilst experiments employing acute tryptophan depletion (ATD) in humans, to reduce serotonin synthesis, have shown no clear effect on SNF, sample sizes have been small. We studied a large sample of healthy volunteers, male and female, and found ATD had no effect on core behavioural measures in PRL. These results indicate that ATD effects can differ from other manipulations of serotonin expected to have a parallel or opposing action.

Service user, patient, survivor or client has the time come to return to 'patient'?

Recently, the Council of the UK Royal College of Psychiatrists agreed to use the term 'patient' as the preferred collective noun when referring to people accessing mental health services in its official documentation. Choices regarding terminology have the power to influence those who use such terms and here, David Christmas and Angela Sweeney debate the issue of whether such a decision is appropriate or whether we need to be more careful about the terms we use.

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman's meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.

Individual oral symptoms in burning mouth syndrome may be associated differentially with depression and anxiety.

BACKGROUND: Burning mouth syndrome (BMS) is an idiopathic disease characterized by the feeling of burning in the oral cavity. Ten per cent of patients presenting to oral medicine clinics have BMS. Anxiety and depression are common co-morbidities in BMS, but it is not known if they are associated with specific BMS symptoms. OBJECTIVE: In an exploratory analysis, this study examined the association of generalized anxiety and depression with individual BMS symptoms. METHODS: Forty-one patients were recruited from a dental outpatient clinic (30 with BMS and 11 with other oral conditions), evaluating specific BMS symptoms and their intensity. Anxiety and depression symptoms were assessed using a standardized measure (Clinical Interview Schedule-Revised). RESULTS: Taste change (p = 0.007), fear of serious illness (p = 0.011), metallic taste (p = 0.018) and sensation of a film on the gums (p = 0.047) were associated with an excess of psychiatric symptoms. More specifically, metallic taste (coefficient = 0.497, 95% CI = 0.149-0.845; p = 0.006) and sensation of film on gums (coefficient = 0.625, 95% CI = 0.148-1.103; p = 0.012) were associated significantly with higher scores for depressive symptoms; taste change (coefficient = 0.269, 95% CI = 0.077-0.461; p = 0.007), bad breath (coefficient = 0.273, 95% CI = 0.065-0.482; p = 0.012) and fear of serious illness (coefficient = 0.242, 95% CI = 0.036-0.448; p = 0.023) were associated with higher anxiety scores. CONCLUSION: Specific BMS symptoms are associated differentially with generalized anxiety and depression. Dental practitioners should ascertain which BMS symptoms are predominant and be mindful of the association of certain symptoms with anxiety or depression and, where necessary, consider medical consultation.

Neurosurgical Treatments for Patients with Chronic, Treatment-Refractory Depression: A Retrospective, Consecutive, Case Series Comparison of Anterior Capsulotomy, Anterior Cingulotomy and Vagus Nerve Stimulation.

BACKGROUND: The evidence base to guide therapeutic choices for patients with chronic and treatment-refractory depression (TRD) remains weak. There is limited comparative information available to guide the choice of intervention for patients with the most severe and disabling forms of illness. OBJECTIVES: The aim of this work was to describe the 12-month clinical outcomes of patients with chronic TRD treated with anterior capsulotomy (ACAPS; n = 5), anterior cingulotomy (ACING; n = 5) or vagus nerve stimulation (VNS; n = 5). METHODS: We performed a retrospective, consecutive, case series comparison. RESULTS: With clinical response defined as a ≥50% reduction from the baseline MADRS score, response rates were 40% for ACAPS, 60% for ACING and 20% for VNS. Adverse effects from all three procedures were relatively mild, consistent with previous reports and, in most cases, transient. Adverse effects from VNS were related to active stimulation, and were modifiable and diminished in severity over time. There were no deaths. CONCLUSIONS: Although based on a small sample, our data represent a unique comparison of ACAPS, ACING and VNS for chronic TRD. The three cohorts were broadly equivalent in terms of baseline clinical characteristics, indices of chronicity, illness severity and estimates of previous failed treatments. ACING and ACAPS, but not VNS, were associated with favourable response rates at 12 months.

Failure of hippocampal deactivation during loss events in treatment-resistant depression.

Major depressive disorder is characterized by anhedonia, cognitive biases, ruminations, hopelessness and increased anxiety. Blunted responses to rewards have been reported in a number of recent neuroimaging and behavioural studies of major depressive disorder. In contrast, neural responses to aversive events remain an under-studied area. While selective serotonergic reuptake inhibitors are often effective in treating major depressive disorder, their mechanism of action remains unclear. Following a series of animal model investigations of depressive illness and serotonergic function, Deakin and Graeff predicted that brain activity in patients with major depressive disorder is associated with an overactive dorsal raphe nucleus with overactive projections to the amygdala, periaqueductal grey and striatum, and an underactive median raphe nucleus with underactive projections to the hippocampus. Here we describe an instrumental loss-avoidance and win-gain reinforcement learning functional magnetic resonance imaging study with 40 patients with highly treatment-resistant major depressive disorder and never-depressed controls. The dorsal raphe nucleus/ periaqueductal grey region of the midbrain and hippocampus were found to be overactive in major depressive disorder during unsuccessful loss-avoidance although the median raphe nucleus was not found to be underactive. Hippocampal overactivity was due to a failure to deactivate during loss events in comparison to controls, and hippocampal over-activity correlated with depression severity, self-report 'hopelessness' and anxiety. Deakin and Graeff argued that the median raphe nucleus normally acts to inhibit consolidation of aversive memories via the hippocampus and this system is underactive in major depressive disorder, facilitating the development of ruminations, while the dorsal raphe nucleus system is engaged by distal cues predictive of threats and is overactive in major depressive disorder. During win events the striatum was underactive in major depressive disorder. We tested individual patient consistency of these findings using within-study replication. Abnormal hippocampal activity correctly predicted individual patient diagnostic status in 97% (sensitivity 95%, specificity 100%) of subjects, and abnormal striatal activity predicted diagnostic status in 84% (sensitivity 79%, specificity 89%) of subjects. We conclude that the neuroimaging findings were largely consistent with Deaken and Graeff's predictions, abnormally increased hippocampal activity during loss events was an especially consistent abnormality, and brainstem serotonergic nuclei merit further study in depressive illness.

Structural MRI-Based Predictions in Patients with Treatment-Refractory Depression (TRD).

The application of machine learning techniques to psychiatric neuroimaging offers the possibility to identify robust, reliable and objective disease biomarkers both within and between contemporary syndromal diagnoses that could guide routine clinical practice. The use of quantitative methods to identify psychiatric biomarkers is consequently important, particularly with a view to making predictions relevant to individual patients, rather than at a group-level. Here, we describe predictions of treatment-refractory depression (TRD) diagnosis using structural T1-weighted brain scans obtained from twenty adult participants with TRD and 21 never depressed controls. We report 85% accuracy of individual subject diagnostic prediction. Using an automated feature selection method, the major brain regions supporting this significant classification were in the caudate, insula, habenula and periventricular grey matter. It was not, however, possible to predict the degree of 'treatment resistance' in individual patients, at least as quantified by the Massachusetts General Hospital (MGH-S) clinical staging method; but the insula was again identified as a region of interest. Structural brain imaging data alone can be used to predict diagnostic status, but not MGH-S staging, with a high degree of accuracy in patients with TRD.

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology.

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers.

OBJECTIVE: Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. METHODS: A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. RESULTS: There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. CONCLUSIONS: A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits.

Cognitive Behavioural Analysis System of Psychotherapy (CBASP) for chronic depression: clinical characteristics and six month clinical outcomes in an open case series.

BACKGROUND: Evidence-based guidance on how best to treat chronic depression is limited. Cognitive Behavioural Analysis System of Psychotherapy (CBASP) has shown some promise with this 'difficult-to-treat' clinical group. This case series was designed to assess the acceptability and utility of this novel treatment in routine clinical practice within the U.K. National Health Service. METHODS: We offered an open trial of CBASP to a cohort of 115 referred patients within primary and secondary care. Diagnostic interview and standardised outcome measures were administered before and after 6 months of CBASP with a trained, accredited therapist. RESULTS: Seventy-four patients entered therapy, with 46 completing. 30% met criteria for remission (≤ 8 HRSD-24 score) and a further 30% met criteria for clinically significant change (> 8 and ≤15 HRSD-24 plus 50% reduction in baseline score). Thirty-nine per cent made "No change". Group measures of quality of life, social functioning and interpersonal functioning also improved. LIMITATIONS: This was an open study design with a moderate sample size and no control group. Ratings were not completed using a blinded procedure. CONCLUSIONS: CBASP is an acceptable therapy for a large proportion of patients with chronic depression and was associated with clinically significant change in 60% of completers.

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients.

BACKGROUND: There are limited treatment options for patients with chronic, treatment-refractory major depression who do not respond to routinely-available treatments. Vagus Nerve Stimulation (VNS) may represent an alternative to ablative neurosurgery for a specific group of patients. METHODS: 12-month response rates for 28 patients with chronic (≥2 years) major depression who had failed to respond to ≥4 adequate treatment trials in the D03 European open clinical trial of VNS were described along with response rates for 13 consecutive patients who underwent VNS within the neurosurgical treatment programme in Dundee. RESULTS: In the D03 cohort (N=28), the response rate at 12 months (defined as a 50% reduction in symptom score) was 35.7%. In the Dundee VNS case series (N=13), the equivalent response rate was 30.8%. LIMITATIONS: These data are from unblinded and open studies, and there is no control group. Other factors may have contributed to some of the improvement seen, although this is unlikely in very chronic populations. Outcomes are not reported beyond 12 months. CONCLUSION: Response rates at 12 months for patients with chronic and highly-refractory major depression are broadly consistent with previously published results in more heterogeneous and less refractory clinical trial populations. In highly treatment-resistant patients, the rate of response with VNS at 12 m is at least twice that anticipated with 'treatment-as-usual'.