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.

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.

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.

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 biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase.

This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway.

Cyproterone to treat aggressivity in dementia: a clinical case and systematic review.

Aggressivity is a common problem in the management of elderly patients with dementia. Medications currently used to diminish aggressive behaviour in dementia can have problematic side effects. We present a case and systematic review of the current knowledge about the use of cyproterone acetate to treat aggressivity (excluding hypersexuality related behaviours) in dementia. An 82-year-old man required psychiatric inpatient admission due to agitation and aggressivity and was diagnosed with Alzheimer's disease. After failed trials of atypical antipsychotics (quetiapine 100 mg/day and risperidone 1 mg/day), drugs for dementia (memantine 20 mg/day and rivastigmine 9 mg/day) and benzodiazepines (lorazepam 0.5-1 mg prn) he was started on cyproterone acetate titrated up to 50 mg twice daily. After two weeks he was calmer and did not express aggressivity. Two months later he was discharged to a community placement where he subsequently remained settled on cyproterone. We reviewed literature on the use of cyproterone in aggressivity (excluding hypersexuality) associated with dementia. We searched the main medical databases including articles in English, Spanish, French and Italian. Only one randomized double-blind trial was found, comparing cyproterone with haloperidol (n = 27). Cyproterone was more effective controlling aggressivity and had lower incidence of side effects. In the one uncontrolled naturalistic observational study identified (n = 19), cyproterone was associated with significant reductions in aggressivity without causing major side effects. Further literature was limited to theoretical discussions. Despite there being evidence to support our observations of a useful role for cyproterone in aggressivity in dementia, further studies are needed to establish the efficacy and safety of this therapeutic option.

Increased serum free tryptophan in patients with diarrhea-predominant irritable bowel syndrome.

Irregularities of serotonin function in irritable bowel syndrome (IBS) may be due to changes in the metabolism of the serotonin precursor l-tryptophan. Dietary alteration of tryptophan intake may impact upon the mood and bowel symptoms of IBS. We hypothesized that diarrhea-predominant irritable bowel syndrome (d-IBS) patients would exhibit an increase in plasma tryptophan due to alterations in tryptophan metabolism. We also hypothesized that a diet low in tryptophan would reverse this change and reduce symptoms. Thirteen patients with d-IBS had fasting serum free and total tryptophan, large neutral amino acids, and 6 kynurenine metabolites measured before and after 2 weeks of a strict dairy-free diet. Baseline tryptophan parameters were compared with an age- and sex-matched control group. Changes in the specific tryptophan parameters before and after dairy-free diet were correlated with symptoms of IBS and mood. Compared with the control group, d-IBS patients at baseline exhibited significantly higher free serum tryptophan (10.5 ± 4.35 vs 4.75 ± 2.43 µmol/L [means ± standard deviation], P = .006) and significantly lower tryptophan dioxygenase and total tryptophan oxidation as measured by the kynurenine to free tryptophan and total kynurenines to free tryptophan ratios (23.37 ± 10.12 vs 55.33 ± 16.02, P < .001 and 49.34 ± 17.84 vs 258.46 ± 98.67, P < .001, respectively). Dairy-free diet did not modulate metabolites of the kynurenine pathway or symptoms. Tryptophan metabolism along the kynurenine pathway is inhibited in d-IBS, and a dairy-free diet does not alter this. Our findings are consistent with possible enhanced serotonin activity in d-IBS.

Equivalent effects of acute tryptophan depletion on REM sleep in ecstasy users and controls.

INTRODUCTION: This study sought to test the association between 3,4-methylenedioxymethamphetamine use, serotonergic function and sleep. MATERIALS AND METHODS: Ambulatory polysomnography was used to measure three nights sleep in 12 ecstasy users and 12 controls after screening (no intervention), a tryptophan-free amino acid mixture (acute tryptophan depletion (ATD)) and a tryptophan-supplemented control mixture. RESULTS: ATD significantly decreased rapid eye movement (REM) sleep onset latency, increased the amount of REM sleep and increased the amount of stage 2 sleep in the first 3 h of sleep. There was no difference between ecstasy users' and controls' sleep on the screening night or after ATD. DISCUSSION: These findings imply that the ecstasy users had not suffered significant serotonergic damage as indexed by sleep.

Antidepressant-induced jitteriness/anxiety syndrome: systematic review.

BACKGROUND: Early worsening of anxiety, agitation and irritability are thought to be common among people commencing antidepressants, especially for anxiety disorders. This phenomenon, which may be termed jitteriness/anxiety syndrome, is cited as an explanation for early treatment failure and caution in using selective serotonin reuptake inhibitors (SSRIs). However, we believe that it is inconsistently defined and that robust evidence to support the phenomenon is lacking. AIMS: To review systematically all evidence relating to jitteriness/anxiety syndrome to identify: constituent symptoms; medications implicated; disorders in which it was reported; incidence; time course; management strategies; relationship of this syndrome to therapeutic response; distinction between syndrome and akathisia; relationship between syndrome and suicide; and genetic predispositions. METHOD: A systematic search identified articles and these were included in the review if they addressed one of the above aspects of jitteriness/anxiety syndrome. RESULTS: Of 245 articles identified, 107 articles were included for review. No validated rating scales for jitteriness/anxiety syndrome were identified. There was no robust evidence that the incidence differed between SSRIs and tricyclic antidepressants, or that there was a higher incidence in anxiety disorders. Published incidence rates varied widely from 4 to 65% of people commencing antidepressant treatment. Common treatment strategies for this syndrome included a slower titration of antidepressant and the addition of benzodiazepines. Conclusive evidence for the efficacy of these strategies is lacking. There was conflicting and inconclusive evidence as to whether the emergence of this syndrome had a predictive value on the response to treatment. It appears to be a separate syndrome from akathisia, but evidence for this assertion was limited. The effect of jitteriness/anxiety syndrome on suicide rates has not been evaluated. Three studies examined genetic variations and side-effects from treatment, but none was specifically designed to assess jitteriness/anxiety syndrome. CONCLUSIONS: Jitteriness/anxiety syndrome remains poorly characterised. Despite this, clinicians' perception of this syndrome influences prescribing and it is cited to support postulated mechanisms of drug action. We recommend systematised evaluation of side-effects at earlier time points in antidepressant trials to further elucidate this clinically important syndrome.

Recent developments in anxiety disorders.

Anxiety disorders are common and debilitating mental illnesses. Current pharmacological treatments are beset by problems of poor efficacy and side effect profiles. Increasing understanding of novel neurotransmitter systems and the interplay between these systems is broadening the scope of anxiolytic drug treatment. This article aims to describe the areas of current interest and possible future development of anxiolytic drugs by outlining recent patents in this field. A patent database was searched for 17 neurotransmitters and their synonyms as well as 23 compounds of recent known interest from May 2003 to May 2005. The internet resources Pubmed and Google Scholar were searched for peer reviewed literature using the same search parameters. Results were grouped into neurotransmitter systems to present an overview of recent developments in the neuropharmacology of anxiety disorders.