David Christmas

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.

Serotonin regulation of the human stress response

Acute tryptophan depletion (ATD) is a technique that has been used to evaluate the effects on humans of acutely reducing serotonin neurotransmission. We have developed a model using a single breath of 35% CO(2) that activates the hormonal axis and produces autonomic and behavioural arousal, thus modelling a stress response. This study combines ATD and single breath 35% CO(2) inhalation to study stress responses in volunteers. A randomised, double-blinded, placebo-controlled, cross-over trial involving 14 healthy adult volunteers aged between 18 and 65 years was undertaken. Subjects underwent double-blind tryptophan depletion over 2 days and were then crossed over 1 week later. During each study day, at the time of peak depletion, participants were single blinded to receive a single breath of 35% CO(2) or air. This was followed 40 min later by the other gas. Psychological outcomes were assessed with the Spielberger State Anxiety Inventory (SSAI), Visual Analogue Scales (VAS), Panic Inventory (PI), Panic and Agoraphobia Scale (PSI) and Beck Depression Inventory (BDI). Physiological outcome was measured by serial plasma cortisol, prolactin and tryptophan levels, pulse and blood pressure. Tryptophan depletion did not exacerbate 35% CO(2) inhalation effects on anxiety symptoms. Single breath CO(2) robustly increased plasma cortisol levels in comparison to an air inhalation; this was less certain for prolactin levels. ATD influenced the HPA axis (associated with higher cortisol levels), apparently independent of CO(2) or air inhalation stressors. ATD and 35% CO(2) inhalation both induced a pressor response and bradycardia in these normal volunteers. Thirty-five percent CO(2) inhalation and ATD independently activate the human stress response, but do not appear to produce synergistic effects when combined, at least for the conditions produced in this study.

Potential Novel Anxiolytic Drugs

Anxiety disorders are common and disabling conditions. Current drug treatment methods have limitations including resistance, delayed efficacy and side effects. The advent of sophisticated imaging techniques and the production of highly selective receptor ligands have increased our knowledge of the biological mechanisms underpinning anxiety. Our aim is to review recent discoveries in important neurological systems to provide an understanding of important current anxiolytic targets. Some of these systems, such as GABA, have been implicated in anxiety disorders for decades, but a recent greater understanding is enabling more sophisticated targeting of treatments. In other systems, including the neuropeptides, we have now developed the pharmacological tools in human subjects to begin exploring their relationship to anxiety disorders. We review GABA, serotonin, glutamate, noradrenaline, dopamine and some neuropeptides herein.

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.

Effect of interferon-α on cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study

BACKGROUND The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α (IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-α and ribavirin. METHOD MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks of treatment with IFN. RESULTS IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. CONCLUSIONS We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.

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

Abstract 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.

Symptoms of generalized anxiety disorder but not panic disorder at age 15 years increase the risk of depression at 18 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study

Background. Generalized anxiety disorder (GAD) and panic disorder (PD) differ in their biology and co-morbidities. We hypothesized that GAD but not PD symptoms at the age of 15 years are associated with depression diagnosis at 18 years. Method. Using longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort we examined relationships of GAD and PD symptoms (measured by the Development and Well-Being Assessment) at 15 years with depression at 18 years (by the Clinical Interview Schedule – Revised) using logistic regression. We excluded adolescents already depressed at 15 years and adjusted for social class, maternal education, birth order, gender, alcohol intake and smoking. We repeated these analyses following multiple imputation for missing data. Results. In the sample with complete data (n = 2835), high and moderate GAD symptoms in adolescents not depressed at 15 years were associated with increased risk of depression at 18 years both in unadjusted analyses and adjusting for PD symptoms at 15 years and the above potential confounders. The adjusted odds ratio (OR) for depression at 18 years in adolescents with high relative to low GAD scores was 5.2 [95% confidence interval (CI) 3.0–9.1, overall p < 0.0001]. There were no associations between PD symptoms and depression at 18 years in any model (high relative to low PD scores, adjusted OR = 1.3, 95% CI 0.3–4.8, overall p = 0.737). Missing data imputation strengthened the relationship of GAD symptoms with depression (high relative to low GAD scores, OR = 6.2, 95% CI 3.9–9.9) but those for PD became weaker. Conclusions. Symptoms of GAD but not PD at 15 years are associated with depression at 18 years. Clinicians should be aware that adolescents with GAD symptoms may develop depression.

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

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.

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.