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The ideal anxiolytic drug would be effective in all anxiety disorders, with a rapid onset of action, across all symptom domains and the spectrum of severity, in achieving remission and minimising disability, in preventing relapse, and in treating comorbid depression. Ideally, the drug would be suitable for once-daily dosage, would have minimal adverse effects or cause minimal interference with everyday life, not lead to the development of tolerance, have no discontinuation symptoms, be suitable in physically ill patients and free from interactions, and be safe in overdose.
But there are no ideal anxiolytic drugs. Response rates to initial treatment can be disappointing, it is not possible to reliably predict likelihood of response; a substantial proportion of patients experience unwanted effects; many will relapse despite treatment adherence; comparatively little is known about further management after initial non-response; and discontinuation symptoms can be troublesome.
Hence there is much room for improvement in identifying those patients who are most likely to benefit from treatment; in choosing between drug and psychological treatments; in choosing the right drug for the right patient groups; in optimising medication dosage to achieve maximum effectiveness whilst minimising adverse effects; in combining drug treatments to enhance efficacy; and in treating over the long term to prevent relapse and recurrence.
Panic disorder is a common condition. Epidemiological studies throughout the world consistently indicate that the lifetime prevalence of panic disorder (with or without agoraphobia) is between 1.5% and 3.5%. Panic disorder shows substantial comorbidity with other forms of mental illness. Major depressive disorder occurs in 50 to 65% of individuals with panic disorder and there is considerable cross-sectional and longitudinal comorbidity with recurrent brief depression and dysthymia. Phobic anxiety disorders, most notably social phobia and generalised anxiety disorder, commonly occur with panic disorder, especially in individuals with more severe agoraphobia. Approximately 35 to 50% of individuals with panic disorder in community settings also have agoraphobia. Panic disorder also shows significant comorbidity with physical illness. Compared with individuals without or with some other psychiatric diagnosis, patients with panic disorder have an increased risk of suffering from multiple medically unexplained symptoms and are associated with high use of medical services and increased mortality from both cardiovascular and cerebrovascular disease.
Anxiety disorders are common, have an early onset, run a long course, cause substantial distress, impair overall function, reduce quality of life and impose a major economic burden, and therefore represent an important public health problem. Many patients do not present or are not recognized, the standard of care is often sub-optimal, and the effectiveness of interventions in real-world practice can be disappointing: there is considerable room for improvement in recognition, care and treatment.
The causes remain largely unknown and this hinders accurate diagnosis, prediction of prognosis, and development of refined treatment approaches. There is much co-morbidity between the disorders and with conditions such as bipolar disorder, depressive illness and physical illness. Research findings in patient samples without co-morbidity may have limited applicability to wider practice, and there is a need to undertake research in fully representative groups. Little is known about determinants of non-response, or next steps in management after the failure of first-line interventions, and there is a clear need for research in the substantial proportion with ‘treatment-resistant’ conditions.
The unmet public health, clinical and research needs could therefore be addressed by developing an independent collaborative European Anxiety Disorders Research Network. This would facilitate harmonization of research and clinical databases and refinement of research methodologies. It should contribute to greater accuracy when predicting clinical outcome, and encourage the evaluation of innovative interventions, particularly in important groups such as in the early stages of illness, those with comorbid disorders, and those who have not responded to initial treatment approaches.
Current evidence-based guidelines for generalized anxiety disorder (GAD) tend to recommend initial treatment with either a selective serotonin reuptake inhibitor or a serotonin-noradrenaline reuptake inhibitor, although there is also good evidence for the efficacy of pregabalin and quetiapine. NICE guidelines recommend that cognitive behaviour therapy is reserved for patients not responding to initial interventions based on self-help and psychoeducation. The findings of a mixed treatment comparison and meta-analysis demonstrate the difficulty in establishing the relative efficacy and tolerability of pharmacological treatments. It is hard to predict which patients will respond well to pharmacological treatment, but response to antidepressants or pregabalin is unlikely if there is no onset of effect within four weeks. The value of combining pharmacological with psychological interventions is uncertain. The small number of relapse prevention studies causes uncertainty about optimal duration of treatment after a satisfactory initial response, but continuing treatment for at least twelve months is advisable. However many patients will not respond well to current interventions, and there is much room for improvement in the development of more effective and better tolerated treatments. Challenge studies in healthy volunteers, involving the inhalation of air ‘enriched’ with 7.5% CO2 provide a robust experimental medicine model of GAD and are being used to evaluate novel pharmacological and psychological interventions. In addition, advances in understanding of the potential role of neuroinflammatory factors in GAD also suggest other potential targets for pharmacological treatment.
The findings of meta-analyses and randomized placebo-controlled treatment studies indicate that a range of approaches are efficacious in acute treatment. Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment. However, acute treatment with cognitive therapy (group or individual) may be associated with a reduced risk of symptomatic relapse at follow-up. Cognitive behaviour therapy is efficacious in adults and children: cognitive therapy appears superior to exposure therapy, but the evidence for the efficacy of social skills training is less strong. It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone, as only 1 of 4 studies of the relative efficacy of combination treatment found evidence for superior efficacy.
Efficacy and length of acute pharmacological treatment
Antidepressant drugs with proven efficacy include most SSRIs, the SNRI venlafaxine, the MAOI phenelzine and the RIMA moclobemide: the potential efficacy of tricyclic antidepressants is unknown. Some benzodiazepines and anticonvulsants and the antipsychotic olanzapine also appear efficacious in acute treatment. A number of small single-dose placebo-controlled crossover studies together suggest that beta-blockers can be beneficial in reducing anxiety symptoms in individuals with ‘performance anxiety’ (for example, when speaking in public), which overlaps with mild non-generalized social anxiety disorder. Acute treatment studies indicate that the proportion of responding patients increases steadily over time. A post-hoc analysis of the clinical trial database with paroxetine indicates that many non-responders to treatment at 8 weeks become responders with a further 4 weeks of double-blind treatment: however a post-hoc analysis of the clinical trial database for escitalopram indicates that response is unlikely if there is no onset of clinical effect within the first 4 weeks of treatment.
Longer-term treatment and further treatment after non-response
The findings of randomized placebo-controlled relapse prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months. Fixed-dose randomized controlled trials do not provide consistent evidence of a dose-response relationship with antidepressant drugs: but a fixed-dose study of pregabalin found that only the higher daily dosage was efficacious. A double-blind randomized controlled dosage escalation trial found no advantage for increasing to a higher daily dosage (of duloxetine), when compared to continuing treatment with a lower dosage. Switching between treatments with proven efficacy may be helpful. An uncontrolled study of augmentation of SSRI treatment with buspirone found some evidence of beneficial effects; but a placebo-controlled crossover-study of the augmentation of paroxetine with pindolol found no evidence of efficacy. A small placebo-controlled study of the augmentation of paroxetine with clonazepam found the combination was marginally short of superiority, when compared to paroxetine alone.
Disclosure of interest
The author has not supplied his declaration of competing interest.
Background: Evidence suggests that insomnia may be an important therapeutic target to improve mental health. Aims: Evaluating changes in symptoms of depression and anxiety after supported digital cognitive behavioural therapy (dCBT) for insomnia delivered via a community-based provider (Self Help Manchester) of the Improving Access to Psychological Therapies (IAPT) service. Method: Supported dCBT for insomnia was delivered to 98 clients (mean age 44.9 years, SD 15.2, 66% female) of Self Help Manchester. All clients received six support calls from an eTherapy coordinator to support the self-help dCBT. During these calls levels of depression (Patient Health Questionnaire, PHQ-9) and anxiety (Generalized Anxiety Disorder, GAD-7) were determined. Results: Depression (Mdifference-5.7, t(70) = 12.5, p < .001) and anxiety [Generalized Anxiety Disorder-7 (GAD-7), Mdifference-4.1, t(70) = 8.0, p < .001] were reduced following supported dCBT for insomnia. This translated into an IAPT recovery rate of 68% for depression and anxiety. Conclusions: These results suggest that dCBT for insomnia alleviates depression and anxiety in clients presenting with mental health complaints in routine healthcare.
A systematic review was performed to evaluate the safety and efficacy of different therapeutic interventions available for the management of isolated cricopharyngeal dysfunction.
Studies were identified using the following databases: Ovid (Medline, Embase), the Cochrane Library, PubMed and Google Scholar. An initial search identified 339 articles. All titles and abstracts were reviewed. Fifty-six relevant articles were inspected in more detail; of these, 47 were included in the qualitative analysis.
No relevant randomised trials were found. A range of case series were used to perform a qualitative analysis. Botulinum toxin A injection and cricopharyngeal dilatation were associated with a higher risk of recurrence, but appear to be more suitable in elderly and co-morbid patients. In those patients requiring formal myotomy, endoscopic approaches appear to be as effective but less morbid when compared with classical open surgery.
There is good evidence for the safety and efficacy of the different therapeutic options for isolated cricopharyngeal dysfunction. However, further studies are required to compare the efficacy of the various treatment modalities.
A geological disposal facility (GDF) will include fissile materials that could, under certain conditions, lead to criticality. Demonstration of criticality safety therefore forms an important part of a GDF's safety case.
Containment provided by the waste package will contribute to criticality safety during package transport and the GDF operational phase. The GDF multiple-barrier system will ensure that criticality is prevented for some time after facility closure. However, on longer post-closure timescales, conditions in the GDF will evolve and it is necessary to demonstrate: an understanding of the conditions under which criticality could occur; the likelihood of such conditions occurring; and the consequences of criticality should it occur.
Work has addressed disposal of all of the UK's higher-activity wastes in three illustrative geologies. This paper, however, focuses on presenting results to support safe disposal of spent fuel, plutonium and highlyenriched uranium in higher-strength rock.
The results support a safety case assertion that post-closure criticality is of low likelihood and, if it was to occur, the consequences would be tolerable.
Although type 2 respiratory failure is a plausible late presentation for laryngeal tumours, very little published literature is available to support this theory.
This paper describes the unusual presentation of a subglottic tumour with uncompensated type 2 respiratory failure.
The patient was initially managed with biphasic positive airway pressure as a bridging measure while awaiting intensive care treatment and to provide sufficient time to arrange a surgical tracheostomy.
This case highlights the importance of clinical suspicion towards subglottic tumours in patients presenting with type 2 respiratory failure. The positive outcome indicates that biphasic positive airway pressure is a potential bridging therapy for upper airway obstruction and a safe and stable treatment option for patients in respiratory distress.
We report on the preparation and characterization of crystalline bismuth oxide thin films via Biased Target Ion Beam Deposition method. A focused blue laser (405nm) is used to write an array of dots in the bismuth oxide thin film and demonstrate clear and circular recording marks in form of “bubbles” or “little volcanos” (FWHM ∼500nm). Results indicate excellent static recording characteristics, writing sensitivity and contrast. The recording mechanism is investigated and is believed to be related to laser-induced morphology change.
The boundaries of psychotic illness and the extent to which operational diagnostic categories are distinct in the long term remain poorly understood. Clarification of these issues requires prospective evaluation of diagnostic trajectory, interplay and convergence/divergence across psychotic illness, without a priori diagnostic or other restrictions.
The Cavan-Monaghan First Episode Psychosis Study (CAMFEPS), conducted using methods to attain the closest approximation to epidemiological completeness, incepts all 12 DSM-IV psychotic diagnoses. In this study we applied methodologies to achieve diagnostic reassessments on follow-up, at a mean of 6.4 years after first presentation, for 196 (97%) of the first 202 cases, with quantification of prospective and retrospective consistency.
Over 6 years, the 12 initial psychotic diagnoses were characterized by numerous transitions but only limited convergence towards a smaller number of more stable diagnostic nodes. In particular, for initial brief psychotic disorder (BrP), in 85% of cases this was the harbinger of long-term evolution to serious psychotic illness of diagnostic diversity; for initial major depressive disorder with psychotic features (MDDP), in 18% of cases this was associated with mortality of diverse causality; and for initial psychotic disorder not otherwise specified (PNOS), 31% of cases continued to defy DSM-IV criteria.
CAMFEPS methodology revealed, on an individual case basis, a diversity of stabilities in, and transitions between, all 12 DSM-IV psychotic diagnoses over 6 years; thus, psychotic illness showed longitudinal disrespect to current nosology and may be better accommodated by a dimensional model. In particular, a first episode of BrP or MDDP may benefit from more vigorous, sustained interventions.
The 2008 UK government White Paper, published as part of the Managing Radioactive Waste Safety programme, identified benefits to disposing of all of the UK's higher activity wastes at the same site. That is, a single geological disposal facility (GDF) could be constructed that consists of a module for low- and intermediate-level waste, and a module for high-level waste and spent fuel.
A safety case for a co-located GDF will have to consider the extent to which evolving thermo-hydro-mechanical-chemical and gas (THMCG) conditions in and around one module may affect conditions in the other module, including the extent to which barrier performance and radionuclide migration behaviour could be altered. Several research projects have been undertaken on behalf of Radioactive Waste Management Directorate aimed at understanding and evaluating the THMCG interactions that might occur during the disposal facility operational and post-closure phases.
This paper describes research on THMCG interactions between disposal modules based on illustrative GDF designs for different host rock environments. Interactions were evaluated using simple analytical solutions and detailed three-dimensional models. The analyses demonstrated that interactions can be controlled by design constraints.