Steve Edwards

Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were rev...

Patients with treatment-resistant depression (TRD) are those with major depressive disorder that has not responded adequately to treatment. The causes of depression are not fully understood, although there is evidence to suggest that depression is a complex interaction among biological, genetic, psychosocial and environmental factors. Strategies available for the treatment of patients with TRD include pharmacological, non-pharmacological, and psychological and psychosocial interventions. Pharmacological treatment options include switching to a different antidepressant, the addition of another antidepressant of a different class, or use of an augmenting agent, such as anticonvulsants, lithium or atypical antipsychotics (AAPs). However, there is limited evidence available on the effectiveness of these strategies in the treatment of TRD. To estimate the clinical effectiveness and cost-effectiveness of augmentation of selective serotonin reuptake inhibitor (SSRI) antidepressant therapy with either lithium or an AAP drug in the management of people with treatment-resistant unipolar depression, defined as failure to respond to two or more antidepressant drugs in their current episode of depression. Databases searched were Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, PsycINFO and NHS Economic Evaluation Database (NHS EED). All databases were searched from inception to August 2011. Additional data were obtained from manufacturers. Systematic reviews of studies evaluating clinical effectiveness, economic analyses and quality of life (QoL) were executed. Quality assessment according to predefined criteria was undertaken independently by two reviewers. Pairwise meta-analyses and mixed-treatment comparisons (MTCs) using both fixed- and random-effects models were undertaken based on intention-to-treat analyses. A probabilistic de novo mathematical model was developed to synthesise the available data on costs and clinical outcomes from the UK NHS perspective over a 1-year time horizon (8 weeks of acute treatment captured by a decision tree and 10 months of maintenance treatment captured by a Markov model). Twelve randomised controlled trials (RCTs) were identified in the review of clinical effectiveness literature; 10 considered SSRI  +  AAP compared with SSRI  +  placebo/no treatment, one considered SSRI  +  AAP compared with SSRI  +  lithium and one considered SSRI  +  lithium compared with SSRI  +  placebo. The RCTs included in the primary analyses used fluoxetine as the background SSRI and olanzapine as the AAP. Results of the MTC showed a non-significant trend in favour of lithium augmentation for response [lithium a priori odds ratio (OR) 1.29; 95% credible interval (CrI) 0.11 to 5.32; lithium post hoc OR 4.15; 95% CrI 0.25 to 20.34 (the trial informing the comparison with lithium reported response using two different definitions)], mean change in Montgomery-Åsberg Depression Rating Scale score from baseline (mean difference -  1.47, 95% CrI -  9.10 to 6.41) and all-cause withdrawals (OR 0.74, 95% CrI 0.10 to 2.66). Four economic evaluations (none directly addressing the review question) and 17 studies that reported on QoL were identified and summarised in narrative reviews. The results of the de novo modelling indicate that augmentation of SSRI with lithium dominates augmentation of an SSRI with AAP (i.e. it resulted in cost savings of £905 per person per year and generated more health benefits, estimated to be 0.03 quality-adjusted life-years). However, sensitivity analyses showed that the model was highly sensitive to changes in acute treatment efficacy (response and remission) or discontinuation. The model was not sensitive to changes in other parameters. In patients with TRD, there is a lack of direct evidence comparing the clinical effectiveness of augmenting an SSRI with an AAP compared with augmenting with lithium. RCTs were identified which facilitated comparison of adding AAP with adding lithium via a MTC. However, variations in the definitions of response implemented in the RCTs, together with differences in patient baseline characteristics across RCTs, introduce bias into the analysis. The direction and extent of the bias is uncertain. Augmentation of SSRIs with lithium or AAP is likely to be beneficial in people with TRD. Clinical evaluation based on the limited evidence identified in this research indicates no statistically significant difference between the two augmentation strategies. Cost-effectiveness analyses suggest that augmentation with lithium is less expensive and more effective than augmentation with AAP. However, the uncertainty in the clinical estimates of discontinuation and treatment response is reflected in the model results. A RCT comparing the two augmentation strategies, reporting relevant outcomes, including QoL, is needed. PROSPERO CRD42011001464.

Anxiety and related disorders include generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder and phobic disorders (intense fear of an object or situation). These disorders share the psychological and physical symptoms of anxiety, but each disorder has its own set of characteristic symptoms. Anxiety disorders can be difficult to recognise, particularly in older people (those aged over 65 years). Older people tend to be more reluctant to discuss mental health issues and there is the perception that older people are generally more worried than younger adults. It is estimated that between 3 and 14 out of every 100 older people have an anxiety disorder. Despite treatment, some people will continue to have symptoms of anxiety. People are generally considered to be 'resistant' or 'refractory' to treatment if they have an inadequate response or do not respond to their first treatment. Older adults with an anxiety disorder find it difficult to manage their day-to-day lives and are at an increased risk of comorbid depression, falls, physical and functional disability, and loneliness. To evaluate the effectiveness of pharmacological, psychological and alternative therapies in older adults with an anxiety disorder who have not responded, or have responded inadequately, to treatment. Electronic databases (MEDLINE, MEDLINE In-Process and Other Non-Indexed citations, EMBASE, The Cochrane Library databases, PsycINFO and Web of Science) were searched from inception to September 2013. Bibliographies of relevant systematic reviews were hand-searched to identify additional potentially relevant studies. ClinicalTrials.gov was searched for ongoing and planned studies. A systematic review of the clinical effectiveness of treatments for treatment-resistant anxiety in older adults was carried out. No randomised controlled trial or prospective comparative observational study was identified meeting the prespecified inclusion criteria. Therefore, it was not possible to draw any conclusions on clinical effectiveness. As no study was identified in older adults, there is uncertainty as to which treatments are clinically effective for older adults with an anxiety disorder who have not responded to prior treatment. The comprehensive methods implemented to carry out this review are a key strength of the research presented. However, this review highlights the extreme lack of research in this area, identifying no comparative studies, which is a marked limitation. Specific studies evaluating interventions in older adults with an anxiety disorder who have not responded to first-line treatment are needed to address the lack of evidence. The lack of evidence in this area means that older adults are perhaps receiving inappropriate treatment or are not receiving a particular treatment because there is limited evidence to support its use. At this time there is scope to develop guidance on service provision and, as a consequence, to advance the standard of care received by older adults with a treatment-resistant anxiety disorder in primary and secondary care. Evaluation of the relative clinical effectiveness and acceptability of pharmacological and psychological treatment in older adults with an anxiety disorder that has not responded to first-line treatment is key future research to inform decision-making of clinicians and patients. An important consideration would be the enrolment of older adults who would be representative of older adults in general, i.e. those with multiple comorbid physical and mental disorders who might require polypharmacy. The protocol for the systematic review is registered on PROSPERO (registration number CRD42013005612). The National Institute for Health Research Health Technology Assessment programme.