Robert Baldwin

Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial

BACKGROUND Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly prescribed drugs, sertraline and mirtazapine, compared with placebo. METHODS We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England. Participants were eligible if they had probable or possible Alzheimers disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no carer. The clinical trials unit at Kings College London (UK) randomly allocated participants with a computer-generated block randomisation sequence, stratified by centre, with varying block sizes, in a 1:1:1 ratio to receive sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo (control group), all with standard care. The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment centre. This study is registered, number ISRCTN88882979 and EudraCT 2006-000105-38. FINDINGS Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1·17, 95% CI -0·23 to 2·58; p=0·10) or mirtazapine (0·01, -1·37 to 1·38; p=0·99), or between participants in the mirtazapine and sertraline groups (1·16, -0·25 to 2·57; p=0·11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107, 43%; p=0·010) or mirtazapine group (44 of 108, 41%; p=0·031), and fewer serious adverse events rated as severe (p=0·003). Five patients in every group died by week 39. INTERPRETATION Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimers disease should be reconsidered. FUNDING UK National Institute of Health Research HTA Programme.

Depression and anxiety in elderly outpatients with chronic obstructive pulmonary disease: prevalence, and validation of the BASDEC screening questionnaire

Objectives. Depressive and anxiety symptoms are common in elderly patients with chronic obstructive pulmonary disease (COPD). However, true prevalence of clinical depression and anxiety is uncertain. We thus aimed to assess prevalence of clinical depression and/or anxiety in elderly COPD patients using the Geriatric Mental State Schedule (GMS) and determine severity of clinical depression by the Montgomery Asberg Depression Rating Scale (MADRS). We also aimed to validate the Brief Assessment Schedule Depression Cards (BASDEC) screening test for depressive symptoms against GMS.

Is subcortical disease associated with a poor response to antidepressants? Neurological, neuropsychological and neuroradiological findings in late-life depression

BACKGROUND Late-life depression is associated with increased subcortical white matter hyperintensities. There is some evidence that they are associated with a poorer response to acute treatment. Neurological signs and neuropsychological dysfunction are further evidence of abnormalities in the brain, but they have not been studied in relation to therapy resistance. METHODS A prospective study of 24 normal controls and 75 consecutive elderly (aged 65 to 85) patients with DSM-III-R major depression entered a naturalistic study of treatment. Assessment of response to monotherapy and then lithium augmentation or ECT created three outcome groups. Investigations included magnetic resonance brain imaging, neuropsychological and neurological examination. RESULTS Response to monotherapy within 12 weeks was shown by 42.7%, a further 37.3% responded to lithium augmentation or ECT within 24 weeks and 20% had responded poorly to all treatments at 24 weeks. Subcortical hyperintensities were significantly increased in the more resistant patients. These included confluent deep white matter, multiple (> 5) basal ganglia lesions and pontine reticular formation lesions. Most of the neuropsychological impairment was restricted to the resistant groups and was of a subcortico-frontal type. Extrapyramidal, frontal and pyramidal neurological signs characterized the resistant groups. The combination of extrapyramidal signs, pyramidal tract signs and impairment of motor hand sequencing strongly predicted resistance to 12 weeks of antidepressant monotherapy with 89% sensitivity and 95% specificity. CONCLUSION In late-life depression a poor response to antidepressant monotherapy can be expected in those patients with a frontal lobe syndrome, extrapyramidal signs or if MRI T2-weighted lesions are present in both the basal ganglia and the pontine reticular formation.

Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles.

To review evidence regarding the prevalence, causation, clinical implications, aspects of healthcare utilisation and management of depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease.

Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine

OBJECTIVE Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. DESIGN Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. SETTING Nine English old-age psychiatry services. PARTICIPANTS A pragmatic trial. Eligibility: probable or possible Alzheimers disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. EXCLUSIONS clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. INTERVENTIONS (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. MAIN OUTCOME MEASURES OUTCOME CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. RESULTS Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). OUTCOME Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). HARMS Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. CONCLUSIONS This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.

Treatment response in late-onset depression: relationship to neuropsychological, neuroradiological and vascular risk factors.

BACKGROUND Late-onset depressive disorder is associated with white matter lesions and neuropsychological deficits that in some studies are linked to a poorer outcome for depression. Some white matter lesions may be vascular in origin. This study investigated the relationship between response or non-response to antidepressant monotherapy and neuropsychological function, structural brain measures and vascular factors. METHOD This was a case control study. Fifty patients with late-onset major depressive disorder (29 who were responders to antidepressant monotherapy and 21 who were not) were compared with 35 non-depressed control subjects. Measures included assessment of vascular risk factors, neuropsychological testing and a magnetic resonance imaging (MRI) scan. RESULTS After adjustment for depressed mood and medication at evaluation, both patient groups had significantly more impairment compared to control subjects on verbal learning tasks involving immediate or delayed recall. Patients who did not respond to antidepressant monotherapy had significantly poorer performance than controls on tests involving visuospatial ability, language, word recognition and tests of executive function, whereas there were no differences between control subjects and responders. On two tests of executive function (verbal fluency and the Stroop test) non-responders scored significantly worse than responders. There were no significant group differences on MRI measures of atrophy or of white matter lesions apart from a higher periventricular hyperintensity score in non-responders compared to controls. There were no group differences on measures of vascular disease. CONCLUSION The results lend support to the emerging evidence that resistance to treatment in late-onset depression may be associated with impaired executive function. Subtle cerebrovascular mechanisms may be involved.

Sertraline in stroke‐associated lability of mood

To assess whether a selective serotonin reuptake inhibitor is effective in the treatment of stroke‐associated lability of mood.

Trade and Growth

The relationships between trade and growth have long been a subject of considerable controversy among economists. In the early post-World War II period, many economic leaders concluded that protective trade policies stimulated growth, and import substitution policies were widely adopted by developing countries. By the 1980s, however, country-specific and general cross-country analyses had demonstrated the failure of the import substitution approach, and consequently export-oriented policies were widely adopted. While subsequent cross-country studies have generally indicated the growth effectiveness of outward-looking policies, recent criticisms of these studies (by Rodriguez and Rodrik, 1999, in particular) have called this conclusion into question ... Les relations entre le commerce et la croissance ont ete depuis longtemps sujet a controverse parmi les economistes. Durant la periode qui a suivi la deuxieme guerre mondiale, beaucoup de leaders dans le domaine de l’economie concluaient que les politiques commerciales protectionnistes etaient stimulantes pour la croissance, et que des politiques de substitution de l’importation etaient largement en vigueur dans les pays developpes. Au cours des annees 80, cependant, les analyses nationales et internationales ont demontre l’inefficacite de l’approche de subsitution de l’importation, et donc les politiques visant l’exportation ont ete favorisees en consequence. Si les etudes internationales ulterieures soulignent en general l’efficacite, en termes de croissance, des politiques favorisant l’exportation, de recentes critiques de ces etudes (en particulier, Rodriguez et Rodrik, 1999) ont conteste cette conclusion ...

A randomised controlled trial to test the feasibility of a collaborative care model for the management of depression in older people.

BACKGROUND Depression is the most common mental health disorder in people aged over 65 years. Late-life depression is associated with chronic illness and disability. AIM To investigate the feasibility of a collaborative care model for depression in older people in a primary care setting. DESIGN OF STUDY Randomised controlled trial with 16-weeks follow up. SETTING A primary care trust in Manchester. METHOD Participants were 105 people aged 60 years or older who scored 5 or more on the Geriatric Depression Scale; 53 were randomly allocated to an intervention group and 52 to a usual care group. The intervention group received care managed by a community psychiatric nurse who delivered an intervention comprising a facilitated self-help programme with close liaison with primary care professionals and old-age psychiatry according to a defined protocol. The usual care group received usual GP care. A nested qualitative study explored the views of the health professionals and patients regarding the acceptability and effectiveness of the intervention. RESULTS The main outcome measure was recovery from depression. Patients in the intervention group were less likely to suffer from major depressive disorder at follow up compared with usual care (0.32, 95% confidence = interval = 0.11 to 0.93, P = 0.036). The qualitative component of the study demonstrated the acceptability of the intervention to patients. CONCLUSION A model of collaborative care for older people with depression, used in a primary care setting with a facilitated self-help intervention is more effective than usual GP care. This study demonstrates that the implementation of a collaborative care model is feasible in UK primary care and that the intervention is effective and acceptable to patients.

Fear of falling more important than pain and depression for functional recovery after surgery for hip fracture in older people.

BACKGROUND Depression and cognitive functioning have a negative impact on functional recovery after hip fracture surgery in older people, and the same has been suggested for pain and fear of falling. These variables, however, have never been studied together, nor has the timing of psychiatric assessment been taken into account. METHOD Two parallel, randomized controlled trials were undertaken aiming to prevent and treat depression after hip fracture surgery in older people. Multiple logistic regression analyses corrected for age and pre-morbid level of functioning were performed to evaluate the effect of depressive symptoms (15-item Geriatric Depression Scale, GDS), pain (Wong-Baker pain scale), cognitive functioning (Mini-mental State Examination, MMSE) and fear of falling (Modified Falls Efficacy Scale, MFES) within 2 weeks after surgery and 6 weeks later on functional recovery at 6 months. Main outcome measures were performance-based measures (up-and-go test, gait test, functional reach) and the self-report Sickness Impact Profile (SIP) questionnaire to assess the impact of the hip fracture on activities of daily living (ADL). RESULTS Two hundred and ninety-one patients participated and outcome measures for 187 (64%) patients were available at 6 months. All mental health variables interfered with functional recovery. However, in the final multivariate model, cognitive functioning and fear of falling assessed 6 weeks after surgery consistently predicted functional recovery, whereas pain and depressive symptoms were no longer significant. CONCLUSION Fear of falling and cognitive functioning may be more important than pain and depression to predict functional recovery after hip fracture surgery. Rehabilitation strategies should take this into account.