Severity of depression and response to antidepressants: GENPOD randomised controlled trial.

BACKGROUND: Antidepressant prescribing is widespread. Nonetheless, response to antidepressants is variable. If it was possible to predict response to medication and thus tailor treatment accordingly, this would not only improve patient outcomes but may also have economic benefits. AIMS: To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors (NARIs) than selective serotonin reuptake inhibitors (SSRIs) compared with individuals with less severe depression. METHOD: Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory (BDI) were randomised to either an SSRI (citalopram 20 mg daily) or a NARI (reboxetine 4 mg twice daily). Randomisation was by means of a remote automated telephone system. The main outcome was depressive symptoms measured by the BDI total score 6 weeks after randomisation. ( TRIAL REGISTRATION: ISRCTN31345163.) RESULTS: In total, 601 participants were randomised (citalopram: n = 298, reboxetine: n = 303). Ninety-one per cent were followed up at 6 weeks (citalopram: n = 274, reboxetine: n = 272). There was little evidence to support an interaction between treatment and severity of depression (interaction term: 0.02, 95% CI -0.59 to 0.62, P = 0.96). Adjustment for potential confounders (age, gender, employment status, history of depression, number of life events and social support) did not affect the findings (interaction term: 0.06, 95% CI -0.54 to 0.66, P = 0.85). CONCLUSIONS: Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care.

Involving patients with depression in research: survey of patients' attitudes to participation.

BACKGROUND: Clinicians report barriers to involving their patients in mental health research and have concerns that participation may have negative effects. AIM: To investigate patients' views on participating in a primary care randomised controlled trial (RCT) comparing two antidepressant drugs. DESIGN OF STUDY: Cross-sectional survey. SETTING: General practices, England. METHOD: Six hundred and one trial participants were surveyed about their reasons for, and experience of, participating. RESULTS: The questionnaire was completed by 252/601 (42%) participants. The most influential factors determining participation were: wanting to help others with depression (94%, 95% confidence interval [CI] = 90 to 97%) of responders rated this as 'important' or 'very important'); friendly researchers (94%, 95% CI = 90 to 96%); and interest in the research (88%, 95% CI = 83 to 91%). Most were glad they took part and would consider participating in future research. Ninety-six per cent (95% CI = 92 to 98%) reported that their confidence in their GP had increased or remained unchanged since referral. Qualitative analysis of free-text responses indicated that patients found participation beneficial and liked: being altruistic, doing something positive, feeling supported by the researchers, and having time to talk. Many gained understanding of their depression and valued feedback on their progress. A minority reported negative views, which commonly related to taking antidepressants, and answering questionnaires. CONCLUSION: GPs have a vital role in facilitating patient involvement in research but report barriers to referring depressed patients to RCTs. However, this data suggests that patients are willing to participate and many find this beneficial. Understanding attitudes to participation in mental health research is a crucial step in designing trials that are more acceptable to patients and GPs. This will strengthen the evidence for therapeutic approaches in primary care.

Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial.

BACKGROUND: Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs). AIMS: To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants. METHOD: In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163). RESULTS: Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype. CONCLUSIONS: It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression.

GENetic and clinical predictors of treatment response in depression: the GenPod randomised trial protocol.

BACKGROUND: The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors - SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors - NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics. Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the 5HT transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs. METHODS/DESIGN: The GenPod trial is a multi-centre randomised controlled trial. GPs referred patients aged between 18-74 years presenting with a new episode of depression, who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse. Patients were interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score > 14) were randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. The final number randomised to the trial was 601. Follow-up assessments took place at 2, 6 and 12 weeks following randomisation. Primary outcome was measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments. DISCUSSION: The results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression. The trial is expected to report in the autumn of 2008. TRIAL REGISTRATION: ISRCTN 31345163.

Fetal programming of body dimensions and percentage body fat measured in prepubertal children with a 4-component model of body composition, dual-energy X-ray absorptiometry, deuterium dilution, densitometry, and skinfold thicknesses.

BACKGROUND: Intrauterine programming of body composition [percentage body fat (%BF)] has been sparsely examined with multiple independent reference techniques in children. The effects on and consequences of body build (dimensions, mass, and length of body segments) are unclear. OBJECTIVE: The study examined whether percentage fat and relation of percentage fat to body mass index (BMI; in kg/m2) in prepubertal children are programmed during intrauterine development and are dependent on body build. It also aimed to examine the extent to which height can be predicted by parental height and birth weight. DESIGN: Eighty-five white children (44 boys, 41 girls; aged 6.5-9.1 y) had body composition measured with a 4-component model (n = 58), dual-energy X-ray absorptiometry (n = 84), deuterium dilution (n = 81), densitometry (n = 62), and skinfold thicknesses (n = 85). RESULTS: An increase in birth weight of 1 SD was associated with a decrease of 1.95% fat as measured by the 4-component model (P = 0.012) and 0.82-2.75% by the other techniques. These associations were independent of age, sex, socioeconomic status, physical activity, BMI, and body build. Body build did not decrease the strength of the associations. Birth weight was a significantly better predictor of height than was self-reported midparental height, accounting for 19.4% of the variability at 5 y of age and 10.3% at 7.8 y of age (17.8% and 8.8% of which were independent of parental height at these ages, respectively). CONCLUSIONS: Consistent trends across body-composition measurement techniques add strength to the suggestion that percentage fat in prepubertal children is programmed in utero (independently of body build and BMI). It also suggests birth weight is a better predictor of prepubertal height than is self-reported midparental height.

Crohn's disease post-cardiac transplantation presenting with severe growth failure and delayed onset of puberty.

We report a 15 yr-old girl who 10 yr post-cardiac transplantation presented with severe growth failure and delayed onset of puberty. She was found to have pan-enteric Crohn's disease and has done remarkably well on principally nutritional therapy with a significant growth spurt and the onset of menarche. The development of bowel disease whilst on immunosuppression is rare and the literature is reviewed.