Aim/ Principal Research Question - The main aim of the “AHEAD” study was to determine the relative cost-effectiveness of three classes of antidepressants: tricyclics (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the tricyclic-related antidepressant lofepramine, as first choice treatments for depression in UK primary care. <br/><br/>Factors of interest - This is the first randomised prospective study in UK primary care to address this question. Most previous work on this topic has relied upon modelling and/or post hoc analysis of data collected for other purposes. The only other published trial of this type was conducted in HMOs in the United States.<br/><br/>Methods - The study was an open label, pragmatic controlled trial with three randomised arms and one preference arm. Patients were followed up for a total of 12 months.<br/>Patients were randomised to receive a tricyclic antidepressant (amitriptyline, dothiepin, or imipramine), a selective serotonin reuptake inhibitor (fluoxetine, sertraline, or paroxetine), or lofepramine. Standardised recommendations about dose and dose escalation based on the BNF were issued to GPs.<br/>Cost effectiveness was based upon an analysis of direct costs from an NHS perspective.<br/><br/>Sample groups - The study was carried out in UK primary care: 73 practices in urban and rural areas in Hampshire, Wiltshire, Dorset, Sussex, and Surrey agreed initially to take part. Patients with a new episode of depressive illness according to GP diagnosis were recruited. A total of 388 patients were referred to the study team by 87 GPs from 55 practices. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves (CEACs) were computed. Estimates were bootstrapped with 5000 replications.<br/><br/>Outcome measures - At baseline the Clinical Interview Schedule, Revised (CIS-R PROQSY computerised version) was administered to establish symptom profiles. Outcome measures over 12 month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression (HAD-D), CIS-R, EuroQol (EQ-5D) for quality of life, Short Form (SF-36) Health Survey for generic health status, and patient and practice records of use of health and social services (UHSS). The primary effectiveness outcome was the number of depression-free weeks (HAD-D less than 8, with interpolation of intervening values), and the primary cost outcome total direct NHS costs. Quality adjusted life years (QALYs) were used as the outcome measure in a secondary analysis. <br/><br/>Findings - 327 patients were randomised. Follow-up rates were 68% at 3 months and 52% at 1 year. Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients randomised to TCAs entered the preference arm than those allocated to the other choices. Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm. There were no significant differences between arms in mean cost per depression-free week. For values placed on an additional QALY of over £5,000, treatment with SSRIs was likely to be the most cost-effective strategy. Tricyclics were the least likely to be cost-effective as first choice of antidepressant for most values of a depression free week or QALY respectively, but these differences were relatively modest.<br/><br/>Conclusion - Given the low probability of significant differences in cost-effectiveness, it is appropriate to base the first choice between these three classes of antidepressant in primary care on doctor and patient preferences. Adopting this policy may lead to less switching of medication subsequently. Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks.<br/><br/>Implications for further research - It is difficult to see how a better study of this topic could be conducted in the primary care setting. The research agenda concerning the management of depression in primary care should move on to address important questions such as the most appropriate threshold of severity at which to commence antidepressant medication, the effectiveness of strategies to improve recognition of depression and quality of management of identified patients, and the efficacy of interventions to improve persistence in treatment taking by patients
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