Title: PAX-D: Randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression
Funder: Medical Research Council

Abstract: Clinical depression is a common disorder usually treated in primary care with psychological therapies and antidepressant medication._x000D_ _x000D_ A significant proportion of people (about 2-3 in 10) do not improve with current first-line therapies and are regarded as having 'treatment resistant depression' (TRD)._x000D_ _x000D_ TRD is a major problem for both patients and society because of the high level of suffering and associated disability. Current medicines for TRD are not particularly effective for many people and often have side effects which patients find distressing._x000D_ _x000D_ The aim of the present study is to test a medicine already commonly used in Parkinson's Disease, pramipexole, for its effectiveness in patients with TRD. Pramipexole is unlike current antidepressant drugs in that it acts like a brain chemical called dopamine, which is known to influence the energy with which people pursue goals and how rewarding they find them._x000D_ _x000D_ We plan to carry out a study in patients with TRD in which pramipexole is compared with a placebo (dummy tablet) over 12 weeks and up to 48 weeks._x000D_ _x000D_ Through this clinical trial we will be able to see how effective pramipexole is in TRD and also to assess its side effects and how patients find the experience of taking it._x000D_ _x000D_ We will also ask patients to carry out a computer task designed to measure how pramipexole affects the dopamine system in the brain and how far this can explain its antidepressant effects._x000D_ _x000D_ Patients have been involved in the design of the study and will continue to play a part in helping us refine the methods we use and understanding the results._x000D_ _x000D_ If pramipexole is effective it could become a very useful treatment option for patients with TRD and this information will be disseminated through scientific publications, meetings with patient groups and NHS innovation programmes

Lay abstract: Treatment resistant depression is associated with considerable personal, social, and economic burdens. Patients who fail to respond to two first-line antidepressant medications (about 20-30%) have a greatly reduced chance of responding to subsequent treatments (less than 20%). Pramipexole is quite distinct pharmacologically from conventional antidepressants and is the only agent proposed for the treatment of resistant depression which stimulates dopamine receptors directly. Dopaminergic signalling plays a key role in learning about and responding to rewarding stimuli. Impairment of the response to reward is a core cognitive process underlying key depressive symptoms such as anhedonia and loss of motivation. Pramipexole therefore potentially offers an innovative approach to the treatment of resistant depression which would have substantial benefits to patients and further economic benefits in view of the large number of working days lost to chronic depressive disorders with a cost to the UK estimated to be £11 billion a year in 2011, according to a House of Commons Report. It also promises new insights into disease mechanism. _x000D_ _x000D_ The aim of the proposed study is to conduct a randomised, double-blind, placebo-controlled, efficacy study of adding the dopamine agonist, pramipexole, to the antidepressant medication of patients with treatment-resistant depression. The trial will provide a more rigorous test of the the potential beneficial effects of higher dose pramipexole that were observed in a recent US case series. In treatment-refractory depressed patients, pramipexole will be titrated with the aim of achieving a daily dose of 3 mg over five weeks. We will study 204 patients (aged above 18) who meet criteria for DSM-5 major depression and who have not responded to at least two courses of antidepressant medication._x000D_ _x000D_ The primary outcome will be symptomatic change on the self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) between baseline and 12 weeks. Other outcome measures will be tolerability, safety, efficacy, health economics, functional outcomes and dropout rates with pramipexole treatment measured up to 48 weeks. Embedded within the placebo-controlled trial is a mechanistic investigation of the effect of pramipexole treatment on computationally measured sensitivity to reward and punishment. This computational measure will be used to assess the dopaminergic mechanism of action of pramipexole in ameliorating depressive symptomatology._x000D_ _x000D_ The sample size for the proposed study is based on achieving 90% power to detect a 3 point between-groups difference on the QIDS-SR while at the same time providing adequate power for the mechanistic/meditational analysis. _x000D_ _x000D_ The duration of the study will be 48 months (3 months set-up, 6 months piloting, 24 months recruitment, 12 months follow-up, 3 month write-up) based on an anticipated recruitment rate of 8 patients per month. The main study will be preceded by an intensively monitored, single site (Oxford) 6 month internal pilot in 20 depressed patients to troubleshoot trial procedures and assure feasibility. This internal ipilot will be used to ascertain the tolerability of pramipexole as well as the probable recruitment rate.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH