PAX-D: Randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression
Around a quarter of people with depression do not get better after trying two or more standard antidepressants, leaving them with few remaining options. A UK team is now testing whether pramipexole—a drug that directly stimulates dopamine receptors, unlike conventional antidepressants—can help these patients when added to their existing medication. The problem is that treatment-resistant depression is common and costly. Patients who fail two antidepressants have less than a 20% chance of responding to further drugs. The condition costs the UK an estimated £11 billion a year in lost productivity. Current treatments largely target serotonin, but many patients’ symptoms—particularly loss of motivation and inability to feel pleasure—may stem from a blunted dopamine-driven reward system. The trial will randomise 204 patients to receive either pramipexole or a placebo alongside their usual antidepressant, tracking depressive symptoms over 12 weeks. A mechanistic component will use computer-based tasks to measure how the drug affects sensitivity to reward and punishment, testing whether dopamine stimulation is the active mechanism. If pramipexole proves effective, it would offer a genuinely different pharmacological approach for a patient group that currently has few evidence-based options. It could also clarify the role of dopamine dysfunction in depression, pointing toward more targeted treatments.
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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. 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. 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. 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. 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.
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