Antidepressants Trial in Parkinson's Disease

Parkinson's disease is a progressive neurological disorder that leads to increasing disability and functional decline. Currently no medications have been shown to halt or delay disease progression and one of the most common complications in patients with this diagnosis is depression . Depressive disorders which affects approximately 40% of patients with Parkinson's disease. They are linked to functional impairment, cognitive decline and faster disease progression and are the main determinant of poor quality of life in Parkinson's disease. Psychological therapies are used via standard access to appropriate psychological services in the NHS, but often antidepressant medications are required. Despite the high incidence of depression in this population, However, no conclusive evidence on appropriate choice of antidepressants in Parkinson's disease exists in the NHS, and the risk of worsening of Parkinsonism and aggravation of non-motor features of Parkinson's disease by antidepressants pose particular challenges in this population.

Based on the previous evidence from small trials, the hypothesis is that both selective serotonin reuptake inhibitors and tricyclic antidepressants are effective compared to placebo and the difference in efficacy between tricyclic antidepressants and selective serotonin reuptake inhibitors is likely to be small, but that the tolerability of selective serotonin reuptake inhibitors is higher in this population than that of tricyclic antidepressants due to the rate of adverse effects. The trial is designed to have statistical power to identify effects that are clinically important and slightly smaller than the pooled effects identified in the existing trials of selective serotonin reuptake inhibitors.

Escitalopram is an selective serotonin reuptake inhibitor similar to citalopram, the most widely used selective serotonin reuptake inhibitor in the UK. Both citalopram and escitalopram, the S-enantiomer, are now off-patent with comparable costs and similar trial results. Until recently, escitalopram has been used less commonly in the NHS as because it was more expensive. However comparative trial data in major depression (including non-industry funded research) suggest that escitalopram is more effective than citalopram with similar or lower rates of side effects, and that it is associated with increased probability of response in trials of older patients with dementia and agitation. In addition, it has been reported that escitalopram has the highest probability of remission and is the most effective and cost-effective pharmacological treatment in a primary care setting.

Amitriptyline is the most widely used tricyclic antidepressants in the UK, but is used predominantly at low doses for pain and insomnia in Parkinson's disease. The side effect profile of amitriptyline makes it poorly tolerated in patients with Parkinson's disease at higher, antidepressant doses. Nortriptyline is a metabolite of amitriptyline. However, unlike amitriptyline it has mainly noradrenergic effects, and weakly blocks dopaminergic reuptake. It also has fewer sedative, α1-blocking and anticholinergic effects than amitriptyline (by a factor of 8). It has been evaluated in multiple trials over several decades and its efficacy and adverse event profile in depressive disorders has been well studied. The trial evidence on tricyclic antidepressants in depression in Parkinson's disease mainly reports on nortriptyline and desipramine (which is not available in the NHS). Whilst nortriptyline has a slightly higher cost than amitriptyline in the NHS, nortriptyline is a more appropriate medication for treatment of depression in this population. In addition, there is accumulating evidence from pre-clinical studies that nortriptyline may delay disease progression in Parkinson's disease.

Patients who meet eligibility criteria at the screening visit will be randomly assigned to receive 52 weeks of double-blind treatment with either escitalopram, or nortriptyline or placebo in a 1-1-1 ratio.

For the first two weeks of double-blind treatment, participants aged 65 years and under will be instructed to take one tablet per day of study drug, containing either 5 mg escitalopram or 25mg nortriptyline or placebo. Thereafter, the daily study medication dosage will be increased by one tablet per day, at two-weekly intervals, to a maximum of four tablets per day unless a subject is experiencing troubling side effects. In those aged over 65 years and in those with hepatic impairment the dose will be increased to two tablets after 2 weeks only, from 5 mg escitalopram to 10mg escitalopram or from 25 nortriptyline to 50mg nortriptyline.

After the primary endpoint at 8 weeks, all participants will continue on the same dose until the study visit at 52 weeks with an intermediate assessment at 26 weeks. Following the study assessment after 52 weeks on medication, the trial drug will be tapered off over 4 weeks in dose reductions of 25 mg for nortriptyline and 5mg for escitalopram every week (4 weeks for participants 65 years or under and 2 weeks for participants aged over 65 years or those with hepatic impairment).