This is a randomised trial in a NHS setting, comparing the clinical effectiveness and cost-effectiveness of the selective serotonin reuptake inhibitor, escitalopram, and of the tricyclic antidepressant, nortriptyline, to placebo, undertaken in a real-life setting in addition to standard psychological care for the treatment of patients with depression in Parkinson's disease. Participants will be randomly allocated 1:1:1 to receive escitalopram or nortriptyline or placebo.

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).

Inclusion Criteria:

1. Patients with a diagnosis of idiopathic Parkinson's Disease, based on a history and neurological exam performed by the enrolling investigator with presence of at least two of the three cardinal signs of Parkinson's Disease: rigidity, bradykinesia, and rest tremor with no evidence of diagnostic alternatives. Patients who have been treated with levodopa must have demonstrated a clear response.
2. Aged 18 years old or above
3. Fulfilling diagnostic (DSM-V) criteria for a depressive disorder (i.e., major depressive disorder or persistent depressive disorder) or operationally defined subsyndromal depression (presence of two or more depressive symptoms at threshold or subthreshold levels, at least one of which has to include depressed mood or anhedonia
4. Beck Depression Inventory-II (BDI-II) score ≥14
5. Written informed consent provided
6. Treatment with antiparkinsonian medication is optimised or stable for at least 4 weeks before date of randomisation and there are no plans to change up to primary endpoint (8 weeks).

Exclusion Criteria:

1. Women who are pregnant, breastfeeding or of childbearing potential without effective contraception (hormonal or barrier method of birth control; or abstinence)

2. Patients not able to communicate answers to the self-rating questionnaires

3. Patients with Montreal Cognitive Assessment (MoCA) score <16 or without capacity to consent

4. Treatment with an antidepressant within 4 weeks of enrolment (except for a small dose of amitriptyline up to 50 mg for indications other than depression)

5. Patients with known severe liver failure.

6. Absolute contraindications to escitalopram or nortriptyline. These include:

   1. Patients with known QT-interval prolongation or congenital long QT syndrome.
   2. Recent myocardial infarction (<3 months), any degree of heart block or other cardiac arrhythmias precluding treatment with nortriptyline or escitalopram according to clinical judgement.

7. Medications contraindicated on nortriptyline or escitalopram. These include:

   1. Non-selective and selective irreversible monoamine oxidase inhibitors (MAOIs) within 14 days. However, the antiparkinsonian selective reversible MAO-B inhibitors rasagiline, selegiline and safinamide are not contraindicated.
   2. Concomitant QT prolonging drugs, including domperidone, apomorphine at high doses (single dose or hourly rate of >6mg), certain neuroleptics (not quetiapine or clozapine), quinine, class IA and III antiarrhythmics (amiodarone, dronedarone and disopyramide), the antihistamines astemizole, mizolastine, the antimicrobial agents sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarian treatment),and some antiretrovirals.

8. Patients indicating active suicidal ideation or intent on the BDI-II item 9 and who, after clinical review of risk using the standardised Suicide Risk Management Protocol, need to be referred for immediate treatment.

9. Participation in another clinical trial of an investigational medicinal product or device within the last 30 days.

10. Any clinical condition which in the opinion/ clinical judgement of the investigator would make the patient unsuitable for the trial due to safety concerns.

Double blind