Title: Antidepressants Trial in Parkinson's Disease (ADepT-PD)
Funder: Department of Health and Social Care

Abstract: DESIGN Multicentre, parallel-group, 3-arm RCT with internal pilot study SETTING Parkinson’s disease clinics in the UK supported by the CLRN and the UK Parkinson’s Excellence Networks and linked with the Tracking-PD study TARGET POPULATION Patients with Parkinson's disease with depressive disorder INCLUSION CRITERIA Diagnosis of idiopathic PD according to the UK Brain Bank criteria; aged 18 to 85 years; DSM V diagnosis of a depressive disorder and BDI-II score >/=14 EXCLUSION CRITERIA Women who are pregnant, breastfeeding or of childbearing potential without effective contraception; patients not able to read or to complete self-rating questionnaires; no patients will be excluded based on PD motor severity, but patients unable to communicate answers to outcome measures will be excluded; patients with minimental state examination score <21 or unable to give consent; mood fluctuations related predominantly to off-periods; treatment with an SSRI or TCA within 4 weeks of enrolment; contraindications to nortriptyline and/or escitalopram Treatment with antiparkinsonian medication should be optimized and stable within 4 weeks of inclusion and with no plans to change up to primary endpoint INTERVENTION Nortriptyline (target dose 100mg), escitalopram (target dose 20mg) or placebo, in addition to available standard psychological care OUTCOME MEASURES Primary BDI II at 8 weeks of treatment. The BDI-II is a patient-completed scale that has been shown to be valid, sensitive and responsive in patients with PD Secondary Clinically significant adverse events and number of drop-outs; Toronto Side Effects Scale; Falls diary; MDS-UPDRS scale; levodopa-equivalence dose; EQ-5D-5L; Shortened Client Service Receipt Inventory; ICECAP capability index measure; Carer EQ-5D-SL and Carers QoL Questionnaire Parkinsonism; Patient-reported Global Clinical Impression scale (CGI); Montreal Cognitive Assessment (MoCA); Parkinson Anxiety Scale; SCOPA-sleep; Demographic data, comorbidities, medication modified; assessment of participant’s awareness of allocated treatment arm; repeat assessments at 26 and 52-weeks SAMPLE SIZE At 90% power and a significance level of 0.025 (to account for multiple comparisons) we require 113 per group to detect a 3-point BDI II difference [SD for change 6.35] for the escitalopram–placebo and the nortriptyline–placebo comparisons at 8 weeks. Allowing for 20% attrition, 136 will need to be recruited per arm (n=408 overall). For the estimation of adverse events, a trial with 136 subjects in each experimental condition will provide 95% confidence intervals on the comparison between active agents ±12% when the rate of events is around 50%, and ±7% when the rate of events is around 10%. TRIAL DURATION 47 months, including a 24 months recruitment period (including 6 months internal Pilot study), with a double-blind trial duration per participant of 8 weeks to primary endpoint and of 52 weeks to secondary endpoint. STOP CRITERIA If recruitment <50% of target, the nortriptyline arm will be stopped. Rate of AEs necessitating withdrawal >30%. Loss to follow up before primary outcome >20%. Adherence to trial medication <60%. PPI INVOLVEMENT The study will receive strong input from our PPI members throughout the study, in advising on and reviewing study methods and materials, engagement, monitoring of the study, and dissemination.

Lay abstract: Parkinson’s disease is a progressive disorder that is associated with physical problems, shakes and mobility problems, as well as psychological distress. Depression is a common feature of the disease. The quality of life of people with Parkinson’s who have depression is much worse than of those who do not. Antidepressants are commonly prescribed, but we do not know whether they are helpful for treating depression in Parkinson’s, especially when available standard psychological care has not worked. Nor do not know which antidepressant is the most useful, as side effects may limit their use in people with Parkinson’s. In the NHS, the first line treatment for depression is a group of antidepressants called SSRIs. However, SSRIs have some side effects that may worsen mobility problems associated with Parkinson’s disease. Another group of antidepressants, called “tricyclics”, have also been used in Parkinson’s. These are generally only recommended as second line treatment in depression, because, overall, they have more side effects than SSRIs. However, they may have fewer specific side effects with respect to movement problems. We propose to determine whether an SSRI called escitalopram and a tricyclic called nortriptyline, which are already available in the NHS, are beneficial at reducing symptoms of depression, measured by a scale called the BDI-II. As people may improve because they believe a treatment works, both these antidepressants will be compared with an inert pill called a placebo. We will use a strategy called “blinding” in which neither the participants nor the researchers will know what treatment has been received, as this may influence the response. We will also compare escitalopram with nortriptyline with regards to side effects and measure these using a standard scale. We aim to recruit 408 people with Parkinson’s and depression from across the UK . All participants will receive standard psychological care and in addition to being allocated to one of three groups by chance using a process called randomisation: group 1 will receive nortriptyline, group 2 escitalopram, and group 3 placebo. Although we will be comparing our interventions at 8 weeks after entry into the study, we also wish to know whether the benefits gained continue for up to a year. Whilst we will try to remain blind to the group allocation, as this may influence how we rate people’s response to treatment, in some cases it may be necessary to break this. This may be necessary where there is a need to start antidepressant treatment or switch antidepressant if the patient is not responding to the current intervention. We shall also collect information about the costs of the different interventions and the use of health service resources. Our Trial Steering Committee, which includes people with Parkinson’s, will advise about various aspects of the study, e.g. assessments, questionnaires, arrangements for baseline and follow-up visits, and dissemination. The research group consists of researchers and clinicians with expertise in Parkinson’s, in depressive disorders, in clinical trials, and in psychology, who have conducted several large trials including in Parkinson’s, and a person with personal experience of depressison in Parkinson’s. The trial will last 47 months and will follow all statutory research governance requirements to ensure that it is high quality, safe and ethical.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL