What is Nortriptyline and why is this drug important in CPT's research programme?

Nortriptyline belongs to a class of antidepressant drugs called 'tricyclics'.

As Parkinson’s affects the whole brain and not just the movement-related centres, it also causes a range of symptoms which include mood and emotional regulation. Indeed, depression constitutes one of the major non-motor symptoms affecting people with Parkinson’s (PD), and tricyclics are often used in its management. Tricyclics are known to have a range of effects on both neurons as well as the surrounding glial cells which support neurons, they have been shown to stimulate neurogenesis and are associated with the release of neurotrophic factors.

Note: Tricyclics are not the only antidepressants available for people with Parkinson’s. Selective serotonin reuptake inhibitors (SSRIs) with a more favourable side effect profile, are also often used.

Why might Nortriptyline be a beneficial treatment in Parkinson’s?

Research in over 2000 people with Parkinson’s taking tricyclics has suggested that these drugs may be associated with a significant delay in the introduction of dopaminergic drugs and stabilisation of UPDRS motor severity scores over the first year of treatment. In addition, a significant body of research in animal models of Parkinson’s has shown that long term tricyclic treatment increases neuronal survival, and prevents the development of movement related problems which are a core feature of Parkinson’s by apparently counteracting the progressive degeneration of dopamine neurons.

Why do researchers think Nortriptyline has the potential to slow, stop or reverse Parkinson’s?

The abnormal clumping of alpha-synuclein (an important protein involved in synaptic transmission) lies at the core of the pathological process underlying Parkinson’s. Although the main functions of alpha-synuclein are still not fully understood, we do know that it is involved in the release of dopamine, a neurotransmitter that is critical in Parkinson's through its central role in movement. A number of studies have addressed the potential of Nortriptyline to interfere with this pathological process directly. Researchers have found that while the drug does not clear up existing toxic aggregates, it does disrupt the aggregation process and renders alpha-synuclein effectively more soluble and hence easier to clear within the cell. Although we do not yet know exactly what causes alpha-synuclein to misfold and form these harmful clumps, targeting this process is a major approach for disease modification. Finding a way to prevent alpha-synuclein accumulation, reducing its gene expression or promote its effective clearance, may therefore lead to a cure.

Why is alpha-synuclein a research target of The Cure Parkinson's Trust (CPT)?

Nortriptyline has been reviewed extensively by the international Linked Clinical Trials committee and was prioritised in 2016 as having biological pathways of interest associated with Parkinson's. An intriguing opportunity has now arisen to investigate whether Nortriptyline can slow, stop or reverse Parkinson’s, through collaboration with a large NIHR funded trial on the efficacy of Nortriptyline versus Escitalopram (an SSRI) for depression in PD. This large, multi-site study led by Professor Anette Schrag at UCL will be run across 30 different sites in the UK. The trial itself will run over four years, however, patient participation will be for one year with assessments at 8 weeks, 6 and 12 months.

CPT is now supporting a sub-study which will be run as an adjunct to the main trial, in which existing participants will simply undergo some additional assessments of their movement symptoms after a year of treatment with Nortriptyline. This approach makes the most of participants’ time and efforts, and maximises all we can learn as a Parkinson’s community from a large scale study on symptom management, through additionally investigating the critical question on the potential of Nortriptyline to alter the actual course of the disease. An exciting and novel feature of this approach will involve the use of wearable technology to allow continuous measurement of movement over a week, in addition to the standard OFF-state UPDRS assessments.

Read more about the trial here.