Title: Pregabalin for treatment resistant generalized anxiety disorder
Funder: Department of Health and Social Care

Abstract: There has been an increase in anxiety disorders in the last few years. Generalised Anxiety Disorder (GAD) is diagnosed when a person has been worrying excessively, and having trouble sleeping and concentrating for at least six months. This problem is more common than depression but is less likely to be recognised. Psychological therapy (“talking treatments”) can help some people, but is not always easy to access. There are also medications that can work: antidepressants are most often prescribed for GAD, and about half of those people who take them find them effective. However, there is no clear guidance for doctors to help them treat those who do not respond to antidepressants._x000D_ _x000D_ It is common to add a second medication when the first drug prescribed is only partly effective. There are other drugs that could be considered for anxiety. Benzodiazepines, such as “Valium”, can be helpful in the short term, but become addictive so are not a good choice for a longer-term problem like GAD. Antipsychotic drugs are sometimes used but they can have serious side effects. Pregabalin, is an effective anti-anxiety drug which is often also prescribed for nerve pain. It is well tolerated and generally considered very safe but there are some concerns that some people may become dependent on pregabalin or find it hard to come off due to withdrawal symptoms. Misuse or pregabalin by people with existing addiction problems led to it becoming a Schedule 3 controlled drug._x000D_ _x000D_ We plan a trial to see if the combination of an antidepressant and pregabalin is effective for anxiety where the antidepressant alone has not been very effective. The best way of doing this is to ask the appropriate people to join a study where they will be put into one of two groups at random. One group will be given pregabalin and the other an inactive placebo to take alongside their antidepressant. The participants and the research team will not know which group they are in. Each participant will be in the trial for just over six months. We will then have a clear and unbiased understanding of whether adding pregabalin to antidepressants was helpful, and if there were any problematic side effects. At the end of the study, we will also ask the participants to gradually reduce their medication and find out if they have withdrawal effects. We will interview some participants to find out their experiences of taking pregabalin and will also interview some GPs to find out if this combination of drugs is something they feel comfortable with prescribing._x000D_ _x000D_ We will recruit people from diverse groups across over 100 general practices in 3 centres, to make sure our results will apply as widely as possible. This is an important study because anxiety is so common and can be disabling, and because so many sufferers do not respond to the current treatments available._x000D_ _x000D_ We will ensure people with lived experience of GAD are involved in the research at all stages so that patient views are fairly represented. We have a PPI co-applicant who will work on the embedded interview study, and will organise a lived experience reference group to contribute to all aspects of the study._x000D_ _x000D_ We will publicise our results to the scientific community, general practitioners, members of the public and patients. We will seek advice and help from our PPI co-applicant and lived experience reference group who will advise on the optimal way to disseminate to patient groups.

Lay abstract: Generalised anxiety disorder (GAD) is characterised by at least 6 months of symptoms including disproportionate worry, nervousness, poor concentration and sleep disturbance. GAD is a disabling condition that is highly comorbid with depression and other anxiety disorders. The prevalence of GAD is higher than depression in the UK yet is less often recognised in general practice. However, the rate of GAD recorded in primary care has increased dramatically especially in young people._x000D_ _x000D_ Both cognitive behavioural therapy (CBT) and antidepressants are effective treatments for GAD but partial or non-response is common. We propose a randomised clinical trial to evaluate the addition of pregabalin to people who have not responded or partially responded to treatment with antidepressants. There is evidence that pregabalin alone is an effective treatment for GAD but the evidence for augmenting antidepressants with pregabalin is very limited._x000D_ _x000D_ AIMS_x000D_ 1) To investigate whether pregabalin, in addition to an antidepressant, is an effective and cost-effective treatment for generalised anxiety disorder (GAD) in people who have not responded to antidepressant treatment_x000D_ 2) To investigate any adverse effects associated with combined treatment of pregabalin and antidepressants_x000D_ 3) To investigate withdrawal symptoms from pregabalin when it is used in combination with antidepressants_x000D_ 4) To investigate the acceptability of prescribing pregabalin in addition to antidepressants for GAD from the perspectives of patients and general practitioners using qualitative methods_x000D_ _x000D_ Eligible participants will have an ICD11 diagnosis of GAD, be aged 18-74 years, be currently taking an antidepressant and meet a symptom severity criterion. They will not have responded to 2 or more antidepressants. Exclusions will include those taking regular benzodiazepines, zolpidem, zopiclone, opioids or antipsychotics. People with psychosis, bipolar disorder or alcohol or substance misuse will be excluded._x000D_ _x000D_ We will randomise between pregabalin 50-200mg and placebo using a flexible dosing strategy that will mimic usual care and enhance retention. All will receive usual care from their general practitioner who will continue to prescribe their existing antidepressant. _x000D_ _x000D_ We will follow up the participants for 26 weeks. Our primary outcome will be anxiety symptoms (assessed using the GAD7) at 12weeks. Secondary outcomes will include depressive symptoms, quality of life and adverse effects. We will collect data on resource use and carry out a health economic analysis. At the end of the study, all those still on study medication will have a double-blind tapered withdrawal over 28 days and an evaluation of any withdrawal effects that were experienced._x000D_ _x000D_ Our qualitative study will interview about 25 participants who have remained in the trial and about 10 who have dropped out early. Our PPI co-applicant will conduct some of these interviews and a lived experience reference group will assist in the design and analysis. We will also interview about 15 general practitioners (GPs) about their experiences. _x000D_ _x000D_ We have a PPI co-applicant and we will arrange a lived experience reference group to inform the trial. We have included costs to reimburse the time of PPI contributors.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH