Pregabalin for treatment resistant generalized anxiety disorder

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.

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.

AIMS

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 2) To investigate any adverse effects associated with combined treatment of pregabalin and antidepressants

3) To investigate withdrawal symptoms from pregabalin when it is used in combination with antidepressants

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

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.

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.

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.

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.

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.