Cognitive-behaviour therapy and losartan
Research type
Research Study
Full title
The effect of single-dose losartan on the basic effects of cognitive-behaviour therapy for panic disorder - a randomized double blind placebo-controlled trial
IRAS ID
191870
Contact name
Andrea Reinecke
Contact email
Sponsor organisation
University of Oxford
Eudract number
2015-003542-68
Duration of Study in the UK
3 years, 0 months, 31 days
Research summary
Research Summary
Panic disorder is characterised by brief periods of intense and sudden physical symptoms, such as extreme palpitations or dizziness, and is usually accompanied by a fear of death or dying. Cognitive-behavioural therapy (CBT) is an effective talking treatment, but courses are long and cost-intensive and difficult to access. This study aims to develop an effective novel combination treatment to reduce duration and costs of interventions. To improve efficacy of treatment, it is important to identify how it works. We have recently shown that CBT for panic disorder affects the way in which the brain processes threatening information. Very early on in treatment, patients already process information in a more positive way, and such early changes are related to how well the patient responds to treatment in the longer term. Treatments which boost these early effects on emotional processing may therefore improve the efficacy of treatment for panic disorder. Research in rodents shows that the blood pressure medication losartan improves the unlearning of fear, possibly by stimulating a mechanism in the brain which plays a core role in our ability to make new connections and retain information. Studies in humans confirm that the drug improves memory, and that it can prevent the development of severe anxiety disorders. This study will establish the potential of single-session CBT in combination with losartan as a stand-alone treatment for panic disorder, and it will determine the basic mechanisms of such an augmentation effect. The findings will have crucial implications for the development of a new and cost-economic treatment with the potential for low-threshold access for a higher number of patients with anxiety disorders.
Summary of Results
Study Background
20% of the population suffer from an anxiety disorder at some point in their lives. However, even the most effective treatment – exposure therapy – only works in less than half of patients. There is an urgent need to improve treatments for anxiety. Neuroscience research has tried to identify brain characteristics that make it more likely for a patient to respond to treatment, to use this knowledge to improve the effectiveness of interventions for more patients.
This line of research has shown that anxiety patients show characteristic negative biases in emotional information processing. For instance, their attention is captured more by negative facial expressions than neutral or positive faces. It is thought that such biases are fuelling anxiety. We have recently shown that a proportion of anxiety patients respond to exposure therapy very rapidly, after only one session. Interestingly, those rapid responders showed a drastic reduction in negative attention bias – within only 24 hrs of single-session exposure therapy. Further, the more attention bias had reduced during treatment, the more patients’ anxiety symptoms improved over the following month. Such findings suggest that reducing negative attention bias is a crucial step towards resolving anxiety symptoms.
We have recently shown in healthy volunteers that a single dose of a licensed blood pressure medication called losartan reduces negative attention bias. This could mean that taking losartan before exposure therapy might help more patients with an anxiety disorder benefit from treatment – by improving the reduction in negative attention bias necessary for anxiety reduction.
Study Question
In this study, we wanted to find out whether having losartan before exposure therapy would reduce negative attention bias more than having a placebo pill. We also wanted to find out if patients who took losartan would feel noticeably less anxious a few weeks after treatment than patients who took placebo.
Study Methods
Between 2018 and 2023, we asked for volunteers with panic disorder to take part in a study based at the University of Oxford. Panic disorder is a severe form of anxiety where normal physical symptoms such as a brief increase in heart rate spiral into severe fear of an imminent medical emergency, such as a heart attack. These patients then often avoid situations where escape is difficult, for fear of not getting medical help in time. Forty volunteers were included in the study.
These volunteers were randomly allocated to one of two groups. The either received a single dose of losartan or a dummy pill containing no medicine (placebo) one hour before a single session of exposure therapy. The tablets looked identical for all volunteers. Neither the re-searchers nor the volunteers knew which type of pill they were taking (known as a ‘double blind’ trial).
Patients visited the department in Oxford on two days in a row. On day 1, they received a capsule either containing losartan or placebo. One hour later, when losartan is thought to be most effective, patients received a single session of exposure therapy. During this session, patients face a situation they usually avoid, for fear of having a panic attack. This allows them the experience that the situation is in fact safe, and not threatening.
Final Report Notification version 1.0, July 2024
On day 2, patients worked on a battery of computer tasks, including a faces dot probe task that allows us to measure attention bias for negative facial expressions over neutral faces.
Before treatment on day 2, on day 2, and also 1 month and 6 months after treatment (online calls), we measured symptoms of anxiety and depression, using patient self-report and clinician-ratings.
STUDY FINDINGS
We had the following main findings:
i) Regarding our primary outcome marker (negative bias in a faces dot probe task), participants given losartan did not show lower negative attention bias than participants given placebo on the day after treatment. This result is likely due to the placebo group showing a more drastic reduction in negative attention bias than that seen in our previous studies of this nature.
However, on a secondary outcome measure that also assesses negative bias (visual search task), losartan participants compared to placebo participants showed significantly lower negative bias on the day after treatment.
ii) Participants given losartan compared to placebo showed higher positive attention bias, that is, a preference for happy facial expressions, on the day after treatment. Such a bias has previously been suggested as a predictor of improved recovery from anxiety symptoms.
iii) Across all participants, higher positive attention bias on the day after treatment predicted stronger reduction in panic symptoms during 1-month follow-up. Negative attention bias was not related to treatment outcome.
iv) Overall, participants in both groups showed significant improvements in anxiety and depression symptoms at 1-month and 6-month follow-up. Participants given losartan compared to placebo did not show stronger improvements in anxiety and depression symptoms at 1- and 6-month follow-ups.
We also recorded experience of side effects. There were no serious side effects reported in the study. Volunteers given had similar levels of side effects than those given placebo.
These findings highlight increased positive attention bias as a neurocognitive potential mechanism by which exposure therapy may exert its clinical effects in anxiety disorder. This effect is in line with previous studies suggesting a relationship between higher positive bias and improved clinical outcome in anxiety. While losartan seems to improve positive attention bias more than placebo within 24hrs of treatment, this effect did not directly translate into improved clinical effects in the losartan group in this study. However, this study was not powered to identify such clinical effects.
ACKNOWLEDGEMENTS
We would like to thank all the volunteers who gave their time to make this research possible. We would also like to thank the many researchers, ethics experts, pharmacy and administrative staff involved. This study was funded by an MQ:Transforming Mental Health fellowship and sponsored by the University of Oxford. The Oxford Health Biomedical Research Centre also supported the study.
For more information about this study, you can email andrea.reinecke@psych.ox.ac.uk.REC name
South Central - Oxford A Research Ethics Committee
REC reference
15/SC/0648
Date of REC Opinion
27 Jan 2016
REC opinion
Further Information Favourable Opinion