Serotonin effects on brain function and their relationship to relapse when stopping antidepressants
| ISRCTN | ISRCTN15397197 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15397197 |
| Integrated Research Application System (IRAS) | 365238 |
| Central Portfolio Management System (CPMS) | 72937 |
| Wellcome Trust grant code | 221826/Z/20/Z |
| Sponsor | University College London |
| Funder | Wellcome Trust |
- Submission date
- 13/03/2026
- Registration date
- 12/05/2026
- Last edited
- 12/05/2026
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
Background and study aims
Many people experience a relapse of depression if and when they stop their antidepressant medication. We do not know how stopping antidepressants leads to depression returning. We also do not know who will have a relapse if they stop their medication. This study aims to understand this better.
The study will use behavioural and brain measurements (magnetoencephalography; MEG). It will look at the effect of briefly and reversibly lowering serotonin through a dietary manipulation (acute tryptophan depletion; ATD) akin to a protein drink. This is thought to ‘simulate’ what happens when antidepressants are stopped. Looking at brain function at this time might help us understand how stopping antidepressants results in relapse. The study will work with people who had depression but are now well, while still taking an antidepressant medication, but would like to stop. Participants will undergo brain imaging and ATD before stopping their medication, and will then be monitored for a relapse of depression for six months. This way, the relationship between lowering serotonin in brain function and the relapse after stopping antidepressants can be better understood.
Ultimately, the hope is that the measurements could help us understand what the mechanisms of depression relapse after antidepressant discontinuation are, and how serotonin is involved in it.
Who can participate?
Adults between 18-64 years who had depression, but are now well, who are taking an antidepressant medication and would like to stop their antidepressant medication.
What does the study involve?
- Participants will stop their antidepressant medication
- They will do tasks on the computer at home after they have stopped their antidepressant medication.
- The study team will monitor how participants are doing through regular phone/video calls.
What are the possible benefits and risks of participating?
Benefits: The study team will monitor participants’ depression carefully while and after they stop their antidepressant medication. This could allow them to restart treatment quickly if another depressive episode occurs. The results of this study may improve treatment and increase understanding of treatments for future patients.
Risks: Acute tryptophan depletion has a well-characterized safety profile. The main risk is a temporary occurrence or worsening of depressive symptoms, with the possibility of temporary suicidal thoughts occurring. These can be mitigated by providing food containing tryptophan. Other possible side effects include nausea, headache, dizziness, or gastrointestinal discomfort, which can be mitigated by mixing the amino acid drinks with chocolate or strawberry flavour to improve the flavour.
Where is the study run from?
University College London (UK).
When is the study starting and how long is it expected to run for?
April 2026 to February 2029
Who is funding the study?
Wellcome Trust, UK
Who is the main contact?
1. Dr Michaela Poppe (public), m.poppe@ucl.ac.uk
2. Professor Quentin Huys (scientific), q.huys@ucl.ac.uk
Contact information
Public, Scientific, Principal investigator
UCL Division of Psychiatry
4th Floor Maple House
149 Tottenham Court Road
London
W1T 7NF
United Kingdom
 ORCID ID |
0000-0002-2685-1933 |
|---|---|
| Phone | +44 (0)20 7679 9311 |
| m.poppe@ucl.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Allocation | Randomized controlled trial |
| Masking | Blinded (masking used) |
| Control | Placebo |
| Assignment | Crossover |
| Purpose | Basic science, Diagnostic |
| Scientific title | Predicting Relapse After Discontinuing Antidepressants using acute tryptophan depletion and Magnetoencephalography |
| Study acronym | PRADAM |
| Study objectives | 1. To examine the reversible and temporary impact of reducing serotonin on cognition in people who have recovered on serotonergic antidepressants and are still taking their antidepressant medication 2. To examine whether the cognitive and affective effects of reducing serotonin relate to who will experience a relapse of depressive symptoms when they stop serotonergic antidepressant medications |
| Ethics approval(s) |
Approved 01/04/2026, East Midlands - Leicester South Research Ethics Committee (3 Piccadilly Place, London Road, Manchester, M1 3BN, United Kingdom; +44 207 104 8193; Leicestersouth.rec@hra.nhs.uk), ref: 26/EM/0044 |
| Health condition(s) or problem(s) studied | Depression |
| Intervention | This is a basic science study involving procedures with human participants. Participants in the study will visit UCL for two study days prior to tapering their antidepressant medication. On these days, they will undergo a within-subject, randomized, double-blind, controlled dietary manipulation and brain imaging using magnetoencephalography (MEG). The randomisation element determines who receives the active amino acid mix on Day 1 and who receives it on Day 2. All participants will receive the active amino acid mixture - some will get the active mixture on Day 1 and the control mixture on Day 2, and others will get the active mixture on Day 2 and the control mixture on Day 1. They will also do behavioural tasks and fill in questionnaires. They will then taper their medication down and enter follow-up for 6 months to assess for a relapse of depression. Study participation will not entail meaningful changes to the participant’s depression treatment. However, monitoring after the discontinuation may help re-engage treatment quickly if appropriate. Antidepressant discontinuation is entirely clinically managed and would occur irrespective of study participation; the research protocol does not prescribe, modify, or evaluate medication dosing. Participants will be free to adjust the tapering speed in consultation with their GP or prescribing doctor. Randomisation: Blocked, fully concealed 1:1 randomisation. A randomiser independent from the study team produced the randomisation list and informed the kit producer directly. Kits were labelled with a random alphanumeric keycode. |
| Intervention type | Other |
| Primary outcome measure(s) |
|
| Key secondary outcome measure(s) |
|
| Completion date | 01/02/2029 |
Eligibility
| Participant type(s) | |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 64 Years |
| Sex | All |
| Target sample size at registration | 70 |
| Key inclusion criteria | 1. Have had at least two episodes of depression 2. Be aged 18 to 64 (older people are excluded as different assessments for depression are used in older age groups) 3. Be taking a serotonergic antidepressant medication (citalopram 20 mg or more, escitalopram 10 mg or more, sertraline 100 mg or more, fluoxetine 20 mg or more, paroxetine 20 mg or more, clomipramine 50 mg or more or mirtazapine 15 mg or more) that was started to treat an episode of depression 4. Be in stable remission for the past 6 weeks, with a Patient Health Questionnaire (PHQ-9) total score less than 7 5. Have satisfactory treatment adherence to medication 6. Be intent on stopping their antidepressant medication |
| Key exclusion criteria | 1. Meet internationally agreed (ICD-10) criteria for a depressive illness 2. Have a baseline PHQ-9 score greater than or equal to 10 3. Have bipolar disorder, psychotic illness, dementia, alcohol or substance use disorder or a terminal illness 4. Are not able to complete self-administered questionnaires in English 5. Are pregnant or intend to get pregnant within the next 6 months 6. Fail the pre-test online behavioural task assessment 7. Meet any MEG exclusion criteria including: 7.1. Epilepsy 7.2. Insulin-dependent diabetes 7.3. Magnetic parts in the upper body or head (such as piercings, dental wire, permanent eye-liner) 7.4. Are otherwise not able to tolerate or not suitable for MEG |
| Date of first enrolment | 13/04/2026 |
| Date of final enrolment | 12/04/2028 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centre
London
WC1E 5BH
England
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. Further details are not yet available. |
Editorial Notes
13/03/2026: Trial's existence confirmed by the National Institute for Health and Care Research (NIHR) (UK).
