A proof-of-concept study of an accessible lithium supplement

ISRCTN ISRCTN12858621
DOI https://doi.org/10.1186/ISRCTN12858621
IRAS number 329291
Secondary identifying numbers IRAS 329291
Submission date
25/07/2024
Registration date
01/08/2024
Last edited
09/10/2024
Recruitment status
Recruiting
Overall study status
Ongoing
Condition category
Mental and Behavioural Disorders
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year

Plain English Summary

Background and study aims:
Depression with mixed features (DMF) is where people experiencing a depressive episode also have symptoms of mania at the same time (for example, agitation, racing thoughts, reduced inhibition). DMF is common, occurring in up to a quarter of people with depression, and is associated with greater disability compared to depression without mixed features. DMF is particularly common in people with bipolar (spectrum) illnesses, and in people without a bipolar diagnosis is a significant risk factor for later receiving a bipolar diagnosis. The difficulties in treating DMF are well documented, and these challenges are compounded by the fact that DMF is often undetected in healthcare services and therefore not treated. (Full-dose) lithium is the gold standard medication for bipolar depression and mania, but is under-used because it requires frequent blood tests to ensure safety for patients. Our work, though, shows benefits of lower doses of lithium for depression and mania (when used alongside other medications) as well as cognitive function (e.g., memory). Because DMF includes symptoms of mania and depression (plus often cognitive difficulties), lower doses of lithium could be an effective add-on treatment. Mixed features are often not recognised in healthcare services, which reduces the potential for prescribed lithium. However, non-medication forms of lithium are available at a low dose (20mg) over-the-counter as a ‘nutraceutical’ (“LiOr”) and could be accessible for many people to take, if found to be effective. My previous research shows that low-dose lithium is safe, and that – anecdotally – people find it helpful for low/fluctuating mood, cognition and agitation, all particularly relevant for DMF. However, LiOr’s potential has not been explored in any reasonable-quality human studies.
This project will provide a ‘proof of concept’ to see whether LiOr could be assessed as a potential therapy at a large scale. We will recruit 40 people with DMF who are under stable ongoing treatment for depression, and measure 1) whether they agree to take 20mg LiOr daily, and how long they take it over a period of up to 6 months, 2) their levels of lithium in the blood, 3) any positive changes (e.g., to mood) over the 6-month study, 3) any negative effects or difficulties participants experience, 4) whether the measures and visits participants are asked to complete are acceptable for people. The results will give us enough information to plan a clinical trial, where LiOr can be robustly compared with a placebo to help determine whether LiOr could have benefits for people with DMF.

Who can participate?
We are looking for people aged 18 - 65 years, who are fluent in English, who do not have a diagnosis of bipolar disorder or are currently very suicidal but are having treatment for depression and have certain symptoms with their depression ('DMF'). People also have to be suitable and willing to try supplementary lithium and visit our research centre for measures 6 times over 6 months (as below).

What does the study involve?
Participants will be asked to visit our research centre 6 times over 6 months for a blood test and some questionnaires. Between visits they will be asked to take LiOr each day, so long as they are willing to do so during this time. After the first visit, we ask that the following visits are 2 weeks, 1 month, 2 months, 4 months and 6 months after the first visit.

What are the possible benefits and risks of participating?
We do not expect any significant risks or negative effects from taking part in the study. It is possible that people may feel some distress during blood tests or some of the questionnaires in visits. It is possible that people may not get on well with the lithium supplement, in which case they can lower the dose or stop taking it. On the other hand, we hope people will find benefits to mood and/or thinking skills and possibly other areas of life from the lithium supplement. Some people find the questionnaire visits interesting. Whether people experience benefits or not, findings from this study may help people in the future, as supplementary lithium is being tested to see if it is helpful for people experiencing a range of mood and brain conditions.

Where is the study run from?
South London and Maudsley NHS Foundation Trust (UK)

When is the study starting and how long is it expecting to run for?
July 2024 to January 2026

Who is funding the study?
Psychiatry Research Trust (UK)

Who is the main contact?
The study team's email address is lithium@kcl.ac.uk.
The lead researcher is Dr Rebecca Strawbridge, becci.strawbridge@kcl.ac.uk

Study website

Contact information

Dr Rebecca Strawbridge
Public, Scientific, Principal Investigator

PO74 Centre for Affective Disorders
103 Denmark Hill
London
SE5 8AZ
United Kingdom

ORCiD logoORCID ID 0000-0002-2984-1124
Phone +44 2078480088
Email becci.strawbridge@kcl.ac.uk

Study information

Study designOpen label single arm proof of concept study
Primary study designInterventional
Secondary study designNon randomised study
Study setting(s)Hospital, University/medical school/dental school
Study typeOther
Participant information sheet ISRCTN12858621 PIS MixLi_329291_v1.1_18092024.pdf
Scientific titleLithium orotate: a potential accessible supplement for people experiencing depression with mixed features.
Study acronymMixLi
Study hypothesisTo establish initial feasibility of studying a commercially available supplement (lithium orotate; LiOr) for its potential mood effects in people with depression including mixed features (DMF).
Ethics approval(s)

Approved 08/10/2024, Westminster Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 207 1048146; westminster.rec@hra.nhs.uk), ref: 24/LO/0620

ConditionPeople experiencing an episode of depression with mixed features
InterventionA lithium supplement which is currently available to purchase worldwide over the counter.
Formulation: Lithium orotate
Dose: up to 20 mg per day
Duration: Up to 6 months
Intervention typeSupplement
Primary outcome measure1. LiOr bioavailability is measured via lithium levels in serum (as per standard assay) at 2, 4, 8, 16 and 26 weeks from baseline.
2. LiOR acceptability is measured via self-report adherence (using the Tablet Routine Questionnaire) at baseline, 2, 4, 8, 16 and 26 weeks – and via discontinuation rates at the same time points.
3. LiOr subjective experiences is measured using participant-reported positive (using non-validated questions) and negative experiences (using the LiSERS scale) baseline, 2, 4, 8, 16 and 26 weeks.
4. Protocol feasibility - rates of recruitment, attrition and missing data (in putative primary outcome; below) at 2, 4, 8, 16 and 26 weeks from baseline.
Secondary outcome measures1. Candidate biomarker changes i.e., c-reactive protein is measured (as per standard assay) at baseline, 2, 4, 8, 16 and 26 weeks.
2. Mood (putative primary outcome measure) changes are measured at baseline, 2, 4, 8, 16 and 26 weeks, using 1) the Maudsley visual analogue scales for depression and mania, 2) the internal states scale (ISS), 3) the generalised anxiety disorder 7-item questionnaire (GAD7), 4) the inventory of depressive symptoms (IDS) and 5) the young mania rating scale (YMRS).
3. Functioning and cognition (putative secondary measures) changes are measured at baseline, 2, 4, 8, 16 and 26 weeks, using 1) the Functional Assessment Short Test (FAST) and 2) the THINC-IT cognitive battery.
Overall study start date25/07/2024
Overall study end date31/01/2026

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
Upper age limit65 Years
SexBoth
Target number of participants40
Participant inclusion criteria1. Aged between 18 - 65 years at study entry
2. Meet DSM-5 criteria for a current depressive episode (MINI) and exceed thresholds indicating presence of mixed features (Internal States Scale; ISS)
3. Undergoing stable pharmacological treatment for depression (intervention/dose unchanged for >6 weeks)
4. Willing to try a commercially available lithium supplement
5. Willing to attend planned study visits
Participant exclusion criteria1. Clinical diagnosis of bipolar disorder.
2. Other health condition that is severely impairing
3. Known contraindication to lithium treatment. This includes currently taking lithium
4. Unable to communicate fluently in English
5. Suicide risk
Recruitment start date28/10/2024
Recruitment end date31/07/2025

Locations

Countries of recruitment

  • England
  • United Kingdom

Study participating centre

South London and Maudsley NHS Foundation Trust
Bethlem Royal Hospital
Monks Orchard Road
Beckenham
BR3 3BX
United Kingdom

Sponsor information

Institute of Psychiatry, Psychology & Neuroscience and South London & Maudsley NHS Foundation Trust joint office
University/education

De Crespigny Park
London
SE5 8AF
England
United Kingdom

Phone +44 20 7848 0790
Email slam-ioppn.research@kcl.ac.uk
Website https://www.kcl.ac.uk/ioppn/research/research-in-slam/rd-approval

Funders

Funder type

Charity

Psychiatry Research Trust
Private sector organisation / Trusts, charities, foundations (both public and private)
Alternative name(s)
The Psychiatry Research Trust, PRT
Location
United Kingdom

Results and Publications

Intention to publish date31/07/2026
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryAvailable on request
Publication and dissemination planIt is intended that the results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals as well as a variety of routes and forms accessible to the general public. We intend to publish the study protocol. A primary publication will include all primary and secondary outcomes as per the protocol.
IPD sharing planThe datasets generated during and/or analysed during the current study are/will be available upon request from Dr Rebecca Strawbridge, becci.strawbridge@kcl.ac.uk, with the type of (anonymised) data depending on the request, available from 26 weeks after data collection has been completed, subject to participants’ consent.

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Participant information sheet version 1.1 18/09/2024 09/10/2024 No Yes
Protocol file version 1.2 08/10/2024 09/10/2024 No No

Additional files

ISRCTN12858621 PIS MixLi_329291_v1.1_18092024.pdf
ISRCTN12858621 Protocol MixLi_329291_v1.2_08102024.pdf

Editorial Notes

09/10/2024: The following changes were made to the trial record:
1. The ethics approval was added.
2. The participant information sheet was uploaded as an additional file.
3. Uploaded protocol (not peer-reviewed) as an additional file.
4. The recruitment start date was changed from 01/10/2024 to 28/10/2024.
5. The participant level data sharing statement was added.
6. The study website was added.
25/07/2024: Trial's existence confirmed by Psychiatry Research Trust.