A Randomized Controlled Trial Comparing Lithium Carbonate and Lamotrigine for Mood Stabilization in Patients with Bipolar Disorder Type II

The primary objective of this study is to evaluate the efficacy of **lithium** compared to **lamotrigine** in achieving mood stabilization in patients with **Bipolar Disorder, Type II** (BDII) over a 6-month period. This is clinically relevant as mood stabilization is a critical outcome for managing BDII, potentially reducing the risk of relapse and improving overall patient outcomes.

Secondary objectives include: - Assessing whether lithium decreases depression and hypomania and improves functioning and cognition compared to lamotrigine. - Evaluating if mood stabilization is higher in patients with high-sensitivity C-reactive protein (hsCRP) values greater than 3 mg/l at inclusion when treated with lithium compared to lamotrigine. - Investigating whether baseline inflammatory marker levels, such as hair cortisol and cytokines in blood samples, are reduced in the lithium treatment group after 6 months compared to the lamotrigine treatment group.

The clinical trial focuses on individuals diagnosed with **Bipolar Disorder, Type II**. The study population includes both male and female participants, aged between 18 and 70 years. Participants are required to speak and write Danish or English at a level equivalent to their mother tongue and must be capable of providing informed consent. The trial does not involve a vulnerable population. Participants are selected from patients newly diagnosed with Bipolar Disorder, Type II, confirmed by a SCAN interview, and can be included during depressive, hypomanic states, or during full or partial remission. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **single-blind randomized controlled trial** to evaluate the effects of **lithium carbonate** and **lamotrigine** in patients diagnosed with **Bipolar Disorder, Type II**. The primary objective is to compare the mood stabilization effects of these two medications over a 6-month period. The trial will assess whether the principal effects are antimanic, antidepressant, or prophylactic against relapse. The study will involve a series of visits, starting with an inclusion (screening) visit, followed by regular follow-up visits, and concluding with an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age (18-70 years), language proficiency, and the ability to provide informed consent. Participants will be included if they are in a depressive state, hypomanic state, or in full or partial remission, with diagnoses confirmed by a SCAN interview.

The trial will commence with a recruitment period starting on May 8, 2024, and is expected to conclude by January 31, 2027. Participants will be involved for a maximum treatment period of 12 months. The study will utilize oral administration of the investigational products, with **Lamictal 25 mg tablets** and **Litiumkarbonat "OBA" film-coated tablets** being the formulations used. The primary endpoint will be mood stabilization, measured by a mood instability score reflecting daily variability in self-monitored mood. Secondary endpoints include assessments using the Young Mania Rating Scale, Hamilton Rating Scale for Depression, functional assessment short test, and Internet-based Cognition Assessment Tool, along with biological markers such as blood-based inflammation markers and hair cortisol levels.

Participants may be terminated early from the study if they no longer meet the inclusion criteria, experience adverse effects, or withdraw consent. The trial is categorized as a low-intervention study, as the investigational medicinal products are used in accordance with their marketing authorization terms, ensuring minimal inconvenience and ethical concerns for participants. The trial is authorized to take place in Denmark, with recruitment and trial activities commencing in 2024.

The clinical trial involves the administration of two experimental medications for the treatment of **bipolar disorder, type II**. The first medication is **Lamictal 25 mg tablets**, which contains the active substance **lamotrigine**. This medication is provided in tablet form and is administered orally. The maximum daily dose of lamotrigine is 400 mg, with a total maximum dose of 146,000 mg over the course of the treatment period. The treatment duration is set for a maximum of 12 months. Lamotrigine is a chemical substance, and its use in this trial is authorized under the marketing authorization number H/96/00871/057 by GlaxoSmithKline Trading Services Limited. The medication is classified under the ATC code N03AX09.

The second experimental medication is **Litiumkarbonat "OBA", filmovertrukne tabletter**, which contains the active substance **lithium carbonate**. This medication is also administered in the form of film-coated tablets and is taken orally. The maximum daily dose for lithium carbonate is 0.8 mmol/l, with the same maximum total dose over the treatment period as the daily dose. The treatment period for lithium carbonate is also set for a maximum of 12 months. Lithium carbonate is a chemical substance, and its use in this trial is authorized under the marketing authorization number 7310 by OBA-Pharma APS. The medication is classified under the ATC code N05AN01.

Both medications are being tested in a single-blinded randomized controlled trial to compare their effects on mood stabilization and other critical patient outcomes in individuals with bipolar disorder, type II. The trial aims to determine whether the principal effects of these medications are antimanic, antidepressant, and/or prophylactic against relapse. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

Efficacy in the clinical trial titled "Lithium versus Lamotrigine in bipolar disorder, type II – a single blinded randomized controlled trial (the LiLa-Bipolar RCT)" will be assessed using both primary and secondary endpoints. The primary endpoint is mood stabilization, which will be measured by a mood instability score. This score reflects the daily variability in self-monitored mood, collected via the Monsenso system. This system is designed to capture fluctuations in mood, providing a quantitative measure of mood stability over time.

Secondary endpoints include a variety of assessments to provide a comprehensive evaluation of patient outcomes. These include the Young Mania Rating Scale and the Hamilton Rating Scale for Depression (17 items), which are validated scales for assessing manic and depressive symptoms, respectively. Additionally, the Functional Assessment Short Test and the Internet-based Cognition Assessment Tool (ICAT) will be used to evaluate functional and cognitive outcomes. Biomarkers will also be assessed, with blood-based inflammation markers collected from blood samples and hair cortisol levels measured to provide insights into physiological changes associated with treatment.