Comparative Efficacy of Lithium and Cariprazine in Acute Bipolar Depression: A Randomized, Open-Label, Multicenter Study

The primary objective of this study is to evaluate the efficacy of **cariprazine** compared to **lithium** in the acute treatment of patients experiencing a depressive episode in **bipolar disorder** type 1 or 2. This is assessed by measuring changes on the Hamilton Depression Scale, 6-item version. The clinical relevance of this objective lies in determining the superior treatment option for managing acute depressive episodes in bipolar disorder, which can significantly impact patient outcomes and treatment strategies.

The clinical trial focuses on individuals experiencing a **depressive episode in bipolar disorder**, specifically targeting those diagnosed with bipolar disorder type 1 or 2. The study population includes both male and female participants, aged between 18 and 64 years. Participants are required to have a severity of depression with a score of at least 21 on the self-reported Major Depression Inventory (MDI). The trial does not involve a vulnerable population. Participants must not have started or increased the dose of psychotropic medication, except for benzodiazepines and benzodiazepine-like drugs, in the two weeks prior to inclusion. Additionally, no new formalized psychotherapy sessions, excluding psychoeducation, should have commenced in the four weeks prior to inclusion. Female participants must be sterile, non-fertile, or use safe contraception with a negative pregnancy test. The duration of the current depressive episode must be between 4 and 52 weeks. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **cariprazine** compared to **lithium** in the acute treatment of patients experiencing a depressive episode in **bipolar disorder**. This study is a randomized, controlled, and open-label trial, conducted over an estimated duration of 8 weeks. Participants will be randomly assigned to receive either cariprazine or lithium, administered orally. The primary objective is to assess changes in the Hamilton Depression Scale, 6-item version (HDS-6), to determine the superiority of one treatment over the other.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of bipolar disorder type 1 or 2, a minimum score of 21 on the Major Depression Inventory, and age between 18 and 65 years. Following randomization, participants will attend follow-up visits at weeks 4 and 8 to monitor treatment response and safety. The end-of-study visit will occur at the conclusion of the 8-week treatment period, where final assessments will be conducted.

The expected length of participant involvement is approximately 8 weeks, with conditions for early termination including lack of treatment efficacy, adverse events, or withdrawal of consent. Secondary endpoints include differences in the Hamilton Depression Scale, 17-item version (HDS-17), and other continuous measures such as the WHO-5 Well-being Index and the Young Mania Rating Scale (YMRS). The trial aims to provide comprehensive data on the comparative effectiveness and safety of cariprazine and lithium in treating depressive episodes in bipolar disorder.

The clinical trial involves the administration of two **experimental medications** for the treatment of bipolar depression. The first medication is **Lithium**, which is classified under the ATC code N05AN01. It is administered in an oral pharmaceutical form, denoted as PHF00082MIG. The maximum daily dose of Lithium is 48 mmol, with a total maximum dose of 2400 mmol over the treatment period. The treatment duration is set for a maximum of 8 weeks. Participants will receive Lithium orally, and compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

The second medication used in the trial is **Cariprazine**, marketed under the name Reagila 1.5 mg hard capsules. Cariprazine is administered in the form of hard capsules, with a maximum daily dose of 3 mg and a total maximum dose of 47 mg over the treatment period. Similar to Lithium, Cariprazine is administered orally, and the treatment period is also set for a maximum of 8 weeks. Participant compliance with the Cariprazine dosing schedule will be closely monitored to ensure accurate data collection and adherence to the study protocol.

Both medications are being evaluated in a head-to-head comparison to determine their efficacy in the acute treatment of bipolar type 1 or 2 depression. The study does not include any non-experimental treatments such as placebo or standard-of-care therapy. The primary objective is to assess the change in depressive symptoms as measured by the Hamilton Depression Scale, 6-item version, to determine the superiority of one treatment over the other.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of **bipolar depression**. The primary endpoint is the change in the Hamilton Depression Scale, 6 item version (HDS-6), to determine whether cariprazine is superior to lithium or vice versa in the acute treatment of patients with bipolar type 1 or 2 during a current depressive episode. Secondary endpoints include a variety of measures such as the Hamilton Depression Scale, 17 item version (HDS-17), and the WHO-five Well-being Index (WHO-5), among others. These endpoints will be measured at specific time points, including weeks 4 and 8, and at the planned or premature endpoint.

The trial will utilize validated scales and questionnaires to collect data on symptom improvement and patient well-being. The Hamilton Depression Scale and WHO-5 are among the tools used to assess the efficacy of the treatments. The analysis will include between-group differences in the proportion of responders and remitters, as well as differences in treatment compliance and reasons for treatment discontinuation. The study will also evaluate the difference-in-differences for secondary continuous measures, such as the Bech-Rafaelsens Mania Scale, Montgomery-Aaberg Depression Rating Scale, and others, to provide a comprehensive assessment of treatment efficacy.