Evaluation of Intensified Pharmacological Regimen with Lithium, Sertraline, and Bupropion Hydrochloride in Bipolar Depression Post First-Line Treatment Failure

The primary objective of this study is to evaluate the **treatment response** in subjects with bipolar depression who experienced a first-time treatment failure on their first-line treatment. This is assessed by comparing the severity of symptoms at baseline and at the end of a six-week treatment period using the Montgomery Åsberg Depression Rating Scale (MADRS). The study aims to determine the efficacy of an early-intensified pharmacological treatment compared to treatment as usual. This is clinically relevant as it may provide insights into optimizing treatment strategies for patients with bipolar depression who do not respond to initial therapies.

Secondary objectives include:

• Comparing changes in severity and improvement in global functioning using the Clinical Global Impression Scale (CGI) between treatment arms.
• Assessing changes in levels of depression and anxiety between treatment arms.
• Evaluating changes in quality of life and functioning measures between treatment arms.
• Comparing changes in cognitive performance between treatment arms.
• Assessing the proportion of subjects in symptomatic remission at visit 4 between treatment arms.
• Comparing the presence of adverse events, both related and unrelated, between treatment arms.
• Evaluating the use of concomitant medication between treatment arms.
• Comparing premature discontinuation, including timing and reason, between treatment arms.
• Assessing changes in suicidal ideation between treatment arms.
• Comparing the occurrence of (hypo)manic episodes during the study between treatment arms.

The clinical trial involves a total of **108 participants** diagnosed with **bipolar depression**, specifically those experiencing a depressive episode in bipolar disorder type I or II. The study population includes both male and female subjects, aged 18 years and older, who have experienced a first-time treatment failure on their first-line treatment for bipolar depression. Participants were selected based on their ability to provide informed consent, with the option for a legal guardian to cosign if necessary. The trial includes individuals who meet the diagnostic criteria according to DSM-5, confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Participants must exhibit a minimum symptom severity threshold, defined as a score of 20 or higher on the Montgomery Åsberg Depression Rating Scale (MADRS), and functional impairment, indicated by a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS). The trial population is characterized by a willingness to change pharmacotherapeutic treatment and includes both inpatients and outpatients. Female participants of childbearing potential are required to use effective contraception, and male participants using valproate acid must also adhere to contraceptive measures during the trial. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of a six-week intensified pharmacological treatment for **bipolar depression** compared to standard treatment in individuals who have experienced a first-time treatment failure with their initial therapy. This study is a randomized, controlled trial, ensuring that participants are randomly assigned to either the experimental treatment group or the control group, which receives treatment as usual. The trial is double-blind, meaning neither the participants nor the researchers know which treatment the participants are receiving, to prevent bias. The trial is expected to last until June 30, 2026, with recruitment starting on January 1, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, willingness to provide informed consent, and a diagnosis of bipolar depression according to DSM-5 criteria. The primary objective is to assess changes in symptom severity using the Montgomery Åsberg Depression Rating Scale (MADRS) from baseline (visit 2) to the end of treatment (visit 4). Secondary endpoints include changes in the Clinical Global Impression Scale, Hospital Anxiety and Depression Scale, and quality of life measures, among others.

The expected duration of participant involvement is six weeks, with study visits scheduled at baseline, during treatment, and at the end of the study. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to discontinue participation. The trial will also monitor the occurrence of (hypo)manic episodes and changes in the Columbia-Suicide Severity Rating Scale throughout the study. The trial aims to provide valuable insights into the effectiveness of intensified pharmacological treatment for individuals with bipolar depression who have not responded to first-line treatments.

The clinical trial involves the administration of several **experimental medications** and comparator treatments to evaluate their efficacy in treating bipolar depression. **Lithium** is used as a comparator treatment in this study. It is administered orally in a pharmaceutical form identified as PHF00212MIG. The maximum daily dose is 800 mg, with a total maximum dose of 33,600 mg over a treatment period of six weeks.

**Sertraline** is one of the test medications, administered orally in the form PHF00006MIG. The maximum daily dose is 200 mg, with a total maximum dose of 8,400 mg over the six-week treatment period. **Bupropion hydrochloride** is another test medication, administered orally in the form PHF00134MIG. The maximum daily dose is 450 mg, with a total maximum dose of 18,900 mg over the treatment period.

**Venlafaxine** is also included as a test medication, administered orally in the form PHF00209MIG. The maximum daily dose is 375 mg, with a total maximum dose of 15,750 mg over six weeks. **Quetiapine** is administered as a comparator treatment, in the form PHF00082MIG, with a maximum daily dose of 600 mg and a total maximum dose of 25,200 mg over the treatment period.

**Sodium valproate**, used as a comparator, is administered orally in the form PHF00211MIG. The maximum daily dose is 2,000 mg, with a total maximum dose of 84,000 mg over six weeks. Lastly, **Citalopram** is administered as a test medication in the form PHF00082MIG, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over the treatment period.

All medications are administered orally, and participant compliance is monitored throughout the study. The trial aims to compare the treatment response of these medications in subjects who experienced a first-time treatment failure on their first-line treatment for bipolar depression. The study evaluates changes in symptom severity using the Montgomery Åsberg Depression Rating Scale (MADRS) over a six-week period.

Efficacy in this clinical trial will be assessed primarily through the **Montgomery Åsberg Depression Rating Scale (MADRS)**. The primary endpoint is the mean change from baseline in symptom severity as measured by the MADRS total score at six weeks. This will be compared between two treatment arms: early-intensified pharmacological treatment (EIPT) and treatment as usual (TAU). The baseline measurement will occur at visit 2, and the final assessment will be at visit 4, marking the end of the treatment period.

Secondary endpoints include changes from baseline in several other measures. These include the severity and improvement sub-scores of the Clinical Global Impression Scale (CGI), total scores and subscales of the Hospital Anxiety and Depression Scale (HADS), and quality of life and functioning measures such as Q-LES-Q-SF, LAPS, QLS-100, and SDS. Cognitive assessments will be conducted using the Trail Making Test, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the Perceived Deficits Questionnaire. Additionally, the presence of symptomatic remission, defined as a MADRS score of 12 or less, will be evaluated at visit 4.

Other secondary endpoints include the presence of reported adverse events, concomitant medication use, premature treatment discontinuation, changes on the Columbia-Suicide Severity Rating Scale (C-SSRS), and the occurrence of (hypo)manic episodes. These assessments will be conducted throughout the study, with specific focus on visit 4 for final evaluations. The tools and scales used in this trial are validated instruments commonly employed in clinical research to ensure reliable and accurate measurement of treatment efficacy.