Bipolar disorder is a long-term mental health condition that causes mood changes, with depressive episodes being the most frequent and disabling. Many people do not fully recover with current treatments, showing the need for new therapeutic options.

Recent research shows that insulin resistance (IR), a condition in which the body does not respond well to insulin, is common in people with bipolar disorder. It is linked to more severe mood symptoms, poorer treatment response, and higher risk of heart disease. IR may raise inflammation and affect how the brain uses energy, which can influence mood regulation.

Empagliflozin is a medicine approved for type 2 diabetes. In addition to its metabolic and heart benefits, studies suggest that it may also protect the brain and reduce inflammation, possibly helping to improve mood.

This open-label, proof-of-concept clinical trial will test how well empagliflozin works and how safe it is as an add-on treatment for people with bipolar depression and insulin resistance. A total of 20 adults with bipolar disorder type I or II, currently in a depressive episode, will take part in the study over a 12-week period.

The main goal is to see whether empagliflozin can lower depressive symptoms, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS). Other measures include changes in insulin resistance and incidence of adverse events.

The study aims to explore whether improving insulin resistance can help both mood and metabolic health in people with bipolar disorder, guiding future clinical research.

This study is an open-label, single-arm, proof-of-concept clinical trial evaluating empagliflozin as an adjunctive treatment for bipolar depression in individuals with insulin resistance. Adults with bipolar disorder type I or II who are currently experiencing a depressive episode and receiving stable pharmacological treatment will receive empagliflozin for 12 weeks.

Depressive symptom severity will be assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Insulin resistance will be evaluated using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and safety will be monitored through assessment of treatment-emergent adverse events throughout the study period.

Inclusion Criteria:

1. Adults aged 18 to 65 years.
2. Diagnosis of Bipolar Disorder type I or II according to DSM-5 criteria, confirmed by the MINI International Neuropsychiatric Interview.
3. Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 15 at screening.
4. Currently receiving stable pharmacological treatment for bipolar disorder, with no medication changes (addition or withdrawal) in the past 4 weeks.
5. Ability to provide informed consent.
6. Insulin resistance, defined as HOMA-IR ≥ 1.8.

Exclusion Criteria:

1. History of hypersensitivity to empagliflozin or any SGLT2 inhibitor.
2. Type 1 or type 2 diabetes mellitus or HbA1c ≥ 6.5% at screening.
3. Known pancreatic disease (pancreatitis or pancreatic surgery).
4. Chronic kidney disease (eGFR < 30 mL/min/1.73m²).
5. Recurrent genital fungal infections.
6. Pregnant or breastfeeding.
7. Alcohol abuse or dependence within the past 12 months.
8. YMRS score ≥ 12 (presence of manic or hypomanic symptoms).

The individual participant data (IPD) will not be shared because this is a small, proof-of-concept, single-site study. The dataset includes sensitive clinical information that could potentially identify participants. Only aggregated and anonymized results will be shared in future scientific publications or presentations.

This is an open-label study; no masking will be used.