DECIDE Study — Deep phenotyping for clinical inferring response in treatment resistant depression

Research into a biomarker combination that predicts response to lithium in severe depression

Major depressive disorder has a lifetime prevalence of approximately 16–20%. Despite comprehensive, interdisciplinary treatment approaches, about one-third of patients do not achieve a satisfactory therapeutic response. In such cases—classified as treatment-resistant depression (TRD)—augmentation with lithium has been shown to enhance the efficacy of antidepressant therapy, with around 40% of patients demonstrating clinical improvement. Lithium has been a well-established therapeutic agent for the treatment of severe unipolar and bipolar depression for several decades. It is believed to modulate neurotransmitter systems and alter functional connectivity between brain regions affected by depression. Despite its proven efficacy, individual responses to lithium vary significantly, and the underlying mechanisms of this variability are not yet fully understood.

Therefore, predicting which patients will benefit from lithium augmentation remains a major challenge. The DECIDE study seeks to identify predictive features associated with a positive response to lithium augmentation in individuals with TRD, with the overarching goal of enabling a more personalized and effective treatment approach by developing a multimodal biomarker signature for lithium response.  

Additionally, we plan to investigate lithium’s mechanisms of action using longitudinal data collected before and after lithium administration, as well as cellular and molecular mechanisms using iPSC derived neurons.

Objectives of the DECIDE Study

Our primary objective is to identify a multimodal biomarker signature that can reliably predict individual response to lithium augmentation in patients with TRD. This could allow for more personalized and targeted treatment strategies, improving outcomes in this difficult-to-treat patient population. Additionally, we plan to investigate lithium’s mechanisms of action on a cellular level using iPSCs.

Study population and recruitment

Study recruitment started August 2024 and will last approx. until May 2028 with target of 130 patients.  We are including patients diagnosed with treatment-resistant depression, for whom lithium augmentation is clinically indicated as part of their treatment plan. TRD is defined as inadequate response to at least one major class of antidepressant medication after ≥ 4 weeks of treatment. Participation in the study is entirely voluntary and includes a comprehensive assessment protocol.

Study protocol

DECIDE is a prospective diagnostic study and all treatment decisions are made solely by the clinical team. Baseline assessments (see below) will take place before the initiation of lithium augmentation. After start of lithium treatment, short questionnaires about symptom severity and potential side effects will be administered weekly. Outcome is defined after 3-6 weeks of treatment with adequate dosage (as measured by lithium serum levels of 0.6-0.8 mmol/L) and optional longitudinal assessments including MRI, MRS, pupillometry, and EEG, can be administered additionally to the outcome interview. Follow-up appointments are planned at 6-8 weeks after outcome as well as after one year.

Study Procedures

To obtain a precise and multidimensional understanding of each participant's clinical profile, a broad range of assessments will be conducted prior to the initiation of lithium treatment and during the early weeks of therapy. These include:
•    Standardized psychological questionnaires (self-ratings)
•    Structured clinical interviews, including a diagnostic interview (MINI), symptom severity scales (e.g., MADRS) as well as assessment of potential side effects (LISERS scale)
•    Neurocognitive assessment
•    Multimodal Magnetic Resonance Imaging (mMRI) including Magnetic Resonance Spectroscopy (MRS)
•    Pupillometry
•    Blood sampling (including proteomics, metabolomics, genomics, exosomes, routine serology and PBMC for iPSC)
•    EEG
•    Thyroid ultrasonography