Bipolar Disorder (BD), Bipolar Disorder (BPD)
Conditions
Brief summary
This preclinical translational study aims to evaluate a new method of delivering lithium using gold nanoparticles for the treatment of bipolar disorder. Lithium is an effective treatment for bipolar disorder, but its clinical use is limited by a narrow therapeutic range and the risk of side effects. The study will investigate whether gold nanoparticles carrying lithium can improve lithium delivery to brain cells while reducing exposure to other tissues. The research will use human induced pluripotent stem cell (iPSC)-derived neural cells generated from blood samples collected from people with bipolar disorder and healthy volunteers, as well as a mouse model of mania. No participants will receive the investigational treatment. Human participants will provide blood samples only for the generation of laboratory cell models. The study will compare the effects of nanoparticle-delivered lithium with conventional lithium salts on cellular lithium uptake, disease-related molecular and functional changes, and biomarkers associated with bipolar disorder. The hypothesis is that lithium delivered by gold nanoparticles will achieve greater therapeutic effects at lower systemic lithium exposure than conventional lithium formulations, providing proof of concept for a safer and more targeted lithium delivery strategy for future clinical development.
Interventions
PROCEDUREPeripheral blood sampling for PBMC isolation
Blood collection in EDTA tubes for isolation of peripheral blood mononuclear cells (PBMCs), followed by reprogramming into induced pluripotent stem cells (iPSCs) via Sendai virus infection and differentiation into human induced neural stem cells (hiNSCs), used for the in vitro experiments of the protocol. No drug or device is administered to participants.
Sponsors
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion criteria for patients * Age: 18-65 years. * Diagnosis of Bipolar I or Bipolar II Disorder, according to DSM-5 criteria. * Currently in a depressive, manic, hypomanic, mixed, or euthymic phase, as defined by DSM-5 and clinical evaluation. * No use of psychotropic medications during the 12 months preceding enrollment, except for low-dose benzodiazepines or antipsychotics used intermittently to manage sleep disturbances or anxiety symptoms. * No prior treatment with lithium at any point in the patient's psychiatric history. * Medically stable and deemed suitable for study participation. * Ability and willingness to provide written informed consent before any study procedure For the Human Healthy Control group * participants aged 18-65 years will be included, while subjects with DSM-5 disorders or a family history of psychiatric disorders will be excluded.
Exclusion criteria
* Current or past diagnosis of schizophrenia, schizoaffective disorder, or borderline personality disorder as the primary psychiatric condition. * Diagnosis of moderate to severe substance use disorder (excluding nicotine) within the past 12 months. * Active suicidal ideation with plan or intent * History of major neurological disorders, including epilepsy, traumatic brain injury, or neurodegenerative disease. * Previous exposure to lithium at any point in the individual's psychiatric history. * Use of psychotropic medication within the 12 months before enrollment. * Presence of uncontrolled or clinically significant medical conditions, including but not limited to severe hepatic, renal, or cardiovascular disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracellular lithium concentration in patient derived neural cells (hiNSCs) treated with LiG-AuNPs versus lithium salts (LiCl) | 1, 2, 6, 12, and 24 hours after in vitro treatment (assessed throughout the 3-year study period) | Quantification of intracellular lithium load by Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) and subcellular gold nanoparticle distribution by Transmission Electron Microscopy (TEM) in neurons, astrocytes, and oligodendrocytes differentiated from participant-derived human induced Neural Stem Cells (hiNSCs), treated with Lithium-loaded, Glutathione-coated Gold Nanoparticles (LiG-AuNPs) or Lithium Chloride (LiCl) at concentrations of 0.15, 0.5, 1, 3, and 6 mEq/L, to compare uptake efficiency between the two delivery methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional and biophysical differences | Assessed at 30 days of in vitro differentiation (within the 3-year study period) | Comparison of neuronal parameters (resting membrane potential, action potential threshold, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) current ratio, frequency/amplitude of miniature excitatory postsynaptic currents, synaptic vesicle release) and astrocytic parameters (intracellular Ca²⁺ signaling, glutamate buffering/Excitatory Amino Acid Transporter 2 (EAAT2) activity, gliotransmitter release) between human induced Neural Stem Cell (hiNSC)-derived neurons/astrocytes from Bipolar Disorder (BD) patients versus healthy controls, before and after lithium exposure. |
| Molecular biomarker expression in patient-derived neural cells | Assessed at 30 days of in vitro differentiation (within the 3-year study period) | Levels of c-Fos, Synaptotagmin-7, Neuronal Pentraxin 2 (NPTX2), B-cell lymphoma 2 (Bcl-2), phospho-Glycogen Synthase Kinase 3 beta (GSK-3β)(Ser9)/total GSK-3β, and phospho-cytosolic Phospholipase A2 (cPLA2)(Ser505)/total cPLA2 in human induced Neural Stem Cell (hiNSC)-derived neurons and astrocytes from Bipolar Disorder (BD) patients. |
| Blood biomarker profile in BD patients versus healthy controls | Baseline (single blood draw) and up to 24 hours after in vitro lithium exposure (within the 3-year study period) | Plasma lithium levels, Thyroid Stimulating Hormone (TSH) levels, lithium load in blood cells, phospho-Glycogen Synthase Kinase 3 beta (pGSK-3β)(Ser9)/total GSK-3β ratio, and phospho-cytosolic Phospholipase A2 (cPLA2)(Ser505)/total cPLA2 levels, measured in blood cells and plasma from Bipolar Disorder (BD) patients (during the manic phase and again after standard lithium therapy) and from healthy controls, for comparison and biomarker identification. |
Countries
Italy
Contacts
CONTACTGabriele Sani
PRINCIPAL_INVESTIGATORGabriele Sani
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Outcome results
None listed