Schizophrenia DisorderNCT07234851
Understanding Mechanisms of Synaptic Degeneration Underlying Clinical Symptoms in Patients With MDs and NDs.
An observational study of Schizophrenia Disorder and Frontotemporal Dementia, Behavioral Variant, run by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau at 1 site in Spain.
Trial summary
Clinical Study A. Retrospective Neuropathological Study of Synapse dysfunction. This is a cross-sectional study of patients retrospectively collected from existing postmortem collections and from existing collections of iPSC-derived neurons. Read more about this study
- Who is it for?
- Ages 40 years and olderHealthy volunteers can take part
- Conditions the study is for
- Schizophrenia Disorder, Frontotemporal Dementia, Behavioral Variant, Major Depressive Disorder (MDD)
- How many people
- 150 participants
- Where
- 1 siteSpain
- Study dates
- 1 Feb 2025to 30 Sep 2029
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Resource 1. Frozen samples and paraffin sections from necropsy tissue will be provided by the University of Basque Country, Bilbao. Autopsies are performed in the Basque Institute of Legal Medicine, Bilbao, Spain. Resource 2. Frozen samples and paraffin sections from necropsy tissue are recruited from the neurological tissue bank collection (IDIBAPS, Barcelona). Resource 3. A collection of human induced pluripotent stem cell clones from clinically and genetically well-phenotyped schizophrenia (Natural and Medical Sciences Institute), behavioural variant frontotemporal dementia patients (University of Eastern Finland) and unaffected controls (both sites) that have already been functionally characterised in previous studies.
Who may be able to join
- Age group: Midlife brain donors (age-at-death>40).
- Sex distribution: % Female in schizophrenia (23%), major depressive disorder and controls (40%), bipolar disorder and controls (55%). These percentages match those typically found in these disorders.
- Antemortem diagnosis of schizophrenia (paranoid-subtype diagnoses only to minimise the impact of potential confounding factors on the results and ensure homogeneity across schizophrenia subjects), major depression or bipolar disorder. Diagnoses are confirrmed antemortem by a psychiatrist using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria, as recorded in the deceased individuals' medical records.
- Age group: Latelife brain donors (age-at-death>50).
- Sex distribution: Alzheimer's disease (60%), frontotemporal dementia (65%). These percentages match those typically found in these diseases.
- Neuropathological confirmation of Alzheimer's disease or frontotemporal lobar degeneration (C9orf72 repeat expansion carrier)Alzheimer's disease
Who cannot join
- For schizophrenia, cases displaying additional neurological or psychiatric conditions, such as histories of substance use disorder will be excluded. Postmortem delay >24h (to minimise perimortem confounding variables potentially affecting tissue quality.
- Postmortem delay >24h (to minimise perimortem confounding variables potentially affecting tissue quality.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
About this study
Official title: SYNAPSING's POSTMORTEM AND IN VITRO STUDIES OF SYNAPSE DYSFUNCTION
Clinical Study A. Retrospective Neuropathological Study of Synapse dysfunction.
This is a cross-sectional study of patients retrospectively collected from existing postmortem collections and from existing collections of iPSC-derived neurons. Postmortem tissue and iPSC-derived neurons from age and sex-matched unaffected volunteers without a MD or ND diagnosis are used as controls.
Read the detailed description
This study will:
- perform RNA sequencing of postmortem synapses from the prefrontal cortex of patients with schizophrenia or frontotemporal dementia and unaffected controls. The data will be combined with already available RNA sequencing data from established iPSC clones from schizophrenia or behavioural variant frontotemporal dementia patients and unaffected controls. The postmortem frontotemporal dementia samples have already been characterised in terms of frontal cortex pathology in a previous study and data from RNA sequencing of homogenates is available for comparison. The prefrontal cortex has been implicated as a core affected region across MDs and NDs making this the perfect region to determine common molecular drivers of synapse dysfunction. Pathway analysis of the RNA sequencing dataset will be performed to identify biological pathways or individual genes that are deregulated in the postmortem samples and iPSC lines from each condition. A total of 3 genes that converge between the postmortem and iPSC datasets will be selected for gene-editing. Each gene will be CRISPR/Cas9-repaired in 1 selected schizophrenia parental line and 1 selected frontotemporal dementia parental line. The impact of the induced transcriptional changes on functional and synaptic morphology phenotypes in neuronal cultures from each gene-edited line will be compared to the respective parental line and to lines from 3 healthy controls. A rescue of the disease phenotypes is expected such that the repaired edited line shows activity and synaptic morphology comparable to the healthy control lines and distinct from the unedited parental line. All experiments will include 3 biological replicates taking the total number of analyses to 420. The study will also determine the role of microglia on neuronal deficits in iPSC-derived neurons from the 20 available clones from patients with schizophrenia or behavioural variant frontotemporal dementia by comparing electrophysiological activity and synapse morphology in iPSC-derived neurons culture alone to those observed in iPSC-derived neurons co-cultured with iPSC-derived microglia differentiated from the same clones.
- compare the molecular composition of postmortem synapses from the prefrontal cortex across 3 MDs (major depressive disorder, bipolar disorder and schizophrenia) and identify differentially expressed proteins and dysfunctional protein networks through pathway analyses. To determine the potential effects of psychotropic drugs on synaptic proteomes, the study will quantify the concentrations of >200 psychoactive drugs and metabolites in both blood and cerebellum postmortem samples from the same donors and determine the correlation with the differentially expressed proteins. While blood analyses provide information on drugs present at the time of death, toxicological data in brain tissue, which accumulates drugs for weeks or even months after the last intake, serves as a better indicator of subjects' adherence to the treatments. Groups larger than 15 subjects are recommended for proteomic studies such as this. Each subject was paired to a control subject, matching sex, age, and postmortem interval and with no evidence of psychiatric or neurological conditions, according to their medical records.
- quantify and compare synapse loss in brain regions shown to be associated with reduced volumes in MD and ND patients postmortem. Specifically, the study will compare synapse density in the prefrontal cortex, hippocampus and striatum from patients with major depressive disorder, bipolar disorder, schizophrenia, Alzheimer's disease, frontotemporal dementia to age and sex-matched unaffected controls.
- Conditions
- Schizophrenia Disorder, Frontotemporal Dementia, Behavioral Variant, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Alzheimer's Disease
- Keywords
- synapse, biomarker, induced pluripotent stem cells, mental disorder, neurodegenerative disorder, biofluids, psychiatric symptoms
- Medical subject headings
- Schizophrenia, Pick Disease of the Brain, Depressive Disorder, Major, Bipolar Disorder, Alzheimer Disease, Mental Disorders, Neurodegenerative Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Major depressive disorder | Cases that arrive to autopsy with a previous clinical diagnosis of major depressive disorder | |
| Schizophrenia | Cases that arrive to autopsy with a previous clinical diagnosis of schizophrenia or iPSC clones derived from a patient with a previous clinical diagnosis of schizophrenia | |
| Bipolar disorder | Cases that arrive to autopsy with a previous clinical diagnosis of major depressive disorder | |
| Control | Cases that arrived to autopsy without a prior diagnosis of a neurodegenerative or psychiatric condition or iPSC clones derived from a cognitively unimpaired healthy volunteer | |
| Alzheimer's disease | Cases that arrive to autopsy with neuropathological confirmation of Alzheimer's disease | |
| frontotemporal dementia | Cases that arrive to autopsy with neuropathological confirmation of frontotemporal lobar degeneration |
What is being measured
The primary outcome is the main question the study is designed to answer.
Synaptic gene dysregulation in schizophrenia and frontotemporal dementia
A list of genes that are differentially expressed in schizophrenia and frontotemporal dementia compared to controls identified by RNA sequencing a) synaptic fractions isolated from postmortem tissue from the prefrontal cortex of autopsy cases with a clinical diagnosis of schizophrenia or confirmation of frontotemporal lobar degeneration and b) established iPSC clones from patients with a clinical diagnosis of schizophrenia or behavioural variant frontotemporal dementia.
Measured: January 2025 to December 2029
Molecular pathways related to synapse dysfunction in major depressive disorder, bipolar disorder and schizophrenia
A list of biological processes that are enriched for proteins that are differentially expressed in major depressive disorder, bipolar disorder and schizophrenia compared to controls identified by proteomic analysis of synaptic fractions isolated from postmortem tissue from the prefrontal cortex of autopsy cases with a clinical diagnosis ofmajor depressive disorder, bipolar disorder or schizophrenia
Measured: January 2025 to December 2029
Impact of psychiatric and neurodegenerative disorders on synapse density in affected brain regions.
Density of immunoreactive objects labelled with an antibody to pre and post synapse markers (vGlut1, PSD-95) in the prefrontal cortex, hippocampus and striatum from autopsy cases with a prior diagnosis of major depressive disorder, bipolar disorder, schizophrenia and unaffected controls and brain donors with neuropathological confirmation of Alzheimer's disease or frontotemporal dementia and unaffected controls.
Measured: January 2028 to December 2029
Secondary outcomes (1)
Effects of psychotropic drugs on molecular pathways at the synapse related to major depressive disorder, schizophrenia and bipolar disorder
A list of proteins that correlate with the concentrations of >200 psychoactive drugs and metabolites in both blood and cerebellum from autopsy cases with a prior diagnosis of major depressive disorder, schizophrenia or bipolar disorder
Measured: July 2025 to December 2027
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Nov 2025
- Study start1 Feb 2025
- Primary completion30 Jun 2029 (estimated)
- Study completion30 Sep 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Schizophrenia DisorderStudies of the same condition, open and under way.
- More trials run by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant PauThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- University of Eastern Finland, University of the Basque Country (UPV/EHU), Natural and Medical Sciences Institute (NMI)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07234851
- Sponsor's protocol ID
- IIBSP-NCP-2024-174
- Status last verified
- Nov 2025
- First submitted
- 17 Mar 2025
- Last updated
- 11 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Pseudoanonymised age, biological sex, ethnicity, country of origin/residence, diagnosis, age-at-death, postmortem interval, suicide attempts, comorbidities, therapies, toxicology, synapse density, transcriptome, proteome will uploaded to Zenodo (or ProteomeXchange Consortium PRIDE repository for genomic and proteomic data), which use DOIs as persistent and unique identifiers
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SYNAPSING's POSTMORTEM AND IN VITRO STUDIES OF SYNAPSE DYSFUNCTION
- ClinicalTrials.gov ID
- NCT07234851
- Acronym / sponsor ID
- IIBSP-NCP-2024-174
- Conditions
- Schizophrenia Disorder, Frontotemporal Dementia, Behavioral Variant, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Alzheimer's Disease
- Keywords
- synapse, biomarker, induced pluripotent stem cells, mental disorder, neurodegenerative disorder, biofluids, psychiatric symptoms
- Study type
- Observational
- Recruitment status
- Enrolling by invitation
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant PauUniversity, hospital or other
- Collaborators
- University of Eastern Finland, University of the Basque Country (UPV/EHU), Natural and Medical Sciences Institute (NMI)
- Study start
- 1 Feb 2025 (actual)
- Primary completion
- 30 Jun 2029 (estimated)
- Study completion
- 30 Sep 2029 (estimated)
- First posted
- 19 Nov 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Clinical Study A. Retrospective Neuropathological Study of Synapse dysfunction.
This is a cross-sectional study of patients retrospectively collected from existing postmortem collections and from existing collections of iPSC-derived neurons. Postmortem tissue and iPSC-derived neurons from age and sex-matched unaffected volunteers without a MD or ND diagnosis are used as controls.
Detailed description
This study will:
- perform RNA sequencing of postmortem synapses from the prefrontal cortex of patients with schizophrenia or frontotemporal dementia and unaffected controls. The data will be combined with already available RNA sequencing data from established iPSC clones from schizophrenia or behavioural variant frontotemporal dementia patients and unaffected controls. The postmortem frontotemporal dementia samples have already been characterised in terms of frontal cortex pathology in a previous study and data from RNA sequencing of homogenates is available for comparison. The prefrontal cortex has been implicated as a core affected region across MDs and NDs making this the perfect region to determine common molecular drivers of synapse dysfunction. Pathway analysis of the RNA sequencing dataset will be performed to identify biological pathways or individual genes that are deregulated in the postmortem samples and iPSC lines from each condition. A total of 3 genes that converge between the postmortem and iPSC datasets will be selected for gene-editing. Each gene will be CRISPR/Cas9-repaired in 1 selected schizophrenia parental line and 1 selected frontotemporal dementia parental line. The impact of the induced transcriptional changes on functional and synaptic morphology phenotypes in neuronal cultures from each gene-edited line will be compared to the respective parental line and to lines from 3 healthy controls. A rescue of the disease phenotypes is expected such that the repaired edited line shows activity and synaptic morphology comparable to the healthy control lines and distinct from the unedited parental line. All experiments will include 3 biological replicates taking the total number of analyses to 420. The study will also determine the role of microglia on neuronal deficits in iPSC-derived neurons from the 20 available clones from patients with schizophrenia or behavioural variant frontotemporal dementia by comparing electrophysiological activity and synapse morphology in iPSC-derived neurons culture alone to those observed in iPSC-derived neurons co-cultured with iPSC-derived microglia differentiated from the same clones.
- compare the molecular composition of postmortem synapses from the prefrontal cortex across 3 MDs (major depressive disorder, bipolar disorder and schizophrenia) and identify differentially expressed proteins and dysfunctional protein networks through pathway analyses. To determine the potential effects of psychotropic drugs on synaptic proteomes, the study will quantify the concentrations of >200 psychoactive drugs and metabolites in both blood and cerebellum postmortem samples from the same donors and determine the correlation with the differentially expressed proteins. While blood analyses provide information on drugs present at the time of death, toxicological data in brain tissue, which accumulates drugs for weeks or even months after the last intake, serves as a better indicator of subjects' adherence to the treatments. Groups larger than 15 subjects are recommended for proteomic studies such as this. Each subject was paired to a control subject, matching sex, age, and postmortem interval and with no evidence of psychiatric or neurological conditions, according to their medical records.
- quantify and compare synapse loss in brain regions shown to be associated with reduced volumes in MD and ND patients postmortem. Specifically, the study will compare synapse density in the prefrontal cortex, hippocampus and striatum from patients with major depressive disorder, bipolar disorder, schizophrenia, Alzheimer's disease, frontotemporal dementia to age and sex-matched unaffected controls.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Major depressive disorder | – | –Cases that arrive to autopsy with a previous clinical diagnosis of major depressive disorder |
| Schizophrenia | – | –Cases that arrive to autopsy with a previous clinical diagnosis of schizophrenia or iPSC clones derived from a patient with a previous clinical diagnosis of schizophrenia |
| Bipolar disorder | – | –Cases that arrive to autopsy with a previous clinical diagnosis of major depressive disorder |
| Control | – | –Cases that arrived to autopsy without a prior diagnosis of a neurodegenerative or psychiatric condition or iPSC clones derived from a cognitively unimpaired healthy volunteer |
| Alzheimer's disease | – | –Cases that arrive to autopsy with neuropathological confirmation of Alzheimer's disease |
| frontotemporal dementia | – | –Cases that arrive to autopsy with neuropathological confirmation of frontotemporal lobar degeneration |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Resource 1. Frozen samples and paraffin sections from necropsy tissue will be provided by the University of Basque Country, Bilbao. Autopsies are performed in the Basque Institute of Legal Medicine, Bilbao, Spain. Resource 2. Frozen samples and paraffin sections from necropsy tissue are recruited from the neurological tissue bank collection (IDIBAPS, Barcelona). Resource 3. A collection of human induced pluripotent stem cell clones from clinically and genetically well-phenotyped schizophrenia (Natural and Medical Sciences Institute), behavioural variant frontotemporal dementia patients (University of Eastern Finland) and unaffected controls (both sites) that have already been functionally characterised in previous studies.
Key inclusion criteria (6 listed)
- Age group: Midlife brain donors (age-at-death>40).
- Sex distribution: % Female in schizophrenia (23%), major depressive disorder and controls (40%), bipolar disorder and controls (55%). These percentages match those typically found in these disorders.
- Antemortem diagnosis of schizophrenia (paranoid-subtype diagnoses only to minimise the impact of potential confounding factors on the results and ensure homogeneity across schizophrenia subjects), major depression or bipolar disorder. Diagnoses are confirrmed antemortem by a psychiatrist using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria, as recorded in the deceased individuals' medical records.
- Age group: Latelife brain donors (age-at-death>50).
- Sex distribution: Alzheimer's disease (60%), frontotemporal dementia (65%). These percentages match those typically found in these diseases.
Key exclusion criteria (2 listed)
- For schizophrenia, cases displaying additional neurological or psychiatric conditions, such as histories of substance use disorder will be excluded. Postmortem delay >24h (to minimise perimortem confounding variables potentially affecting tissue quality.
- Postmortem delay >24h (to minimise perimortem confounding variables potentially affecting tissue quality.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Synaptic gene dysregulation in schizophrenia and frontotemporal dementia
Time frame: January 2025 to December 2029
A list of genes that are differentially expressed in schizophrenia and frontotemporal dementia compared to controls identified by RNA sequencing a) synaptic fractions isolated from postmortem tissue from the prefrontal cortex of autopsy cases with a clinical diagnosis of schizophrenia or confirmation of frontotemporal lobar degeneration and b) established iPSC clones from patients with a clinical diagnosis of schizophrenia or behavioural variant frontotemporal dementia.
Molecular pathways related to synapse dysfunction in major depressive disorder, bipolar disorder and schizophrenia
Time frame: January 2025 to December 2029
A list of biological processes that are enriched for proteins that are differentially expressed in major depressive disorder, bipolar disorder and schizophrenia compared to controls identified by proteomic analysis of synaptic fractions isolated from postmortem tissue from the prefrontal cortex of autopsy cases with a clinical diagnosis ofmajor depressive disorder, bipolar disorder or schizophrenia
Impact of psychiatric and neurodegenerative disorders on synapse density in affected brain regions.
Time frame: January 2028 to December 2029
Density of immunoreactive objects labelled with an antibody to pre and post synapse markers (vGlut1, PSD-95) in the prefrontal cortex, hippocampus and striatum from autopsy cases with a prior diagnosis of major depressive disorder, bipolar disorder, schizophrenia and unaffected controls and brain donors with neuropathological confirmation of Alzheimer's disease or frontotemporal dementia and unaffected controls.
1 secondary outcome
Effects of psychotropic drugs on molecular pathways at the synapse related to major depressive disorder, schizophrenia and bipolar disorder
Time frame: July 2025 to December 2027
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2025.
- Individual participant dataSharing planned: Yes. Pseudoanonymised age, biological sex, ethnicity, country of origin/residence, diagnosis, age-at-death, postmortem interval, suicide attempts, comorbidities, therapies, toxicology, synapse density, transcriptome, proteome will uploaded to Zenodo (or ProteomeXchange Consortium PRIDE repository for genomic and proteomic data), which use DOIs as persistent and unique identifiers
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Schizophrenia Disorder and Frontotemporal Dementia, Behavioral Variant, run by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: enrolling by invitation, as of the sponsor's last update on 11 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Synaptic gene dysregulation in schizophrenia and frontotemporal dementia (time frame: January 2025 to December 2029). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2025.