Longitudinal PET Imaging of Antipsychotic Binding to the Dopamine-3 Receptor in Schizophrenia
15 luglio 2026 aggiornato da: Ragy Girgis, New York State Psychiatric Institute
This is a clinical trial in which 40 participants with schizophrenia will be randomized to 15 days of treatment with cariprazine (CAR) or brexpiprazole (BREX) in a single-blind manner.
[11C]PHNO PET scans will be obtained before treatment and after 1 day and 15 days of treatment to examine the effects of antipsychotic medications on the dopamine-3 receptor (D3R).
The overall objectives of the current study are to: 1) measure the acute binding of CAR/BREX to the D3R; 2) measure D3R availability for evidence of upregulation following subchronic administration of CAR/BREX in the same set of patients; 3) examine relationships between subchronic binding of CAR/BREX to, and upregulation of, the D3R vs. D2R and changes in positive symptoms, negative symptoms, and cognitive deficits.
Relationships between subchronic binding of CAR/BREX and EPS will be explored.
Panoramica dello studio
Stato
Non ancora reclutamento
Intervento / Trattamento
Descrizione dettagliata
There is a great need for the development of new treatments for schizophrenia (SCZ).
Aside from the recently approved muscarinic agonist xanomeline, all current treatments have been assumed to function by blocking dopamine-2 receptors (D2Rs).
Interest in the dopamine-3 receptor (D3R) was encouraged by preclinical findings that D3R antagonists reverse cognitive impairment and improve negative symptoms.
In vivo imaging of the D3R became possible with the development of [11C]-(+)-PHNO, a D3R-preferring radioligand.
However, while numerous preclinical studies have demonstrated that the D3R is relevant to both the neurobiology and treatment of SCZ, in vivo studies initially and surprisingly reported that, after several weeks of administration, antipsychotic medications may not bind to the D3R and may paradoxically increase levels of the D3R.
These findings were discrepant with our own findings in non-human primates and individuals with SCZ demonstrating that acute doses of antipsychotic medications bind to the D3R and D2R in ratios predicted by their in vitro binding profiles.
In a later study conducted by our group, 10 days of chronic dosing of the D2R-preferring antipsychotic medication brexpiprazole (BREX) also led to increased levels of the D3R at 1mg and negligible binding at 4mg.
Finally, in our study of the D3R-preferring antipsychotic medication cariprazine (CAR), there was robust binding to the D3R and D2R after both acute and subchronic dosing.
These seemingly discrepant findings may be related to methodological differences, differences in the binding profiles of D2R- vs. D3R-preferring antipsychotic medications, or to homeostatic responses to chronic antipsychotic treatment (i.e., upregulation).
Upregulation is a potentially critical, though underexamined, effect common to all D2R/D3R-binding antipsychotic medications, including partial agonists.
It has been hypothesized to be largely responsible for differences in occupancy estimates from single and repeat dose studies and contribute to waning effects of antipsychotic medications and tardive dyskinesia.
The goals of this proposal are to elucidate the contribution of D3R, compared to D2R, binding to antipsychotic action, both acutely (SA1) and subchronically (SA2), in the same patients.
The relationship between occupancy, upregulation, and clinical effects (SA3, EA) will be investigated.
Tipo di studio
Interventistico
Iscrizione (Stimato)
100
Fase
- Fase 1
Contatti e Sedi
Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.
Contatto studio
- Nome: Ragy Girgis, MD
- Numero di telefono: 646-774-5553
- Email: ragy.girgis@nyspi.columbia.edu
Criteri di partecipazione
I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.
Criteri di ammissibilità
Età idonea allo studio
- Adulto
Accetta volontari sani
No
Descrizione
Inclusion Criteria:
- Individuals, any gender or sex, aged 18 to 55, inclusive at screen
- Capable of understanding the study procedures and able to provide informed consent
- Diagnosed with schizophrenia, schizoaffective, or schizophreniform disorder
- Negative urine toxicology
- Antipsychotic free (by choice and for reasons unrelated to the study), and for at least 3 weeks (4 for aripiprazole or LAIs) at the time of the baseline PET scan, inclusive of any antipsychotic-free time prior to consent. [Any patient who requires inpatient hospitalization or acute medication treatment for clinical stabilization during the medication free period will not be included in this study; any participant who in the clinical judgment of the PIs or any involved clinician is not stable or appropriate for a medication free period will not be included.]
- PANSS total score > 80 and < 120 (inclusive)
Exclusion Criteria:
- Diagnosis of substance use disorder within the previous month
- A history of poor or inadequate response or hypersensitivity to CAR or BREX for any reason
- EKG abnormality that is clinically significant including a QTc interval > 450 msec for men and > 470 msec for women,
- Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum β-hCG pregnancy test at Visit 1, must have been using an acceptable method of contraception for 30 days before the study (i.e., before the first PET or MRI scan, whichever comes first), and must agree to do so for the whole study and 30 days after (unless post-menopausal or surgically sterile)
- Any clinically significant or unstable medical/neurological illness, condition, or disorder that is anticipated to potentially compromise participant safety on study medication
- Any material in the body that is a contraindication for MRI procedures or participated in prior nuclear medicine procedures in the past year that exceed FDA-defined limits when combined with radiation dosimetry from PET scanning in this protocol to avoid exceeding annual dosimetry limits (metal screener repeated before MRI scan). Individuals exposed to radiation in the workplace in the previous year will be excluded.
- Acute risk for suicide (i.e., score of 4-5 within the previous month or 6 within the previous 3 months on the CSSRS) or violence/homicide (e.g., homicidal ideation), or history of severe violent behavior or behavioral dyscontrol while antipsychotic-free
- A history of treatment resistance to antipsychotics or who have a duration of illness of greater than 20 years
- Claustrophobia
- Use of nicotine products within the previous month (prior to first PET scan)
Piano di studio
Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Altro
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Separare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
|
Sperimentale: Cariprazine 1mg
Cariprazine 1mg daily for 15 days
|
Cariprazine is an antipsychotic medication
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
|
|
Sperimentale: Cariprazine 2mg
Cariprazine 2mg daily for 15 days
|
Cariprazine is an antipsychotic medication
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
|
|
Sperimentale: Cariprazine 3mg
Cariprazine 3mg daily for 15 days
|
Cariprazine is an antipsychotic medication
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
|
|
Sperimentale: Cariprazine 4mg
Cariprazine 4mg daily for 15 days
|
Cariprazine is an antipsychotic medication
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
|
|
Sperimentale: Brexpiprazole 1mg
Brexpiprazole 1mg daily for 15 days
|
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
Brexpiprazole is an antipsychotic medication
|
|
Sperimentale: Brexpiprazole 2mg
Brexpiprazole 2mg daily for 15 days
|
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
Brexpiprazole is an antipsychotic medication
|
|
Sperimentale: Brexpiprazole 3mg
Brexpiprazole 3mg daily for 15 days
|
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
Brexpiprazole is an antipsychotic medication
|
|
Sperimentale: Brexpiprazole 4mg
Brexpiprazole 4mg daily for 15 days
|
This is the radiotracer that will be used to examine antipsychotic binding to D2 and D3 receptors in this study.
It is experimental and used for imaging purposes.
Brexpiprazole is an antipsychotic medication
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Acute D2 and D3 Receptor Occupancy
Lasso di tempo: Day 1
|
Delta BPND in poscommissural putamen and midbrain
|
Day 1
|
|
Upregulation of D3 receptor following subchronic administration of antipsychotics
Lasso di tempo: Day 15
|
The availability of D3Rs following two weeks of antipsychotic treatment will be measured.
|
Day 15
|
Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Positive and Negative Syndrome Scale (PANSS) Total Positive Symptoms
Lasso di tempo: 15 days
|
Correlations between changes in PANSS total positive symptoms and receptor binding will be examined.
|
15 days
|
|
Positive and Negative Syndrome Scale (PANSS) Total Negative Symptoms
Lasso di tempo: 15 days
|
Correlations between changes in PANSS total negative symptom scores and receptor binding will be examined.
|
15 days
|
|
MATRICS Cognitive Deficits (Composite Score)
Lasso di tempo: 15 days
|
Correlations between changes in cognitive deficits (MATRICS composite score) and receptor binding will be examined.
|
15 days
|
Altre misure di risultato
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Abnormal Involuntary Movement Scale (AIMS) Score
Lasso di tempo: 15 days
|
Correlations between changes in extrapyramidal side effect scores (AIMS) and receptor binding will be examined.
|
15 days
|
|
Simpson-Angus Scale (SAS) Score
Lasso di tempo: 15 days
|
Correlations between changes in extrapyramidal side effect scores (SAS) and receptor binding will be examined.
|
15 days
|
|
Barnes Akathisia Rating Scale (BARS) Score
Lasso di tempo: 15 days
|
Correlations between changes in extrapyramidal side effect scores (BARS) and receptor binding will be examined.
|
15 days
|
Collaboratori e investigatori
Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.
Studiare le date dei record
Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.
Studia le date principali
Inizio studio (Stimato)
1 dicembre 2026
Completamento primario (Stimato)
30 agosto 2030
Completamento dello studio (Stimato)
30 novembre 2030
Date di iscrizione allo studio
Primo inviato
11 luglio 2026
Primo inviato che soddisfa i criteri di controllo qualità
15 luglio 2026
Primo Inserito (Effettivo)
20 luglio 2026
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
20 luglio 2026
Ultimo aggiornamento inviato che soddisfa i criteri QC
15 luglio 2026
Ultimo verificato
1 luglio 2026
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
Altri numeri di identificazione dello studio
- NYSPI2026-31
- 1R01MH139651-01A1 (Sovvenzione/contratto NIH degli Stati Uniti)
Piano per i dati dei singoli partecipanti (IPD)
Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?
SÌ
Descrizione del piano IPD
Data will be shared via the NIH data archive.
Periodo di condivisione IPD
Data will be shared after the study has been completed, as per NIH guidelines.
Informazioni su farmaci e dispositivi, documenti di studio
Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti
Sì
Studia un dispositivo regolamentato dalla FDA degli Stati Uniti
No
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .