Longitudinal PET Imaging of Antipsychotic Binding to the Dopamine-3 Receptor in Schizophrenia
2026年7月15日 更新者：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.
調査の概要
詳細な説明
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.
研究の種類
介入
入学 (推定)
100
段階
- フェーズ 1
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究連絡先
- 名前：Ragy Girgis, MD
- 電話番号：646-774-5553
- メール：ragy.girgis@nyspi.columbia.edu
参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
- 大人
健康ボランティアの受け入れ
いいえ
説明
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)
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：他の
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：独身
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：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.
|
|
実験的：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.
|
|
実験的：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.
|
|
実験的：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.
|
|
実験的：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
|
|
実験的：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
|
|
実験的：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
|
|
実験的：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
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Acute D2 and D3 Receptor Occupancy
時間枠：Day 1
|
Delta BPND in poscommissural putamen and midbrain
|
Day 1
|
|
Upregulation of D3 receptor following subchronic administration of antipsychotics
時間枠：Day 15
|
The availability of D3Rs following two weeks of antipsychotic treatment will be measured.
|
Day 15
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Positive and Negative Syndrome Scale (PANSS) Total Positive Symptoms
時間枠：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
時間枠：15 days
|
Correlations between changes in PANSS total negative symptom scores and receptor binding will be examined.
|
15 days
|
|
MATRICS Cognitive Deficits (Composite Score)
時間枠：15 days
|
Correlations between changes in cognitive deficits (MATRICS composite score) and receptor binding will be examined.
|
15 days
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Abnormal Involuntary Movement Scale (AIMS) Score
時間枠：15 days
|
Correlations between changes in extrapyramidal side effect scores (AIMS) and receptor binding will be examined.
|
15 days
|
|
Simpson-Angus Scale (SAS) Score
時間枠：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
時間枠：15 days
|
Correlations between changes in extrapyramidal side effect scores (BARS) and receptor binding will be examined.
|
15 days
|
協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (推定)
2026年12月1日
一次修了 (推定)
2030年8月30日
研究の完了 (推定)
2030年11月30日
試験登録日
最初に提出
2026年7月11日
QC基準を満たした最初の提出物
2026年7月15日
最初の投稿 (実際)
2026年7月20日
学習記録の更新
投稿された最後の更新 (実際)
2026年7月20日
QC基準を満たした最後の更新が送信されました
2026年7月15日
最終確認日
2026年7月1日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- NYSPI2026-31
- 1R01MH139651-01A1 (米国 NIH グラント/契約)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
はい
IPD プランの説明
Data will be shared via the NIH data archive.
IPD 共有時間枠
Data will be shared after the study has been completed, as per NIH guidelines.
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
はい
米国FDA規制機器製品の研究
いいえ
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。