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Regulation of Arginine-vasopressin (AVP) (REGAVP)

Primary Purpose

Schizophrenia, Depression

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Procedural

About this trial

This is an interventional diagnostic trial for Schizophrenia focused on measuring vasopressin, AVP, NMDA, osmolality

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria for healthy controls:

Ages of 18-55 years from all ethnic backgrounds.
Male or female.
Smoker or nonsmoker.
Written informed consent.

Exclusion criteria for healthy controls:

DSM-IV diagnosis of psychotic, anxiety, mood disorder.
History of major psychiatric disorder in first-degree relatives.
A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test).
A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus.
Subjects with hypertension (BP > 140/90).
Current hyponatremia.
Serum Ca2+ and uric acid levels that are above normal range.
Serum creatinine outside of normal range for age.
Creatinine clearance <70 ml/min using the Cockcroft-Gault equation (Cockcroft et al 1976) [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)].
Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine.
Current substance abuse/dependency determined by urine toxicology.
Current treatment with medications with psychotropic effects.
Current pregnancy, unsatisfactory birth control method report for females.
IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence.
Non-English speaking.

Inclusion criteria for patients with schizophrenia:

Ages of 21-55 years from all ethnic backgrounds.
Male or female.
Smoker or nonsmoker.
Written informed consent.
DSM-IV diagnosis of schizophrenia or schizoaffective disorder.
For treated patients: The patient has been on a stable dose of antipsychotics for the past month and does not require a change of medications or dose adjustment at study entry.
For untreated patients: Has refused to be treated with medications, maintains regular clinic appointments with the clinicians, and does not pose an imminent danger to himself or others.

Exclusion criteria for patients with schizophrenia

A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test).
A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus.
Serum Ca2+ and uric acid levels that are above normal range.
Serum creatinine outside of normal range for age.
Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)].
Subjects with hypertension (BP > 140/90).
Current hyponatremia.
Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine.
Currently on clozapine as clozapine may interfere with brain water regulation (Leadbetter and Shutty, 1994).
Current substance abuse/dependency determined by urine toxicology.
Current pregnancy, unsatisfactory birth control method report for females.
IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence.
Non-English speaking.

Inclusion criteria for patients with depression:

Ages of 21-55 years from all ethnic backgrounds.
Male or female.
Smoker or nonsmoker.
Written informed consent.
DSM-IV diagnosis of major depressive disorder, unipolar.
For treated patients: The patient has been on a stable dose of medications (antidepressants) for the past month and does not require a change of medications or dose adjustment at study entry.
For untreated patients: Has refused to be treated with medications, maintains regular clinic appointments with the clinicians, and does not pose an imminent danger to himself or others.

Exclusion criteria for patients with depression:

A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test).
A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus.
Serum Ca2+ and uric acid levels that are above normal range.
Serum creatinine outside of normal range for age.
Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)].
Subjects with hypertension (BP > 140/90).
Current hyponatremia.
Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine.
Current substance abuse/dependency determined by urine toxicology.
Current pregnancy, unsatisfactory birth control method report for females.
IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence.
Non-English speaking.

Inclusion criteria for patients from the PRIME Clinic:

Ages of 18-40 years from all ethnic backgrounds.
Male or female.
Smoker or nonsmoker.
Written informed consent.

Exclusion criteria for patients from the PRIME Clinic:

A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test).
A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus.
Serum Ca2+ and uric acid levels that are above normal range.
Serum creatinine outside of normal range for age.
Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)].
Subjects with hypertension (BP > 140/90).
Current hyponatremia.
Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine.
Currently on clozapine as clozapine may interfere with brain water regulation (Leadbetter and Shutty, 1994).
Current substance abuse/dependency determined by urine toxicology.
Current pregnancy, unsatisfactory birth control method report for females.
IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence.
Non-English speaking.

Sites / Locations

The John Pierce Laboratory
VA Connecticut Healthcare System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Healthy Control

Depression

Schizophrenia

Prodromal subjects

Arm Description

This group is represented by healthy controls

This experimental group is represented by subjects with depression

This experimental group is represented by subjects with schizophrenia

This experimental group is represented by subjects with prodromal symptoms for schizophrenia

Outcomes

Primary Outcome Measures

AVP response to plasma osmolality as measured by slopes between the two variables

Secondary Outcome Measures

Full Information

NCT ID

NCT02626832

First Posted

November 4, 2015

Last Updated

December 8, 2015

Sponsor

Yale University

Collaborators

VA Connecticut Healthcare System, The John B. Pierce Laboratory

1. Study Identification

Unique Protocol Identification Number

NCT02626832

Brief Title

Regulation of Arginine-vasopressin (AVP)

Acronym

REGAVP

Official Title

Regulation of Arginine-vasopressin (AVP) in Psychiatric Disorders

Study Type

Interventional

2. Study Status

Record Verification Date

December 2015

Overall Recruitment Status

Completed

Study Start Date

February 2010 (undefined)

Primary Completion Date

November 2013 (Actual)

Study Completion Date

December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Yale University

Collaborators

VA Connecticut Healthcare System, The John B. Pierce Laboratory

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study aims to develop a method for the assessment of central NMDA receptor functioning in patients with depression and schizophrenia. For this purpose a transitional approach is used based on preclinical studies that show a dose-dependent relationship between the activity of hypothalamic NMDA receptor and plasma AVP response to increasing plasma osmolality. Patients with schizophrenia, depression and healthy controls participated in this study. The Investigators found that in a subgroup of patients with schizophrenia the AVP response was low and that in a subgroup of subjects with depression the AVP response was high compared to healthy controls.

Detailed Description

Evidence suggests that altered N-methyl-D-aspartate (NMDA) receptor activity and glutamate signaling may underlie the pathogenesis of both schizophrenia and depression at least in subgroups of patients. In schizophrenia, pharmacologic modeling, postmortem and imaging data suggest reduced NMDA signaling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signaling. The Investigators have conducted a proof of concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function. For this purpose the investigators used a translational approach, based on findings from animal studies that NMDA receptor is a key mediator of arginine-vasopressin (AVP) release into the bloodstream. Using hypertonic saline to induce AVP release, as done in animal studies, it was found that in a subgroup of depressed patients, NMDA receptor mediated AVP release was significantly increased, whereas in a subgroup of schizophrenia patients, the same response was abnormally low. Previous research has demonstrated that this response is well conserved. These findings are consistent with implicated NMDA receptor related abnormalities in depression and schizophrenia in subgroups of patients, and provide the first in vivo evidence towards this dichotomy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia, Depression

Keywords

vasopressin, AVP, NMDA, osmolality

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Healthy Control

Arm Type

Experimental

Arm Description

This group is represented by healthy controls

Arm Title

Depression

Arm Type

Experimental

Arm Description

This experimental group is represented by subjects with depression

Arm Title

Schizophrenia

Arm Type

Experimental

Arm Description

This experimental group is represented by subjects with schizophrenia

Arm Title

Prodromal subjects

Arm Type

Experimental

Arm Description

This experimental group is represented by subjects with prodromal symptoms for schizophrenia

Intervention Type

Other

Intervention Name(s)

Procedural

Intervention Description

All subjects receive intravenous hypertonic saline and serial blood samples are drawn for AVP concentrations

Primary Outcome Measure Information:

Title

AVP response to plasma osmolality as measured by slopes between the two variables

Time Frame

Within 3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria for healthy controls: Ages of 18-55 years from all ethnic backgrounds. Male or female. Smoker or nonsmoker. Written informed consent. Exclusion criteria for healthy controls: DSM-IV diagnosis of psychotic, anxiety, mood disorder. History of major psychiatric disorder in first-degree relatives. A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test). A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus. Subjects with hypertension (BP > 140/90). Current hyponatremia. Serum Ca2+ and uric acid levels that are above normal range. Serum creatinine outside of normal range for age. Creatinine clearance <70 ml/min using the Cockcroft-Gault equation (Cockcroft et al 1976) [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)]. Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine. Current substance abuse/dependency determined by urine toxicology. Current treatment with medications with psychotropic effects. Current pregnancy, unsatisfactory birth control method report for females. IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence. Non-English speaking. Inclusion criteria for patients with schizophrenia: Ages of 21-55 years from all ethnic backgrounds. Male or female. Smoker or nonsmoker. Written informed consent. DSM-IV diagnosis of schizophrenia or schizoaffective disorder. For treated patients: The patient has been on a stable dose of antipsychotics for the past month and does not require a change of medications or dose adjustment at study entry. For untreated patients: Has refused to be treated with medications, maintains regular clinic appointments with the clinicians, and does not pose an imminent danger to himself or others. Exclusion criteria for patients with schizophrenia A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test). A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus. Serum Ca2+ and uric acid levels that are above normal range. Serum creatinine outside of normal range for age. Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)]. Subjects with hypertension (BP > 140/90). Current hyponatremia. Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine. Currently on clozapine as clozapine may interfere with brain water regulation (Leadbetter and Shutty, 1994). Current substance abuse/dependency determined by urine toxicology. Current pregnancy, unsatisfactory birth control method report for females. IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence. Non-English speaking. Inclusion criteria for patients with depression: Ages of 21-55 years from all ethnic backgrounds. Male or female. Smoker or nonsmoker. Written informed consent. DSM-IV diagnosis of major depressive disorder, unipolar. For treated patients: The patient has been on a stable dose of medications (antidepressants) for the past month and does not require a change of medications or dose adjustment at study entry. For untreated patients: Has refused to be treated with medications, maintains regular clinic appointments with the clinicians, and does not pose an imminent danger to himself or others. Exclusion criteria for patients with depression: A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test). A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus. Serum Ca2+ and uric acid levels that are above normal range. Serum creatinine outside of normal range for age. Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)]. Subjects with hypertension (BP > 140/90). Current hyponatremia. Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine. Current substance abuse/dependency determined by urine toxicology. Current pregnancy, unsatisfactory birth control method report for females. IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence. Non-English speaking. Inclusion criteria for patients from the PRIME Clinic: Ages of 18-40 years from all ethnic backgrounds. Male or female. Smoker or nonsmoker. Written informed consent. Exclusion criteria for patients from the PRIME Clinic: A history of significant medical/neurological disease. Unstable medical condition based on EKG, vital signs, physical examination and laboratory work-up (CBC with differential, SMA-7, uric acid, creatinine clearance, LFTs, TFTs, UA, Utox, Urine pregnancy test). A history of cardiac disease including arrhythmias; history of syncope or unexplained loss of consciousness; history of renal stones or renal failure; history of diabetes mellitus or diabetes insipidus. Serum Ca2+ and uric acid levels that are above normal range. Serum creatinine outside of normal range for age. Creatinine clearance <70 ml/min using the Cockcroft-Gault equation [(140-age)*(weight in kg)*(.85 if female)/(72*Cr)]. Subjects with hypertension (BP > 140/90). Current hyponatremia. Any medication that in the opinion of the PI could interfere with either the safety of the study and/or the outcome measures, such as diuretics of any type, lithium, carbamazepine. Currently on clozapine as clozapine may interfere with brain water regulation (Leadbetter and Shutty, 1994). Current substance abuse/dependency determined by urine toxicology. Current pregnancy, unsatisfactory birth control method report for females. IQ < 70 as determined by Wechsler Abbreviated Scale of Intelligence. Non-English speaking.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Handan Gunduz-Bruce, MD, MBA

Organizational Affiliation

Yale University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The John Pierce Laboratory

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06519

Country

United States

Facility Name

VA Connecticut Healthcare System

City

West Haven

State/Province

Connecticut

ZIP/Postal Code

06516

Country

United States

12. IPD Sharing Statement

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Regulation of Arginine-vasopressin (AVP)

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