Regulation of Arginine-vasopressin (AVP)
| Status: | Completed |
|---|---|
| Conditions: | Depression, Schizophrenia |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 4/21/2016 |
| Start Date: | February 2010 |
| End Date: | December 2014 |
Regulation of Arginine-vasopressin (AVP) in Psychiatric Disorders
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.
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.
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.
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.
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.
We found this trial at
2
sites
Click here to add this to my saved trials
VA Connecticut Healthcare System VA Connecticut encompasses an inpatient facility and Ambulatory Care Center in...
Click here to add this to my saved trials