Antipsychotics and Blood Vessel Function
| Status: | Completed |
|---|---|
| Conditions: | Schizophrenia, Psychiatric, Bipolar Disorder |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 8/25/2018 |
| Start Date: | September 2007 |
| End Date: | December 2014 |
Cardiovascular Complications of First-line, Second-generation Antipsychotics
Over the last decade, second generation antipsychotics have been increasingly utilized. Since
their introduction, however, atypical antipsychotics have been increasingly associated with
significant metabolic complications including hyperlipidemia, insulin resistance/diabetes
mellitus, and obesity. These metabolic complications increase the risk for cardiovascular
disease in populations with an already elevated risk.
The initial goal of the proposed study is to identify early signs of endothelial dysfunction
and vascular disease in those treated with atypical antipsychotics. The identification of
early signs of vascular disease may further link metabolic complications with any
cardiovascular risk. Demonstration of changes in vascular function associated with atypical
antipsychotics represents an important identifiable intermediate of more long-term
cardiovascular risk.
The second goal of the proposed study is to identify genetic factors that may be associated
with the development of cardiovascular disease, which can later serve as a guide to predict
risk. Accurate prediction of risk may facilitate the future development of an empirical,
risk-based, individualized selection process for antipsychotic medications.
Aim 1: To quantify the role of antipsychotic-induced metabolic complications on the
development of vascular disease using measures of endothelial function.
Hypothesis 1: Atypical antipsychotics will lead to greater impairments in endothelial
function, evidenced by decreased flow-mediated dilation from baseline measures and compared
with changes over time in controls. Medication-induced metabolic complications will be
temporally associated with these impairments in endothelial function.
Aim 2: To investigate the role of candidate pharmacogenetic polymorphisms with cardiovascular
and metabolic complications of atypical antipsychotics.
Hypothesis 2: Profiles of polymorphisms at receptors targeted by atypical antipsychotics will
be associated with impaired cardiovascular function and metabolic complications.
their introduction, however, atypical antipsychotics have been increasingly associated with
significant metabolic complications including hyperlipidemia, insulin resistance/diabetes
mellitus, and obesity. These metabolic complications increase the risk for cardiovascular
disease in populations with an already elevated risk.
The initial goal of the proposed study is to identify early signs of endothelial dysfunction
and vascular disease in those treated with atypical antipsychotics. The identification of
early signs of vascular disease may further link metabolic complications with any
cardiovascular risk. Demonstration of changes in vascular function associated with atypical
antipsychotics represents an important identifiable intermediate of more long-term
cardiovascular risk.
The second goal of the proposed study is to identify genetic factors that may be associated
with the development of cardiovascular disease, which can later serve as a guide to predict
risk. Accurate prediction of risk may facilitate the future development of an empirical,
risk-based, individualized selection process for antipsychotic medications.
Aim 1: To quantify the role of antipsychotic-induced metabolic complications on the
development of vascular disease using measures of endothelial function.
Hypothesis 1: Atypical antipsychotics will lead to greater impairments in endothelial
function, evidenced by decreased flow-mediated dilation from baseline measures and compared
with changes over time in controls. Medication-induced metabolic complications will be
temporally associated with these impairments in endothelial function.
Aim 2: To investigate the role of candidate pharmacogenetic polymorphisms with cardiovascular
and metabolic complications of atypical antipsychotics.
Hypothesis 2: Profiles of polymorphisms at receptors targeted by atypical antipsychotics will
be associated with impaired cardiovascular function and metabolic complications.
Participants will have all evaluations related to metabolic complications performed in the
University of Iowa Clinical Research Unit (CRU) or in the EndoPAT laboratory located in Room
269 GH. For all visits, weights will be measured without shoes, in light clothing, using an
electronic scale that measures to the nearest 0.25 kg. Standing heights will be measured
without shoes, to the nearest 0.1 cm using a free-standing stadiometer. These weights and
heights will be utilized for the computation of body mass index (BMI). Waist circumference
will be measured horizontally at the tip of the right iliac crest in the standing position
using a measuring tape. Blood pressure and heart rate will be measured in the sitting
position after five minutes of silent rest, using an automated sphygmomanometer. An
ambulatory blood pressure will also be obtained at each visit. An EKG will be conducted
during Visit 1. Dual energy X-ray absortionmetry (DEXA) will assess percentage of body fat at
intake, Visit 4 and Visit 8. If a participant is unable to complete a DEXA scan, body fat
will be determined using the BOD POD® Gold Standard Body Composition Tracking System. The BOD
POD® is an integrated system consisting of a digital scale to measure subject mass, a large
egg-shaped fiberglass air displacement plethysmography (ADP) to determine body volume (BV),
and a computer that operates the equipment and calculates body composition. Body density is
determined from subject mass and volume measurements and then percent fat is calculated using
one of several standard formulas. CRU dieticians will perform skin fold measurements at
intake and completion. Fasting measures of triglycerides, LDL-C, HDL-C, IDL, VLDL,
apolipoprotein A, apolipoprotein B, Lp(a) cholesterol, C-reactive protein, IL-6, leptin
levels, insulin levels, and glucose will be obtained at baseline, 2 weeks, 12 weeks, 26
weeks, 1 year, 2 years, 3 years and 4 years. Hemoglobin A1C will be collected at baseline and
weeks 12 and 26, 1 year, 2 years, 3 years and 4 years. Cholesterol levels will be determined
by an enzymatic calorimetric test using cholesterol esterase and cholesterol oxidase. LDL-C
and HDL-C fractions will be obtained via a homogeneous enzymatic in vitro colorimetric assay.
For the determination of triglyceride levels, free glycerol is eliminated prior to hydrolysis
of triglycerides in a preliminary reaction where lipase and 4-aminophenazone are omitted,
followed by enzymatic hydrolysis of triglycerides and determination of the liberated glycerol
by a fully enzymatic colorimetric assay reaction. Apolipoproteins and other lipid parameters
will be measured using beta quantification through the Mayo Medical Laboratories (unit code
83673).
Endothelial and Cardiovascular Function: Participants will have endothelial function measured
at baseline, and each subsequent visit. To maximize completion rates, participants planning
to discontinue their antipsychotic between weeks 16 and 26 will have their final measures
taken at the time of discontinuation. Prior to these appointments, participants will be
instructed to not eat or drink anything (including caffeinated products such as coffee, tea,
soda, etc.) except water for at least 12 hours prior to the appointment. They will also be
instructed to not drink any alcohol for 24 hours prior to each study. They will be asked not
to smoke for the two hours prior to the study. Administration of blood pressure and lipid
lowering medications for that day will be delayed until after the procedures. Measures of
endothelial function will be obtained in the Clinical Research Unit (CRU).
CONDUIT VESSEL FUNCTION: Conduit vessel endothelial function will be assessed non-invasively
via ultrasound measurement of brachial artery diameter during changes in brachial artery
flow. The technique uses a 10-13 MHz linear array transducer ultrasound system (Biosound
ESAOTE, Indianapolis, IN). A 5 cm length of the brachial artery is imaged in longitudinal
section above the antecubital fossa and the optimal probe site on the skin marked. Baseline
images of brachial artery diameter and Doppler velocities from the center of the vessel are
recorded on videotape. While images for brachial artery diameter are being continuously
recorded, an occluding forearm cuff placed just below the antecubital fossa is inflated for 5
minutes. The brachial artery diameter and Doppler velocities are continuously recorded
before, during and after cuff deflation. After approximately 5 minutes, once basal diameter
and flow have been restored, nitroglycerin (300 mcg) will be administered sublingually and
measurements made for an additional 6 minutes.
HEART RATE AND BLOOD PRESSURE VARIABILITY: We will also assess blood pressure and heart rate
variability using recordings of indirect arterial pressure with a beat-to-beat finger
systolic and diastolic blood pressure recording in conjunction with the electrocardiogram
tracing during the conduit vessel function procedures. Data from this measurement will allow
us to assess blood pressure and heart rate variability. Cardiovascular variability (HRV) is a
marker for cardiovascular risk whereby lower variability indicates greater risk for
myocardial infarct and stroke. This procedure can be performed during assessment of conduit
vessel function so requires no additional time.
ARTERIAL TONOMETRY: We will utilize arterial tonometry through measurement of pulse wave
analysis (PWA) and pulse wave velocity (PWV) using a SphygmorCor machine. This machine uses a
noninvasive probe, pressed lightly on the skin over the carotid, radial and femoral arteries
for about five minutes each. These measurements will provide a measure of arterial
compliance, stiffness, and other hemodynamic information. The PWA system is a computerized
diagnostic tool for the assessment of central blood pressure. The peripheral pressure pulse
waveform contains information in addition to the maximum and minimal values (systolic and
diastolic pressures). The PWA system can derive the central aortic pressure waveform from the
peripheral pressure waveform recorded at the radial or carotid arteries. The system uses
mathematical transforms to derive the central aortic pressure pulse waveform and then
calculates a range of central indices of ventricular-vascular interaction, which are
displayed both graphically and numerically. The PWV system measures the velocity of the blood
pressure waveform between any two superficial artery sites. A pressure tonometer is used to
transcutaneously record the pressure pulse waveforms in the underlying artery. The pressure
pulse waveform is recorded simultaneously with an electrocardiogram (ECG) signal, which
provides an R-wave timing reference. Pressure pulse recordings are performed consecutively at
the two superficial artery sites over the carotid and femoral artery. The software processes
each set of pressure pulse and ECG waveform data to calculate the mean time difference
between the R-wave and the pressure wave- on a beat-by-beat basis. The PWV is then calculated
using the mean time difference and the arterial path length between the two recording sites.
The velocity of the blood pressure pulse waveform is dependent on the stiffness of the artery
along which the pulse is traveling. Serial measurement of pulse wave velocity in a section of
artery will indicate the magnitude of change in arterial stiffness in that section of the
artery.
PSYCHIATRIC ASSESSMENT: Detailed historical information will be gathered including age,
occupation, education, race, height, weight, medical history, treatment history, family
history of medical illness with focus on risk factors for metabolic syndrome, and substance
use history including tobacco. Basic clinical information will be obtained to verify
psychiatric diagnosis and assess cardiac risk by the Framingham Heart Study formula. It is
estimated that this history will take 45 minutes to complete. Affective and psychotic
symptomatology will be cross-sectionally assessed using the Montgomery Asberg Depression
Rating Scale, the Young Mania Scale, and the Brief Psychotic Rating Scale.
University of Iowa Clinical Research Unit (CRU) or in the EndoPAT laboratory located in Room
269 GH. For all visits, weights will be measured without shoes, in light clothing, using an
electronic scale that measures to the nearest 0.25 kg. Standing heights will be measured
without shoes, to the nearest 0.1 cm using a free-standing stadiometer. These weights and
heights will be utilized for the computation of body mass index (BMI). Waist circumference
will be measured horizontally at the tip of the right iliac crest in the standing position
using a measuring tape. Blood pressure and heart rate will be measured in the sitting
position after five minutes of silent rest, using an automated sphygmomanometer. An
ambulatory blood pressure will also be obtained at each visit. An EKG will be conducted
during Visit 1. Dual energy X-ray absortionmetry (DEXA) will assess percentage of body fat at
intake, Visit 4 and Visit 8. If a participant is unable to complete a DEXA scan, body fat
will be determined using the BOD POD® Gold Standard Body Composition Tracking System. The BOD
POD® is an integrated system consisting of a digital scale to measure subject mass, a large
egg-shaped fiberglass air displacement plethysmography (ADP) to determine body volume (BV),
and a computer that operates the equipment and calculates body composition. Body density is
determined from subject mass and volume measurements and then percent fat is calculated using
one of several standard formulas. CRU dieticians will perform skin fold measurements at
intake and completion. Fasting measures of triglycerides, LDL-C, HDL-C, IDL, VLDL,
apolipoprotein A, apolipoprotein B, Lp(a) cholesterol, C-reactive protein, IL-6, leptin
levels, insulin levels, and glucose will be obtained at baseline, 2 weeks, 12 weeks, 26
weeks, 1 year, 2 years, 3 years and 4 years. Hemoglobin A1C will be collected at baseline and
weeks 12 and 26, 1 year, 2 years, 3 years and 4 years. Cholesterol levels will be determined
by an enzymatic calorimetric test using cholesterol esterase and cholesterol oxidase. LDL-C
and HDL-C fractions will be obtained via a homogeneous enzymatic in vitro colorimetric assay.
For the determination of triglyceride levels, free glycerol is eliminated prior to hydrolysis
of triglycerides in a preliminary reaction where lipase and 4-aminophenazone are omitted,
followed by enzymatic hydrolysis of triglycerides and determination of the liberated glycerol
by a fully enzymatic colorimetric assay reaction. Apolipoproteins and other lipid parameters
will be measured using beta quantification through the Mayo Medical Laboratories (unit code
83673).
Endothelial and Cardiovascular Function: Participants will have endothelial function measured
at baseline, and each subsequent visit. To maximize completion rates, participants planning
to discontinue their antipsychotic between weeks 16 and 26 will have their final measures
taken at the time of discontinuation. Prior to these appointments, participants will be
instructed to not eat or drink anything (including caffeinated products such as coffee, tea,
soda, etc.) except water for at least 12 hours prior to the appointment. They will also be
instructed to not drink any alcohol for 24 hours prior to each study. They will be asked not
to smoke for the two hours prior to the study. Administration of blood pressure and lipid
lowering medications for that day will be delayed until after the procedures. Measures of
endothelial function will be obtained in the Clinical Research Unit (CRU).
CONDUIT VESSEL FUNCTION: Conduit vessel endothelial function will be assessed non-invasively
via ultrasound measurement of brachial artery diameter during changes in brachial artery
flow. The technique uses a 10-13 MHz linear array transducer ultrasound system (Biosound
ESAOTE, Indianapolis, IN). A 5 cm length of the brachial artery is imaged in longitudinal
section above the antecubital fossa and the optimal probe site on the skin marked. Baseline
images of brachial artery diameter and Doppler velocities from the center of the vessel are
recorded on videotape. While images for brachial artery diameter are being continuously
recorded, an occluding forearm cuff placed just below the antecubital fossa is inflated for 5
minutes. The brachial artery diameter and Doppler velocities are continuously recorded
before, during and after cuff deflation. After approximately 5 minutes, once basal diameter
and flow have been restored, nitroglycerin (300 mcg) will be administered sublingually and
measurements made for an additional 6 minutes.
HEART RATE AND BLOOD PRESSURE VARIABILITY: We will also assess blood pressure and heart rate
variability using recordings of indirect arterial pressure with a beat-to-beat finger
systolic and diastolic blood pressure recording in conjunction with the electrocardiogram
tracing during the conduit vessel function procedures. Data from this measurement will allow
us to assess blood pressure and heart rate variability. Cardiovascular variability (HRV) is a
marker for cardiovascular risk whereby lower variability indicates greater risk for
myocardial infarct and stroke. This procedure can be performed during assessment of conduit
vessel function so requires no additional time.
ARTERIAL TONOMETRY: We will utilize arterial tonometry through measurement of pulse wave
analysis (PWA) and pulse wave velocity (PWV) using a SphygmorCor machine. This machine uses a
noninvasive probe, pressed lightly on the skin over the carotid, radial and femoral arteries
for about five minutes each. These measurements will provide a measure of arterial
compliance, stiffness, and other hemodynamic information. The PWA system is a computerized
diagnostic tool for the assessment of central blood pressure. The peripheral pressure pulse
waveform contains information in addition to the maximum and minimal values (systolic and
diastolic pressures). The PWA system can derive the central aortic pressure waveform from the
peripheral pressure waveform recorded at the radial or carotid arteries. The system uses
mathematical transforms to derive the central aortic pressure pulse waveform and then
calculates a range of central indices of ventricular-vascular interaction, which are
displayed both graphically and numerically. The PWV system measures the velocity of the blood
pressure waveform between any two superficial artery sites. A pressure tonometer is used to
transcutaneously record the pressure pulse waveforms in the underlying artery. The pressure
pulse waveform is recorded simultaneously with an electrocardiogram (ECG) signal, which
provides an R-wave timing reference. Pressure pulse recordings are performed consecutively at
the two superficial artery sites over the carotid and femoral artery. The software processes
each set of pressure pulse and ECG waveform data to calculate the mean time difference
between the R-wave and the pressure wave- on a beat-by-beat basis. The PWV is then calculated
using the mean time difference and the arterial path length between the two recording sites.
The velocity of the blood pressure pulse waveform is dependent on the stiffness of the artery
along which the pulse is traveling. Serial measurement of pulse wave velocity in a section of
artery will indicate the magnitude of change in arterial stiffness in that section of the
artery.
PSYCHIATRIC ASSESSMENT: Detailed historical information will be gathered including age,
occupation, education, race, height, weight, medical history, treatment history, family
history of medical illness with focus on risk factors for metabolic syndrome, and substance
use history including tobacco. Basic clinical information will be obtained to verify
psychiatric diagnosis and assess cardiac risk by the Framingham Heart Study formula. It is
estimated that this history will take 45 minutes to complete. Affective and psychotic
symptomatology will be cross-sectionally assessed using the Montgomery Asberg Depression
Rating Scale, the Young Mania Scale, and the Brief Psychotic Rating Scale.
Inclusion Criteria:
- 18-50 years of age
- Being started on a first-line, second-generation, antipsychotic associated with weight
gain (risperidone, olanzapine, or quetiapine) for the treatment of an affective or
psychotic disorder -OR- psychiatric controls not taking antipsychotic medications will
also be enrolled
Exclusion Criteria:
- Exclusion criteria will include the presence of any of the following: neoplasm, active
thyroid disease (i.e. not euthyroid), pregnancy or planned pregnancy, diabetes
mellitus, Raynaud's disease, anticoagulant therapy, or inability to provide informed
consent. We will exclude participants who have started valproic acid derivatives in
the preceding 6 months, given its association with insulin resistance and weight gain.
Participants with active substance abuse or dependence will also be excluded.
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