A Phase 4 interventional study of Escitalopram and Placebo in Depression, sponsored by Stony Brook University. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-12-15.
Sponsored by Stony Brook University · Phase 4, Interventional, and Treatment
Despite current medications, morbidity and mortality of Major Depressive Disorder (MDD) remain high. According to the World Health Organization, MDD affects 121 million people worldwide, and is projected to be the second leading cause of global disability by 2020. Monotherapy with selective serotonin reuptake inhibitors (SSRIs) is the most widely used treatment for MDD. However, on average, SSRIs require six weeks for onset of action, and two-thirds of those on SSRIs fail to achieve remission. Compounding this problem, patients with residual symptoms are significantly more likely to discontinue treatment or relapse, be hospitalized for medical and psychiatric conditions, or die of suicide and other causes. Although eliminating ineffective treatment trials would significantly reduce patient suffering and healthcare costs,clinicians currently do not have the tools to objectively select treatment based on an individual's likelihood of remission. Therefore, there is an urgent need to identify markers predictive of an individual's SSRI treatment outcome. Developing this personalized treatment requires increased understanding of the relationship between pretreatment neurobiology, SSRI-induced biological changes, and the corresponding symptom improvements.
Aim 1: Determine a Pretreatment Marker of SSRI Effectiveness Using Positron Emission Tomography (PET). With the goal of reducing MDD burden, many studies have assessed the utility of 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) - PET in antidepressant treatment prediction. However, due to the limitations listed above, there is no consensus on which brain regions are predictive of treatment efficacy. In addition to serving as a biomarker of SSRI effectiveness, only conclusive determination of these regions will provide insight into depression pathophysiology, helping uncover SSRI mechanism of action, and aiding in the search of novel therapeutics. Based on the investigators' preliminary data and other, similar studies, the investigators hypothesize that SSRI-induced change in the Hamilton Depression Rating Scale (deltaHDRS) will be correlated with pretreatment metabolic rate of glucose (MRGlu, quantified using arterial blood analysis) in three potential regions: (1) midbrain, (2) right anterior insula, and/or (3) left ventral prefrontal cortex.
Aim 2: Isolate the Neurobiological Basis of the "Loss" Research Domain Criteria (RDoc) and the Change Associated with Treatment. Using a factor analysis of the HDRS, the investigators have previously demonstrated that the "loss" RDoC criteria is significantly correlated to MRGlu in frontal cortical areas. The investigators therefore hypothesize that change in MRGlu (pre to post treatment) in these regions will be correlated with symptom improvement specifically in "loss" symptoms. As an exploratory extension, the investigators will determine whether these changes are treatment-specific (i.e. to SSRI or placebo). A validation of the hypothesis suggests a targeted mechanism of action, and provides a significant step forward for precision treatment. If regional changes in MRGlu are not correlated to improvement in this RDoC category, it suggests that SSRI (or placebo) induced changes may be a downstream effect that should be examined further.
Aim 3: Validate NonInvasive Full Quantification of MRGlu Using Simultaneous Estimation. Full quantification of brain MRGlu with FDG (as performed in this study) requires measuring FDG in arterial plasma (input function) from arterial catheter insertion and blood analysis. This costly and invasive procedure creates a barrier to widespread PET use. The investigators have developed an innovative method for Simultaneous Estimation (SimE) of input information and PET outcome measures (e.g. MRGlu). SimE fully quantifies brain MRGlu without requiring an arterial catheter. In the case of FDG, the investigators' data suggests that SimE used with a single venous sample can provide accurate results. The investigators further hypothesize that the venous sample may be entirely replaced by study data (e.g., injected dose) and biometrics (e.g., body surface area, lean body mass index). Using two different approaches (statistical imputation and physiological parametric modeling) and previously collected data, the investigators will train the SimE for accurate quantification in the absence of blood data. The rich data collected in this study will then provide a robust benchmark for validation of the SimE approach.
Aim 4: Validate Noninvasive Estimates of Plasma Radioactivity from a Novel mini-Positron Emission Tomography (miniPET) Scanner. In parallel to SimE (algorithm/software) development, the investigators will test a noninvasive method of plasma analysis using hardware. FDG concentration will be measured at the wrist, arm, ankle or leg with a novel synchronized PET scanner developed by co-Investigator, Dr. Paul Vaska.
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This study's enrollment of 85 is close to the median of 84 across 6,720 interventional studies indexed under Depression.
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Active Comparator: Escitalopram (Lexapro) 10mg Week 1, 20mg Weeks 2 and 3, and 30mg for Weeks 4 to 8 (or until 12 for patients close to remission)
Drug: Escitalopram
Lactose pill manufactured to mimic Escitalopram pill
Drug: Placebo
Participants randomized to the escitalopram group will be given the medication for 8 weeks, after which they will be given the option to continue for 4 more weeks if they are close to remission. This additional 4-week treatment option is something offered to participants outside the clinical trial, and therefore was not treated as part of the main study.
Also known as: Lexapro
To reduce the burden of the patients on placebo, the placebo trial will have a target of 8 weeks. To provide an opportunity for placebo non-responders to receive active drug and to aid in recruitment, we will provide 8-12 weeks of SSRI treatment to placebo non-responders. This treatment option is something offered to participants outside the clinical trial, and therefore was not treated as part of the main study.
Also known as: Lactose pill
Change From Baseline in Hamilton Depression Rating Scale at 8 Weeks
Comparison of Hamilton Depression Rating Scale-17 score at pretreatment and post-treatment. Minimum score 0, maximum possible score 52, with remission defined as \<=7. The higher the score on the scale, the more severe the degree of depression.
Time frame: 8 weeks
Change From Baseline in Metabolic Rate of Glucose (MRGlu), Quantified Using Arterial Blood Analysis, at 8 Weeks
Difference between MRGlu Metabolism in Right Insular Cortex before treatment (baseline) and after treatment (week 8). Details on methods and criteria used to assess brain glucose metabolism rates can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551925/
Time frame: 8 weeks
Quantification of Brain MRGlu Without an Arterial Catheter by Training Simultaneous Estimation (SimE)
Using Simultaneous Estimation, we imputed the arterial input function from a single venous sample. When we compared the resulting imputed arterial input function to the actual arterial input function collected from plasma samples, we calculated the percent difference in activity and report it here.
Time frame: Baseline
Bias of VersaPET Scanner From Measurements Taken at the Wrist and Ankle
Our goal was to determine the Bias of plasma radioactivity measurements taken at the ankle with a Novel Positron Emission Tomography (VersaPET) Scanner compared to radioactivity from arterial sampling taken at the wrist. Bias refers to the offset between the ground truth and estimated data. A bias of 0% is ideal.
Time frame: Baseline
Correlation Coefficient of VersaPET Scanner From Measurements Taken at the Wrist or Ankle
Arterial measurements from samples taken at the wrist were compared to the values from the VersaPET scanner (at the ankle) where the correlation coefficient between the scanner and arterial sampling are being reported. Correlation coefficient ranges from -1 to 1. The closer the value is to 1, the higher the correlation or stronger the relationship.
Time frame: Baseline
| Milestone | Escitalopram | Placebo |
|---|---|---|
| Started | 42 | 43 |
| Completed | 38 | 40 |
| Not completed | 4 | 3 |
| Withdrew: Lost to follow-up or discontinued intervention | 4 | 3 |
Comparison of Hamilton Depression Rating Scale-17 score at pretreatment and post-treatment. Minimum score 0, maximum possible score 52, with remission defined as \<=7. The higher the score on the scale, the more severe the degree of depression.
| score on a scale | Escitalopram | Placebo |
|---|---|---|
| Change From Baseline in Hamilton Depression Rating Scale at 8 Weeks | 11.81 ± 7.02 | 9.41 ± 5.66 |
Difference between MRGlu Metabolism in Right Insular Cortex before treatment (baseline) and after treatment (week 8). Details on methods and criteria used to assess brain glucose metabolism rates can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551925/
| mg/(min*100 ml) | Escitalopram | Placebo |
|---|---|---|
| Change From Baseline in Metabolic Rate of Glucose (MRGlu), Quantified Using Arterial Blood Analysis, at 8 Weeks | 0.507489448 ± 0.102327217 | 0.068629964 ± 0.048866182 |
Using Simultaneous Estimation, we imputed the arterial input function from a single venous sample. When we compared the resulting imputed arterial input function to the actual arterial input function collected from plasma samples, we calculated the percent difference in activity and report it here.
| Percent of Activity | Mixed |
|---|---|
| Quantification of Brain MRGlu Without an Arterial Catheter by Training Simultaneous Estimation (SimE) | 2.0 ± 7.1 |
Our goal was to determine the Bias of plasma radioactivity measurements taken at the ankle with a Novel Positron Emission Tomography (VersaPET) Scanner compared to radioactivity from arterial sampling taken at the wrist. Bias refers to the offset between the ground truth and estimated data. A bias of 0% is ideal.
| Percent | Mixed |
|---|---|
| Bias of VersaPET Scanner From Measurements Taken at the Wrist and Ankle | 5 |
Arterial measurements from samples taken at the wrist were compared to the values from the VersaPET scanner (at the ankle) where the correlation coefficient between the scanner and arterial sampling are being reported. Correlation coefficient ranges from -1 to 1. The closer the value is to 1, the higher the correlation or stronger the relationship.
| Correlation Coefficient | Mixed |
|---|---|
| Correlation Coefficient of VersaPET Scanner From Measurements Taken at the Wrist or Ankle | 0.97 |
Collected over Adverse event data were collected over a period of up to 6-weeks during the pre-treatment washout phase (when necessary), and for the complete 8-week treatment period.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Escitalopram | 0/42 (0%) | 0/42 (0%) | 0/42 (0%) |
| Placebo | 0/43 (0%) | 0/43 (0%) | 0/43 (0%) |
| Age, Categorical(Participants) | Escitalopram | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 42 | 43 | 85 |
| >=65 years | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Escitalopram | Placebo | Total |
|---|---|---|---|
| Female | 27 | 29 | 56 |
| Male | 15 | 14 | 29 |
| Race/Ethnicity, Customized(Participants) | Escitalopram | Placebo | Total |
|---|---|---|---|
| Race/Ethnicity Categories — Caucasian - White | 26 | 26 | 52 |
| Race/Ethnicity Categories — Caucasian - Non-white | 2 | 1 | 3 |
| Race/Ethnicity Categories — African American / Black | 2 | 2 | 4 |
| Race/Ethnicity Categories — Asian - South Asian | 5 | 2 | 7 |
| Race/Ethnicity Categories — Asian - East Asian | 3 | 4 | 7 |
| Race/Ethnicity Categories — Asian - Southeast Asian | 0 | 1 | 1 |
| Race/Ethnicity Categories — Pacific Islander | 0 | 1 | 1 |
| Race/Ethnicity Categories — Mixed | 4 | 6 | 10 |
| Region of Enrollment(participants) | Escitalopram | Placebo | Total |
|---|---|---|---|
| United States | 42 | 43 | 85 |
| Hamilton Depression Scale (HAM-D) Rating(Scores on Scale) | Escitalopram | Placebo | Total |
|---|---|---|---|
| Mean | 18.86 ± 5.09 | 16.79 ± 3.84 | 17.81 ± 4.59 |
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