Contact: Developing New Clinical Management Strategies

• ClinicalTrials.gov Identifier: NCT03812588
• Recruitment Status: Completed
• First Posted: January 23, 2019
• Last Update Posted: September 5, 2021
• Sponsor: New York State Psychiatric Institute
• Collaborator: University of Haifa
• Information provided by (Responsible Party): Bret Rutherford, New York State Psychiatric Institute

Study Description

Brief Summary:

The goal of this study is to develop new methods of administering antidepressant medications that will result in improved drug/placebo separation in randomized controlled trials (RCTs) for Major Depressive Disorder (MDD) and enhanced medication response in open clinical treatment. The highly intensive, weekly visit schedule followed in most antidepressant RCTs radically differs from how antidepressant medications are prescribed in standard clinical practice and is believed to be a major reason why the majority of studies submitted to the Food and Drug Administration (FDA) fail to show a significant difference between medication and placebo. Moreover, a "one size fits all" approach to psychopharmacologic management (i.e., weekly visits for all patients) does not take into account differences between patients that may predispose some individuals to respond positively to frequent follow-up visits, while others may respond negatively or not at all. Clinic visits comprise multiple components that may be therapeutic for depression, including activating patients' behavior, exposing them to medical procedures, permitting social interactions with research staff, and providing supportive meetings with clinicians. Two independent meta-analyses have associated more frequent study visits with increased antidepressant and placebo response as well as decreased separation between medication and placebo. Despite the high costs and potential disadvantages of weekly follow-up visits for patients receiving antidepressant medication, this clinical management strategy has not been studied prospectively to date. It is unknown whether weekly follow-up visits are needed to ensure treatment compliance and patient safety in clinical trials and to what degree contacts with clinicians influence medication and placebo response.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: Escitalopram; Drug: Placebo	Phase 4

Detailed Description:

This study utilizes a 2 x 2, double-blind, acute, prospective design randomizing adult

outpatients with MDD to "Research Frequency Management" (RFM, weekly study visits) vs. "Community Frequency Management" (CFM, every 4 weeks study visits) and antidepressant medication vs. placebo. Specifying visit frequency as the independent variable in this study has the distinct advantages of being easily operationalized for research purposes avoiding a priori assumptions about which components of study visits influence antidepressant and placebo response (i.e., behavioral activation vs. doctor-patient relationship vs. medical procedures). Close monitoring of all subjects will be assured by telephone evaluations of individuals randomized to CFM at intervals between monthly visits, and additional study contacts will be scheduled as necessary to maintain patient safety (all extra-protocol contacts will be recorded and included as a variable in outcome analyses). Additionally, subjects will be characterized extensively on clinical, demographic, and psychological measures to pilot the study assessment battery and search for predictor variables influencing the effects of contact frequency on medication and placebo response.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Developing New Clinical Management Strategies for Antidepressant Treatments
• Actual Study Start Date: January 30, 2019
• Actual Primary Completion Date: August 1, 2021
• Actual Study Completion Date: August 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Clinical Frequency Management: Placebo; Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.	Drug: Placebo; A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient.
Placebo Comparator: Research Frequency Management: Placebo; Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.	Drug: Placebo; A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient.
Active Comparator: Clinical Frequency Management: Escitalopram; Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.	Drug: Escitalopram; Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain.; Other Name: Lexapro
Active Comparator: Research Frequency Management: Escitalopram; Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.	Drug: Escitalopram; Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain.; Other Name: Lexapro

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline Hamilton Rating Scale for Depression at Study Completion (8 or 20 Weeks) [ Time Frame: Up to 20 Weeks ]

   Scale for depressive symptoms administered by trained rater. The Hamilton is the standard measure of depression severity for clinical trials of antidepressants and was chosen as the primary outcome measure over other depression rating scales to ensure compatibility of study results with our meta-analyses and ongoing studies of expectancy. Although the Hamilton list 24 items, the scoring is based on both the first 17 items and the full 24 items.

   sum of the scores of the first 17 items (range from 0 to 54): 0-7 = NORMAL 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression >=23 = Very Severe Depression

Secondary Outcome Measures :

1. Hamilton Anxiety Rating Scale 14-item scale [ Time Frame: Up to 20 Weeks ]
   Scale for anxiety symptoms administered by trained rater. The Hamilton Anxiety is a standard measure of anxiety severity in pharmacotherapy studies that has been shown to have acceptable reliability and validity in studies of depressed patients. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and25-30 moderate to severe.

Other Outcome Measures:

1. Clinical Global Impressions [ Time Frame: Up to 20 Weeks ]

   Scales developed to measure the clinician's view of subjects' global functioning before and after initiating a study medication. The Clinical Global Impressions correlates well with other standard outcome measures for depression (e.g., HRSD), is sensitive to change in antidepressant trials, and offers clinically understandable anchor points.

   7-point scale: 0 = Not assessed 4 = Moderately ill

   1 = Normal, not at all ill 5 = Markedly ill 2 = Borderline mentally ill 6 = Severely ill 3 = Mildly ill 7 = Among the most extremely ill patients

2. Treatment Emergent Symptom Scale [ Time Frame: Up to 20 Weeks ]

   Rating scale for physical symptoms reported during the study. This is a standard means of recording drug-related adverse effects that will allow us to assess whether contact frequency is associated with differences in side effects among study subjects.

   *Each Symptom* range: 0-3; higher scores correlate with worse outcome. There is no total score.

3. Working Alliance Inventory-Short Revised [ Time Frame: Up to 20 Weeks ]

   The Working Alliance Inventory, the most widely used measure of the therapeutic alliance, has excellent psychometric properties (Elvins & Green, 2008) and has been consistently correlated with psychotherapeutic outcome (Horvath et al., 2011). Similarly to previous antidepressant medication studies, we have slightly modified the scale to substitute "pharmacotherapy" for "counseling" on relevant questions (e.g., Zilcha-Mano et al., 2015). The Working Alliance Inventory total score will be used for analyses.

   Each item scale is rated from 1-7; neither end is necessarily "better". Total score is summed from each individual score, for a range of 0-98.

4. Blind assessment-Clinician Version [ Time Frame: Up to 20 Weeks ]
   Rates clinician's guess as to the identity of study medication and the confidence in that guess. This assessment is necessary to document the effectiveness of the study's methods of treatment allocation concealment.
5. Quick Inventory of Depressive Symptoms-Self Report 16 item scale [ Time Frame: Up to 20 Weeks ]

   Rating scale for depressive symptoms based on DSM criteria. A self-report measure for depressive symptoms is valuable in this study, because it is less susceptible to clinician and rater bias. It has been increasingly used in antidepressant studies due to its equivalent weightings for each symptom item, clearly understandable anchor points, and inclusion of all DSM criteria for depression.

   Each item is scored from 0-3 Total is summed from each individual item item; total score range is 0-48

6. Treatment Credibility and Expectancy Scale [ Time Frame: Up to 20 Weeks ]
   8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. It is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. For this study, the primary measure of expectancy will be item 4: "By the end of the treatment period, how much improvement in your depressive symptoms do you think will occur?" (0-100%).
7. Client Satisfaction Questionnaire 8 [ Time Frame: Baseline week. ]
   Self-administered scale with items rating respondents' satisfaction with mental health services they are receiving on a 4 point Likert scale. Use of this measure will allow us to determine whether CFM and RFM are associated with differences in participant satisfaction.
8. Cornell Treatment Preference Index [ Time Frame: Baseline week. ]
   Scale used in mental health studies to document the type and strength of patients' treatment preferences. We will use a modified version in this study asking subjects "Based on your experience and how you feel right now, which of the visit frequencies in this study would be your first choice?" The strength of this preference will be measured on a 5-point Likert scale.
9. Revised Life Orientation Test [ Time Frame: Baseline week. ]
   Scale developed to assess individual differences in generalized optimism versus pessimism. Degree of optimism on this scale has been correlated with the magnitude of placebo response observed in studies of placebo analgesia, and we will determine whether these scores moderate effects of therapeutic contact.
10. Blind assessment-Patient Version [ Time Frame: Baseline week. ]

    Rates subject's guess as to the identity of study medication and the confidence in that guess. This assessment is necessary to document the effectiveness of the study's methods.

    of treatment allocation concealment.

11. Experiences in Close Relationships Scale - Short Form [ Time Frame: Baseline week. ]

    Scale assessing patients' attachment orientation. Both dimensions will be used and assessed at baseline: 6 items assess the attachment anxiety dimension and 6 the avoidance dimension. A self-report questionnaire will be used for assessing attachment orientation because it will be easy and inexpensive to implement, enabling translation of the findings into personalized medicine in clinical practice.

    Scale is from 1-7 for each item, total score is from 0-252.

12. Inventory of Interpersonal Problems - Circumplex [ Time Frame: Baseline week. ]
    A 64-item self-report questionnaire assessing interpersonal difficulties and distress. Patients rate two types of items: interpersonal behaviors that are "hard for you to do" (e.g., "it is hard for me to let other people know when I am angry") and interpersonal behaviors that "you do too much" (e.g., "I am too afraid of other people"). Ratings of the degree to which each problem is distressing are made on a 5-point scale, ranging from 0 (not at all) to 4 (extremely).
13. Big Five Personality Traits [ Time Frame: Baseline week. ]

    This questionnaire is a widely used assessment tool for personality traits that we will also use to identify predictors of response to varying visit frequency.

    Each item scale is from 1-5; total is from 0-220.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Inclusion Criteria Method of Ascertainment

1. Men and women aged 18-75 years 1. Clinical interview
2. Diagnosis with Diagnostic and Statistical Manual (DSM) V Major Depressive Disorder (MDD) 2. Clinical interview, Structured Clinical Interview for DSM-V
3. 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16 and ≤ 28; 17-item Hamilton Rating Scale for Depression (HRSD) score < 25 3. HRSD by trained rater
4. Capable of providing informed consent and complying with study procedures 4. Clinical interview
5. Using appropriate contraceptive method if woman of child-bearing age and not currently pregnant 5. Clinical interview

Exclusion Criteria:

1. Current comorbid Axis I DSM V disorder other than Mild Substance Use Disorder, Adjustment Disorder, Anxiety Disorder or Personality Disorder 1. Clinical interview, SCID
2. Diagnosis of Moderate to Severe Substance Use Disorder within the past 12 months 2. Clinical interview, SCID, Urine tox
3. present or past history of psychosis, psychotic disorder, mania, or bipolar disorder 3. Clinical interview, SCID
4. baseline HRSD 24-item score > 28 or HRSD suicide item > 2 or baseline HRSD 17-item score ≥ 25 4. HRSD by trained rater
5. History of allergic or adverse reaction to escitalopram, or non-response to adequate trial of escitalopram (at least 4 weeks at dose of 20mg) during the current episode 5. Clinical interview
6. Current treatment with psychotherapy, antidepressants, antipsychotics, or mood stabilizers 6. Clinical interview
7. CGI-Severity score of 6 or greater at baseline 7. CGI based on Clinical interview
8. Acute, severe, or unstable medical illness 8. Clinical interview, Physical Exam, Screening Labs

Contacts and Locations

Locations

United States, New York

New York State Psychiatric Institute

New York, New York, United States, 10032

Sponsors and Collaborators

New York State Psychiatric Institute

University of Haifa

Investigators

• Principal Investigator: Bret Rutherford, MD; New York State Psychiatric Institute

More Information

• Responsible Party: Bret Rutherford, Associate Professor in Clinical Psychiatry, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT03812588
• Other Study ID Numbers: 7738
• First Posted: January 23, 2019
• Last Update Posted: September 5, 2021
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Depressive Disorder; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Citalopram; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs