Sustaining Remission of Psychotic Depression (STOP-PD)

• ClinicalTrials.gov Identifier: NCT01427608
• Recruitment Status: Completed
• First Posted: September 1, 2011
• Results First Posted: March 5, 2019
• Last Update Posted: March 5, 2019
• Sponsor: Weill Medical College of Cornell University
• Collaborators: University of Toronto; University of Massachusetts, Worcester; University of Pittsburgh
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Tracking Information

• First Submitted Date: August 30, 2011
• First Posted Date: September 1, 2011
• Results First Submitted Date: December 17, 2018
• Results First Posted Date: March 5, 2019
• Last Update Posted Date: March 5, 2019
• Study Start Date: October 2011
• Actual Primary Completion Date: November 30, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2019)

Number of Subjects at Risk of Relapse During the Randomized Phase. [ Time Frame: From entry into randomized phase (baseline) and 36 weeks or earlier relapse ]

Relapse criteria include at least one of the following: 1)Structured Clinical Interview for Diagnostic Statistical Manual #4 Trade Revision (DSM-IV-TR) Axis 1 Disorders (SCID) symptoms of major depression maintained over two weeks 2)17-item Hamilton Depression Rating Scale score of >17 maintained for more than one week + a mean increase of 5 points from entry into randomized phase 3)Re-emergence of psychosis for more than one week, with a SADS (Schedule for Affective Disorders and Schizophrenia) score of >2 on delusion or hallucination severity items 4)Significant clinical worsening defined as either emergence of high-risk of suicide, and/or development of mania for greater than one week, and/or psychiatric hospitalization.

Original Primary Outcome Measures (submitted: August 31, 2011)

Risk of relapse during the randomized phase. [ Time Frame: From entry into randomized phase until 36 weeks or earlier relapse ]

Relapse criteria include at least one of the following: 1)SCID symptoms of major depressive episode maintained over two weeks 2)17-item HAM-D score of >17 maintained for more than one week + a mean increase of 5 points from entry into randomized phase 3)Re-emergence of SCID defined psychosis for more than one week, with a score of >2 on SADS delusion or hallucination severity items 4)Significant clinical worsening defined as either emergence of high-risk of suicide, and/or development of mania for greater than one week, and/or psychiatric hospitalization.

Current Secondary Outcome Measures (submitted: February 13, 2019)

• Changes in Metabolic Measures: Weight [ Time Frame: From entry into randomized phase (baseline) and 36 weeks ]
  Change in weight from entry into randomized phase (baseline) and 36 weeks.
• Changes in Metabolic Measure: Cholesterol [ Time Frame: From entry into randomized phase (baseline) and 36 weeks ]
  Change in cholesterol from entry into randomized phase (baseline) and 36 weeks.
• Changes in Metabolic Measures: Triglycerides [ Time Frame: From entry into randomized phase (baseline) and 36 weeks ]
  Change in triglycerides from entry into randomized phase (baseline) and 36 weeks.

Original Secondary Outcome Measures (submitted: August 31, 2011)

Changes in metabolic measures [ Time Frame: From entry into randomized phase until up to 36 weeks later ]

Weight and clinical laboratory analyses of cholesterol and triglycerides

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sustaining Remission of Psychotic Depression
• Official Title: Sustaining Remission of Psychotic Depression

Brief Summary

The acute phase of this study will monitor the response to a combination of an atypical antipsychotic medication olanzapine with an antidepressant medication sertraline in the acute treatment of the disorder. It is predicted that this combination will improve symptoms of psychotic depression and be associated metabolic side effects. Factors that moderate tolerability will be monitored. Improvement in symptoms could take between 4 and 12 weeks, followed by a period of 8 weeks during which participants will continue to take the same medications to stabilize the remission from symptoms of psychotic depression.

The maintenance phase will be a randomized, double-blind, placebo-controlled study of olanzapine for a period of up to 36 weeks to test whether continuing this combination decreases the risk of relapse and whether discontinuing the combination leads to improvement in metabolic measures. Subjects who complete the acute phase will be asked to consent separately to the randomized maintenance phase.

• Detailed Description: The original STOP-PD study established that the combination of olanzapine and sertraline was significantly better than olanzapine alone in achieving remission of psychotic depression. This STOP-PD-II Sustaining Remission study aims to assess the long-term tolerability of taking this combination of medications and their efficacy at preventing a relapse of the symptoms. The acute phase of the study will monitor the efficacy and tolerability of the olanzapine and sertraline combination, including investigation of weight and metabolic variables, age effects on treatment response and tolerability, and the association of genetic polymorphisms to response or relapse. When subjects are stabilized on these medications for a period of 8 weeks they will be invited to participate in the randomized phase of the research: the olanzapine will be placebo-controlled, meaning half of the subjects will continue to take the olanzapine/sertraline combination and half will take a sertraline/placebo combination, for a period of 36 weeks. Symptoms and side effects will be monitored regularly throughout this phase. Randomization will be stratified on a 1:1 basis by age 60 and above.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Psychotic Depression

Intervention

• Drug: Sertraline + Olanzapine
  Olanzapine 15mg/day. Adjustment of dose to 5mg/day to a maximum of 20mg/day will be permitted if necessitated by significant side-effects or clinical worsening
  Other Name: Zyprexa
• Drug: Sertraline + Placebo
  Taper from current dose of olanzapine to placebo over 4 weeks. Continue placebo for remainder of 36 week study.
  Other Name: Placebo

Study Arms

• Active Comparator: Sertraline + Olanzapine
  Randomized to continue with sertraline and olanzapine under double-blind conditions.
  Intervention: Drug: Sertraline + Olanzapine
• Placebo Comparator: Sertraline + Placebo
  Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions.
  Intervention: Drug: Sertraline + Placebo

Publications *

• Voineskos AN, Mulsant BH, Dickie EW, Neufeld NH, Rothschild AJ, Whyte EM, Meyers BS, Alexopoulos GS, Hoptman MJ, Lerch JP, Flint AJ. Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features: Neuroimaging Findings in the Context of a Randomized Placebo-Controlled Clinical Trial. JAMA Psychiatry. 2020 Jul 1;77(7):674-683. doi: 10.1001/jamapsychiatry.2020.0036.
• Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Alexopoulos GS, Rudorfer MV, Marino P, Banerjee S, Pollari CD, Wu Y, Voineskos AN, Mulsant BH; STOP-PD II Study Group. Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial. JAMA. 2019 Aug 20;322(7):622-631. doi: 10.1001/jama.2019.10517.
• Bingham KS, Whyte EM, Mulsant BH, Rothschild AJ, Rudorfer MV, Marino P, Banerjee S, Butters MA, Alexopoulos GS, Meyers BS, Flint AJ; STOP-PD Study Group. Health-related quality of life in remitted psychotic depression(✰). J Affect Disord. 2019 Sep 1;256:373-379. doi: 10.1016/j.jad.2019.05.068. Epub 2019 May 28.
• Flint AJ, Meyers BS, Rothschild AJ, Whyte EM, Mulsant BH, Rudorfer MV, Marino P; STOP-PD II Study Group. Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II. BMC Psychiatry. 2013 Jan 25;13:38. doi: 10.1186/1471-244X-13-38.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 8, 2017): 269
• Original Estimated Enrollment (submitted: August 31, 2011): 392
• Actual Study Completion Date: November 30, 2017
• Actual Primary Completion Date: November 30, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Aged 18-85 years, inclusive
2. Diagnosis: Diagnostic Statistical Manual-IV Trade Revision (DSM IV-TR) non-bipolar major depression with psychotic features established by both clinical interview with research psychiatrist and administration of SCID-IV.
3. Score >2 on Schedule for Affective Disorders (SADS) delusion severity item
4. Score >1 on any of the three conviction items of the Delusion Assessment Scale (DAS) (does not alter belief in response to reality testing)
5. 17-item HAM-D score of >20

Exclusion Criteria:

1. Current or lifetime DSM-IV-TR history of schizophrenia or other psychotic disorders or meeting current criteria for brief psychotic disorder, body dysmorphic disorder or obsessive-compulsive disorder
2. Current or lifetime DSM-IV-TR bipolar affective disorder
3. History of DSM-IV-TR defined alcohol or substance abuse or dependence within the past three months
4. Dementia or clinically significant cognitive impairment prior to index episode of depression, and/or a mean score >3 on 26-item caregiver assessment
5. Type 1 diabetes mellitus (defined as insulin-dependent diabetes mellitus with onset before age 35, and/or diabetes mellitus complicated by prior documented episode of ketoacidosis
6. Acute or unstable medical illness within the past 3 months; current abnormal serum free T4; current abnormally low vitamin B4 or folic acid level; medical conditions and/or medications for which psychotic or depressive symptoms can be a direct manifestation; neurological disease associated with extrapyramidal signs and symptoms; epilepsy, if the person has had one or more grand mal seizures within the past 12 months.
7. The need for treatment with any psychotropic medication other than sertraline, olanzapine or lorazepam; or with an anticonvulsant medication with mood-stabilizing properties.
8. Current pregnancy or plan to become pregnant during the course of the study; breast feeding in women with infants.
9. A documented history of being unable to tolerate olanzapine or sertraline including significant bradycardia (heart rate of <50 bpm), and serum sodium level of 129mmol/L or below.
10. History of non-response of the index episode of psychotic depression to at least a 6-week trial of at least 150mg/day sertraline combined with 15mg/day olanzapine
11. Patients showing ongoing improvement in current episode of psychotic depression with treatment other than sertraline or olanzapine
12. Patients who are in immediate need of electroconvulsive therapy (ECT) (imminent risk of suicide, refusing to eat, catatonic)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01427608
• Other Study ID Numbers: STOP-PD-II
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Weill Medical College of Cornell University
• Study Sponsor: Weill Medical College of Cornell University

Collaborators

• University of Toronto
• University of Massachusetts, Worcester
• University of Pittsburgh

Investigators

• Principal Investigator: George Alexopoulos, MD; Weill Medical College of Cornell University
• Principal Investigator: Alastair Flint, MD; University of Toronto
• Principal Investigator: Anthony Rothschild, MD; University of Massachusetts, Worcester
• Principal Investigator: Ellen Whyte, MD; University of Pittsburgh

• PRS Account: Weill Medical College of Cornell University
• Verification Date: February 2019