STOP-PD: Sustaining Remission of Psychotic Depression

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01427608
• Collaborator: University of Toronto (Other), University of Massachusetts, Worcester (Other), University of Pittsburgh (Other)
• Enrollment: 269
• Locations: 4
• Arms: 2
• Duration (Months): 74
• Patients Per Site: 67.3
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Psychotic Depression	Drug: Sertraline + Olanzapine; Drug: Sertraline + Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 269 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Sustaining Remission of Psychotic Depression
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Nov 30, 2017
• Actual Study Completion Date: Nov 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sertraline + Olanzapine Randomized to continue with sertraline and olanzapine under double-blind conditions.	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 Names: Zyprexa
Placebo Comparator: Sertraline + Placebo Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions.	Drug: Sertraline + Placebo; Taper from current dose of olanzapine to placebo over 4 weeks. Continue placebo for remainder of 36 week study.; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Subjects at Risk of Relapse During the Randomized Phase. [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.

Secondary Outcome Measures

1. Changes in Metabolic Measures: Weight [From entry into randomized phase (baseline) and 36 weeks]

   Change in weight from entry into randomized phase (baseline) and 36 weeks.

2. Changes in Metabolic Measure: Cholesterol [From entry into randomized phase (baseline) and 36 weeks]

   Change in cholesterol from entry into randomized phase (baseline) and 36 weeks.

3. Changes in Metabolic Measures: Triglycerides [From entry into randomized phase (baseline) and 36 weeks]

   Change in triglycerides from entry into randomized phase (baseline) and 36 weeks.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anthony Rothschild, MD	Worcester	Massachusetts	United States	01605
2	George Alexopoulos, MD	White Plains	New York	United States	10605
3	Ellen Whyte, MD	Pittsburgh	Pennsylvania	United States	15213
4	Alastair Flint, MD	Toronto		Canada

Sponsors and Collaborators

• Weill Medical College of Cornell University
• 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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 27, 2018

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01427608
• Other Study ID Numbers: STOP-PD-II
• First Posted: Sep 1, 2011
• Last Update Posted: Mar 5, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Depression; Depressive Disorder; Mental Disorders; Psychotic Disorders; Bipolar Disorder; Depressive Disorder, Major; Olanzapine; Sertraline

Study Results

Participant Flow

Pre-assignment Detail	269 participants were enrolled in the open-label phase. However, only 126 participants were eligible and consented to participate in the RCT phase. Reasons for not being eligible for the RCT phase included failure to achive remission criteria, discontinuation of treatment prior to the RCT, or decision by the participant not to consent to the RCT.

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions
Period Title: Overall Study
STARTED	64	62
COMPLETED	43	24
NOT COMPLETED	21	38

Baseline Characteristics

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo	Total
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions	Total of all reporting groups
Overall Participants	64	62	126
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	45 70.3%	42 67.7%	87 69%
>=65 years	19 29.7%	20 32.3%	39 31%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.0 (15.1)	55.7 (14.9)	55.3 (14.8)
Sex: Female, Male (Count of Participants)
Female	37 57.8%	41 66.1%	78 61.9%
Male	27 42.2%	21 33.9%	48 38.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 9.4%	9 14.5%	15 11.9%
Not Hispanic or Latino	58 90.6%	53 85.5%	111 88.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	4 6.3%	3 4.8%	7 5.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 9.4%	9 14.5%	15 11.9%
White	54 84.4%	49 79%	103 81.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.6%	1 0.8%
Region of Enrollment (participants) [Number]
Canada	24 37.5%	23 37.1%	47 37.3%
United States	40 62.5%	39 62.9%	79 62.7%
Hamilton Depression Rating Scale 17-Item Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.3 (3.6)	5.6 (3.6)	5.5 (3.6)
Weight (pounds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pounds]	178.6 (39.4)	182.5 (39.8)	180.5 (39.5)
Total Cholesterol level (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	209.0 (51.3)	220.4 (46.8)	214.7 (49.3)
Triglycerides (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	134	121	127

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions
Measure Participants	64	62
Count of Participants [Participants]	13 20.3%	34 54.8%

2. Secondary Outcome

Title	Changes in Metabolic Measures: Weight
Description	Change in weight from entry into randomized phase (baseline) and 36 weeks.
Time Frame	From entry into randomized phase (baseline) and 36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions
Measure Participants	64	62
Mean (95% Confidence Interval) [pounds]	5.70	-3.11

3. Secondary Outcome

Title	Changes in Metabolic Measure: Cholesterol
Description	Change in cholesterol from entry into randomized phase (baseline) and 36 weeks.
Time Frame	From entry into randomized phase (baseline) and 36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions. 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	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions. Sertraline + Placebo: Taper from current dose of olanzapine to placebo over 4 weeks. Continue placebo for remainder of 36 week study.
Measure Participants	64	62
Mean (95% Confidence Interval) [mg/dL]	-0.46	-22.28

4. Secondary Outcome

Title	Changes in Metabolic Measures: Triglycerides
Description	Change in triglycerides from entry into randomized phase (baseline) and 36 weeks.
Time Frame	From entry into randomized phase (baseline) and 36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline + Olanzapine	Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions	Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions
Measure Participants	64	62
Mean (95% Confidence Interval) [mg/dL]	-3.85	-18.18

Adverse Events

Time Frame	36 Weeks of RCT Phase
Adverse Event Reporting Description	Are based on items of the Udvalg for Kliniske Undersogelser Side effect scale (UKU), based on the following system: 1) Items with an increase of ≥2 points from baseline and items rated as a 3 on the UKU that were rated <3 at baseline. Exceptions include the following items: 35=Weight Gain, 36= Weight Loss. 2) Weight gain and weight loss AEs were determined by the following definitions: a. weight gain of >7% from pre-morbid weight, b. weight loss of >7% from pre-morbid weight in the RCT phase.
Arm/Group Title	Sertraline + Olanzapine		Sertraline + Placebo
Arm/Group Description	Randomized to continue with sertraline and olanzapine under double-blind conditions		Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions
All Cause Mortality
	Sertraline + Olanzapine		Sertraline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/64 (1.6%)		0/62 (0%)
Serious Adverse Events
	Sertraline + Olanzapine		Sertraline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/64 (17.2%)		12/62 (19.4%)
Surgical and medical procedures
Hospitalisation	11/64 (17.2%)	11	12/62 (19.4%)	12
Other (Not Including Serious) Adverse Events
	Sertraline + Olanzapine		Sertraline + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/64 (45.3%)		23/62 (37.1%)
Gastrointestinal disorders
Constipation	0/64 (0%)	0	1/62 (1.6%)	1
Diarrhoea	4/64 (6.3%)	4	1/62 (1.6%)	2
Dry mouth	0/64 (0%)	0	1/62 (1.6%)	1
Nausea	2/64 (3.1%)	2	4/62 (6.5%)	5
General disorders
Fatigue	2/64 (3.1%)	2	1/62 (1.6%)	1
Infections and infestations
Urinary tract infection	1/64 (1.6%)	1	0/62 (0%)	0
Investigations
Weight decreased	3/64 (4.7%)	5	3/62 (4.8%)	3
Weight increased	9/64 (14.1%)	11	3/62 (4.8%)	3
Musculoskeletal and connective tissue disorders
Musculoskeletal stiffness	1/64 (1.6%)	1	0/62 (0%)	0
Nervous system disorders
Dizziness postural	5/64 (7.8%)	5	2/62 (3.2%)	2
Headache	3/64 (4.7%)	3	1/62 (1.6%)	1
Hypersomnia	2/64 (3.1%)	2	3/62 (4.8%)	3
Somnolence	4/64 (6.3%)	5	2/62 (3.2%)	2
Psychiatric disorders
Abnormal dreams	1/64 (1.6%)	2	1/62 (1.6%)	1
Depression	1/64 (1.6%)	1	0/62 (0%)	0
Indifference	1/64 (1.6%)	1	0/62 (0%)	0
Insomnia	2/64 (3.1%)	2	4/62 (6.5%)	4
Libido decreased	4/64 (6.3%)	4	0/62 (0%)	0
Tension	3/64 (4.7%)	3	0/62 (0%)	0
Renal and urinary disorders
Polyuria	1/64 (1.6%)	1	0/62 (0%)	0
Pollakiuria	1/64 (1.6%)	1	0/62 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/64 (1.6%)	1	2/62 (3.2%)	2
Pruritus	0/64 (0%)	0	1/62 (1.6%)	1
Rash	2/64 (3.1%)	2	0/62 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.