Psychotic Depression
Conditions
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.
Interventions
DRUGSertraline + 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
DRUGSertraline + Placebo
Taper from current dose of olanzapine to placebo over 4 weeks. Continue placebo for remainder of 36 week study.
Sponsors
University of Toronto
University of Massachusetts, Worcester
University of Pittsburgh
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Sertraline + Olanzapine Randomized to continue with sertraline and olanzapine under double-blind conditions | 64 |
| Sertraline + Placebo Randomized to continue with sertraline and substitute placebo for olanzapine under double-blind conditions | 62 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Events not attributed to study meds | 0 | 1 |
| Overall Study | Relapsed-all cause | 13 | 34 |
| Overall Study | Withdrawal by Subject | 7 | 3 |
Baseline characteristics
| Characteristic | Sertraline + Olanzapine | Total | Sertraline + Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 39 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 87 Participants | 42 Participants |
| Age, Continuous | 55.0 years STANDARD_DEVIATION 15.1 | 55.3 years STANDARD_DEVIATION 14.8 | 55.7 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 15 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 111 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hamilton Depression Rating Scale 17-Item Total Score | 5.3 units on a scale STANDARD_DEVIATION 3.6 | 5.5 units on a scale STANDARD_DEVIATION 3.6 | 5.6 units on a scale STANDARD_DEVIATION 3.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 54 Participants | 103 Participants | 49 Participants |
| Region of Enrollment Canada | 24 participants | 47 participants | 23 participants |
| Region of Enrollment United States | 40 participants | 79 participants | 39 participants |
| Sex: Female, Male Female | 37 Participants | 78 Participants | 41 Participants |
| Sex: Female, Male Male | 27 Participants | 48 Participants | 21 Participants |
| Total Cholesterol level | 209.0 mg/dL STANDARD_DEVIATION 51.3 | 214.7 mg/dL STANDARD_DEVIATION 49.3 | 220.4 mg/dL STANDARD_DEVIATION 46.8 |
| Triglycerides | 134 mg/dL | 127 mg/dL | 121 mg/dL |
| Weight | 178.6 pounds STANDARD_DEVIATION 39.4 | 180.5 pounds STANDARD_DEVIATION 39.5 | 182.5 pounds STANDARD_DEVIATION 39.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 64 | 0 / 62 |
| other Total, other adverse events | 29 / 64 | 23 / 62 |
| serious Total, serious adverse events | 11 / 64 | 12 / 62 |
Outcome results
Primary
Number of Subjects at Risk of Relapse During the Randomized Phase.
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sertraline + Olanzapine | Number of Subjects at Risk of Relapse During the Randomized Phase. | 13 Participants |
| Sertraline + Placebo | Number of Subjects at Risk of Relapse During the Randomized Phase. | 34 Participants |
Secondary
Changes in Metabolic Measure: Cholesterol
Change in cholesterol from entry into randomized phase (baseline) and 36 weeks.
Time frame: From entry into randomized phase (baseline) and 36 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sertraline + Olanzapine | Changes in Metabolic Measure: Cholesterol | -0.46 mg/dL |
| Sertraline + Placebo | Changes in Metabolic Measure: Cholesterol | -22.28 mg/dL |
Secondary
Changes in Metabolic Measures: Triglycerides
Change in triglycerides from entry into randomized phase (baseline) and 36 weeks.
Time frame: From entry into randomized phase (baseline) and 36 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sertraline + Olanzapine | Changes in Metabolic Measures: Triglycerides | -3.85 mg/dL |
| Sertraline + Placebo | Changes in Metabolic Measures: Triglycerides | -18.18 mg/dL |
Secondary
Changes in Metabolic Measures: Weight
Change in weight from entry into randomized phase (baseline) and 36 weeks.
Time frame: From entry into randomized phase (baseline) and 36 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sertraline + Olanzapine | Changes in Metabolic Measures: Weight | 5.70 pounds |
| Sertraline + Placebo | Changes in Metabolic Measures: Weight | -3.11 pounds |