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Risperidone vs. Olanzapine as add-on Treatment in Treatment Resistant Depression

This study has been completed.
Sponsor:
Information provided by:
Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier:
NCT01282632
First received: January 21, 2011
Last updated: January 24, 2011
Last verified: September 2010
  Purpose

Atypical neuroleptics may have antidepressant qualities in bipolar depression and in unipolar depression. Some data support the use of both Risperidone and Olanzapine, but there are no direct comparisons of their relative efficacy and tolerability in treatment resistant depression. The current study was designed as a pilot study to examine efficacy and tolerability of Olanzapine vs. Risperidone add on to a failed serotonin re-uptake inhibitor (SSRI) in depression.


Condition Intervention Phase
Subjects Had Unipolar, Non-psychotic Major Depression
Drug: Risperidone
Drug: Olanzapine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double Blind Pilot Trial to Evaluate Efficacy Trends and Safety of Risperidone and Olanzapine as add-on Therapy to Serotonin Type Antidepressants in Subjects With Treatment Resistant Depression (TRD)

Resource links provided by NLM:


Further study details as provided by Sunnybrook Health Sciences Centre:

Primary Outcome Measures:
  • Change from Baseline in Hamilton Depression Rating Scale at 1 week [ Time Frame: day one ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 1 week [ Time Frame: day one ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 1 week [ Time Frame: day one ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.

  • Change from Baseline in Hamilton Depression Rating Scale at 2 weeks [ Time Frame: day 8 ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Hamilton Depression Rating Scale at 3 weeks [ Time Frame: day 15 ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Hamilton Depression Rating Scale at 4 weeks [ Time Frame: day 22 ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Hamilton Depression Rating Scale at 5 weeks [ Time Frame: day 29 ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Hamilton Depression Rating Scale at 6 weeks [ Time Frame: day 43 ] [ Designated as safety issue: Yes ]
    Subject to be eligible for this trial must have a minimum score of 16 on the 17 item HAM-D which will be obtained at screening. Efficacy will be measured on the HAM-D 17 and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 2 weeks [ Time Frame: day 8 ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 3 weeks [ Time Frame: day 15 ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 4 weeks [ Time Frame: day 22 ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 5 weeks [ Time Frame: day 29 ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from Baseline in Montgomery Asberg Depression Scale (MADRS)at 6 weeks [ Time Frame: day 43 ] [ Designated as safety issue: Yes ]
    MADRS will be obtained at screening. Efficacy will be measured by the MADRS and defined as a 50% decrease from baseline to week 6.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 2 weeks [ Time Frame: day 8 ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 3 weeks [ Time Frame: day 15 ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 4 weeks [ Time Frame: day 15 ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 5 weeks [ Time Frame: day 22 ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.

  • Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) at 6 weeks [ Time Frame: day 43 ] [ Designated as safety issue: Yes ]
    Impact on anxiety will be measured by the HAM-A over the 6 weeks.


Secondary Outcome Measures:
  • Clinical Global Improvement Scale - Improvement [ Time Frame: day one ] [ Designated as safety issue: Yes ]
    Subjects currently taking a SSRI or a SNRI for at least 4 weeks, at adequate dosage and not responding, as defined by a score of 3 or more on the CGI-I.

  • Change from Baseline of Weight at 6 weeks [ Time Frame: day 43 ] [ Designated as safety issue: No ]
    Weight (Kg) will be measured with subjects at screening then at week 6.


Enrollment: 42
Study Start Date: August 2002
Study Completion Date: March 2004
Primary Completion Date: March 2004 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Risperidone
Commence at 0.5 mg once daily Increase, blindly, to 1 mg and then by 1 mg at discretion of clinicians through weeks 1-4 to a maximum of 3 mg.
Drug: Risperidone
Risperidone will commence at 0.5 mg per day in a single daily dose given once in the evening. Clinicians will have the option, at each visit of increasing the risperidone dose to a maximum of 3 mg/day based on subject response and tolerability (please see Titration Recommendations below).
Experimental: Olanzapine
Commence at 2.5 mg once daily Increase to 5.0 mg, blindly, and then by 5 mg at the discretion of the clinician through weeks 1 - 4 to a maximum of 15 mg
Drug: Olanzapine
Olanzapine will commence at 2.5 mg per day in a single daily dose given once in the evening. Clinicians will have the option, at each visit, of increasing the olanzapine dose to a maximum of 15 mg/day based on subject response and tolerability.

Detailed Description:

Overview of Study Design

This is a Canadian, multicentre, double blind, comparator trial in 42 patients with TRD. TRD is defined as the failure to respond adequately to two successive courses of different antidepressants at an adequate dose (at least fluoxetine 20 mg, citalopram 20 mg, paroxetine 20 mg, sertraline 100 mg, fluvoxamine 150 mg, venlafaxine 225 mg)) for at least 4 weeks. All subjects, at entry to the study will be currently not responding to treatment of at least 4 weeks duration of a serotonin re-uptake inhibitor (SSRI) or a selective nor-epinephrine and serotonin re-uptake inhibitor (SNRI). Non-response is defined as a score of 3 ("minimal improvement") or worse on the Clinical global Impression of Improvement .

The objective is to assess the appropriateness of the trial design and to determine sample size requirements for future controlled trials. In addition the efficacy and safety of oral doses of risperidone (.5-3 mg/day) and olanzapine (2.5-15 mg.day) as add-on therapy to any SSRI or SNRI in treatment resistant depression will be evaluated. Subjects meeting the screening criteria will enter a 6-week trial with risperidone or olanzapine added on to the current SSRI or SNRI therapy.

A medical/ psychiatric history, HAM-D-29 (only the first 17 items will be used for outcome), MADRS and HAM-A will be obtained at screening. At subsequent visits HAM-D, HAM-A, and MADRS will be performed and adverse events (spontaneous and using the CASES checklist) and concomitant medications will be collected.

Recruitment:

Subjects will drawn from two sources:

  1. Outpatients currently attending the clinic at the sites. These subjects will already be in treatment or may have been referred from the local communities of the clinics involved in this study for consultation. Should these subjects drop out or once they have completed the study they will receive the treatment as usual at each site.
  2. Advertisements. Advertisements will be placed in local media (radio, television, newspaper) identifying the nature of the study and providing a contact number. These advertisements will be approved by the local IRB's prior to posting.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects who meet all of the following criteria are eligible for this trial:

  1. Male or female out-patients;
  2. Aged between 18 and 65 years (extremes included);
  3. Subjects suffering from a current episode of non-psychotic, unipolar depression as determined by the depression section of the SCID-IV.
  4. Subjects with treatment resistant depression defined as failure to respond to two successive courses of monotherapy given in adequate doses for a minimum of 4 weeks with different antidepressants (the current course of antidepressant can be considered to second failed course) and;
  5. Subjects currently taking a SSRI or a SNRI for at least 4 weeks, at adequate dosage and not responding, as defined by a score of 3 or more on the CGI-I. and no dose change for 2 weeks prior to entry.
  6. A minimum score of 16 on the 17 item HAM-D
  7. Ability to provide informed consent.

Exclusion Criteria:

Subjects meeting one or more of the following criteria cannot be selected:

  1. Subjects who are actively suicidal as determined by a score of 3 on the suicide item on the HAM-D or in the opinion of the treating physician;
  2. Other current (active symptomatology within the last 2 months) Axis I DSM IV diagnosis other than nicotine or caffeine dependence or other than an Anxiety disorder.
  3. Use of disallowed concomitant therapy; or other psychotropic medication except occasional benzodiazepines. (See "Rescue Medication");
  4. History of alcohol or drug abuse or dependence, within 3 months of entry into the trial);
  5. Seizure disorder requiring medication;
  6. Active medical condition that requires urgent attention or that would contra-indicate the use of risperidone or olanzapine. For example stable thyroid disease or asthma would be acceptable, whereas acute hepatitis would not;
  7. Participation in an investigational drug trial within 30 days prior to the start of the trial
  8. Known sensitivity to risperidone, olanzapine or the antidepressant;
  9. History of neuroleptic malignant syndrome (NMS);
  10. Subjects who are at imminent risk of injury to self or others, or causing significant damage to property, as judged by the investigator;
  11. Female subjects who are pregnant or breast-feeding;
  12. Female subject of childbearing potential without adequate contraception (sterilization, barrier, IUD, oral contraceptives, intramuscular or subdermal administration of depot-progestagens);

15. Previous exposure to risperidone or olanzapine during the current episode.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01282632

Locations
Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
Principal Investigator: Anthony Levitt, MD Sunnybrook Health Sciences Centre
Study Director: Raymond Lam, MD University of British Columbia
Study Director: Yves Chaput, MD University of Manitoba
Study Director: Murray Enns, MD University of McGill
  More Information

No publications provided

Responsible Party: Dr. Anthony Levitt, Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT01282632     History of Changes
Other Study ID Numbers: ro123
Study First Received: January 21, 2011
Last Updated: January 24, 2011
Health Authority: Canada: Janssen Ortho Canada

Keywords provided by Sunnybrook Health Sciences Centre:
depression
treatment resistant depression
unipolar
non- psychotic major depression
add-on to a serotonin type antidepressants
risperidone
olanzapine
double blind comparison
randomized

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mental Disorders
Mood Disorders
Antidepressive Agents
Olanzapine
Risperidone
Antiemetics
Antipsychotic Agents
Autonomic Agents
Central Nervous System Agents
Central Nervous System Depressants
Dopamine Agents
Dopamine Antagonists
Gastrointestinal Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Antagonists
Serotonin Uptake Inhibitors
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on November 20, 2014