The Quietude Study: Quetiapine Use for Agitated Depression

Focus of Study:

Many individuals with major depressive disorder manifest clinically significant agitation. Concurrent agitation in a depressed individual is associated with an intensification of mood symptoms, decreased probability of recovery, increased recurrence risk, suicidality, and increased medical-service utilization. The occurrence of anxiety/agitation phenomenology in the depressed patient often invites the need for augmentation strategies (e.g. atypical antipsychotics, benzodiazepines, etc.) and complicated polypharmacy regimens. Moreover, individuals with major depressive disorder often report worsening of symptom severity, irritability, hostility, dysphoria, and significant subjective distress (This response pattern is similar to individuals with bipolar disorder).

Results from large research studies provide evidence indicating that quetiapine is capable of offering clinically significant multidimensional symptom relief in bipolar depression. Moreover, results from several trials in major depressive disorder and generalized anxiety disorder have established the efficacy of quetiapine therapy for unipolar depression and anxiety syndromes. So far, no atypical antipsychotic agent has been evaluated specifically for the treatment of agitated depression.

In this study, it is hypothesized that persons with major depressive disorder and prominent agitation (i.e. agitated depression) will exhibit a more favourable response and tolerability profile to quetiapine XR when compared to escitalopram.

Condition:

Depression with Prominent Agitation

Intervention:

Drug: Quetiapine XR; Drug: Escitalopram

Study Type:

Interventional

Study Design:

Allocation: Randomized

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Primary Outcome Measures:

Change from baseline to endpoint in the Hamilton Depression Rating Scale 17-Item (HAMD-17) total score [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to assess the range of symptoms of depression

Secondary Outcome Measures:

Change in anxiety factor score on the Hamilton Depression Rating Scale 17-item (HAMD-17) from baseline to endpoint [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to assess the range of symptoms of depression

Change from baseline to endpoint in Hamilton Anxiety Rating Scale (HAMA) total score [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to measure severity of symptoms of anxiety

Change in Clinical Global Impression score from baseline to endpoint [ Time Frame: Screening Visit, Day 1, Day 8, Day 15, Day 29, Day 43, Day 57 ] [ Designated as safety issue: No ]

A tool to assess illness severity, improvement and response to treatment

Change from baseline to endpoint in Sheehan Disability Scale (SDS) sub-scales and total score [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to assess functional impairment

Change in Hamilton Depression Rating Scale 17-item (HAMD-17) sleep disturbance factor score on the from baseline to endpoint [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to assess the range of symptoms of depression

Change in Hamilton Anxiety Rating Scale (HAMA) somatic and psychic anxiety factor scores from baseline to endpoint [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: No ]

A tool to measure severity of symptoms of anxiety

Change from baseline in the Sex Functioning Questionnaire (Sex FX) [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: Yes ]

A tool to assess sexual functioning

Change in blood pressure and heart rate from baseline to end of treatment [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: Yes ]

Change in weight, BMI, waist circumference from baseline to end of treatment [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: Yes ]

Change in findings from physical examination from baseline to end of treatment [ Time Frame: Screening, Day 57 ] [ Designated as safety issue: Yes ]

Tabulation of spontaneous adverse events [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: Yes ]

Tabulation of clinical haematology and chemistry results [ Time Frame: Screening, Day 57 ] [ Designated as safety issue: Yes ]

Incidence of premature study withdrawal due to inadequate control of depressive symptoms [ Designated as safety issue: Yes ]

Proportion of patients with HAM-D Item 3 score > 2 at any time after randomization or adverse events of suicidality/suicidal ideation/suicide attempts/suicide completion [ Time Frame: Day 1, Day 57 ] [ Designated as safety issue: Yes ]

Enrollment:

250

Study Start Date:

October 2010

Primary Completion Date:

April 2013

Groups:

Active Comparator: Quetiapine XR

Active Comparator: Escitalopram

Active Comparator: Quetiapine XR
Active Comparator: Escitalopram

Assigned Interventions:

Drug: Quetiapine XR

Dosage form: tablets Day 1-2: 50 mg Day 3-7: 150 mg Day 8-57: either 150 or 300 mg/day (flexible)

Other Name: Seroquel XR

Drug: Escitalopram

Dosage form: capsules Day 1-7: 10 mg Day 8-57: 10 or 20 mg/day (flexible)

Other Name: Cipralex

Ages of Eligibility:

18 years to 65 years

Gender:

Both

Inclusion Criteria:

Male or female
Age 18 to 65
Outpatient at enrolment
A diagnosis of major depressive disorder
Baseline HAMD-17 score > 20 and HAMD Item1 score > 2 both at enrolment and baseline
Significant agitation
CGI-S score > 4 at screening and baseline
Negative serum pregnancy test at enrolment and use of a reliable method of birth control during the study
Able to understand and comply with the requirements of the study
Able and willing to give meaningful informed written consent

Exclusion Criteria:

Another Axis I diagnosis of primary focus within 6 months of enrolment
Axis II disorder causing impact on current diagnosis
Current depressive episode <4 weeks
Substance or alcohol abuse or dependency as defined by DSM IV within 6 months of enrolment
Any pervasive developmental disorder or dementing disorder
Treatment with other antipsychotics, mood stabilizer or other psychoactive drugs less than 7 days prior to randomization
Treatment with fluoxetine less than 28 days prior to baseline
Treatment with MAO inhibitors, anxiolytic drugs in excess of 2 mg lorazepam equivalents/day.
Known lack of antidepressant response to quetiapine at a dose of at least 50 mg/day x 4 weeks
Known lack of antidepressant response to escitalopram at a dose of at least 10 mg/day
Known intolerance or hypersensitivity to quetiapine or escitalopram
Treatment with Electroconvulsive therapy within 90 days prior to baseline
Use of Potent P450 3A4 inhibitors or inducers within 14 days of baseline
AST & ALT ≥ 3X ULN
TSH ≥ 10% ULN
Unstable medical condition
Medical condition the would affect absorption, distribution, metabolism or excretion of study treatment
Significant ECG abnormalities
Pregnancy or lactation
Patients with increased suicidal risks, HAM-D item 3 ≥3 or have made a suicide attempt within the past 6 months.
Patients who, in the investigators opinion, will require psychotherapy (other than supportive psychotherapy) during the study period, unless psychotherapy has been ongoing for a minimum of 3 months prior to randomisation
A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
Unstable DM defined as enrolment glycosylated haemoglobin (HbA1c) >8.5%.
Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
Not under physician care for DM.
Physician responsible for patient's DM care has not indicated that patient's DM is controlled.
Physician responsible for patient's DM care has not approved patient's participation in the study
Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomisation. For thiazolidinediones (glitazones) this period should not be less than 8 weeks.
Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study
Clinically significant deviation from the reference range in clinical laboratory test results
An absolute neutrophil count (ANC) of 1.5 x 109 per liter
Those who are involved in the planning and/or conduct of the study cannot be enrolled as subjects
Previous enrolment or randomization in the present study
Participation in another medication trial within 4 weeks prior to enrolment into the study herein

Contacts:

Contact: Alissa Powell, BA

647.780.9533

quietude.study@gmail.com

Contact Hanna Woldeyohannes, HBSc

quietude.pren@gmail.com

Locations:

Canada, Ontario

Sponsors & Collaborators:

Physicians' Research And Education Network, INC.

Investigators:

Study Director: Roger McIntyre, MD, FRCPC

Physicians' Research and Education Network, INC.

Responsible Party:

Roger S. McIntyre, MD, FRCPC, Physicians' Research and Education Network

Study ID Numbers:

D1443C00037

Health Authority:

Canada: Health Canada