Project to Improve Symptoms and Mood in People With Spinal Cord Injury (PRISMS)

A Controlled Trial of Venlafaxine XR for Major Depression After Spinal Cord Injury: A Multi-site Study

Depression is likely the most prevalent and disabling psychological complication associated with spinal cord injury (SCI). Yet no controlled depression treatment trials have been performed in this population. The proposed study is a multi-site, randomized, double-blind, placebo controlled trial of venlafaxine XR (Effexor XR) in 133 adults with SCI and major depressive disorder (MDD) or dysthymia who are at least one month post injury. Participants will be recruited from four SCI Model System sites, the University of Washington, Rehabilitation Institute of Chicago, University of Michigan, University of Alabama, Birmingham and Baylor Institute for Rehabilitation, Dallas, TX. The purpose of the study is to examine the efficacy and tolerability of venlafaxine XR as a treatment for MDD. The primary outcome will be the percent of responders (those who report at least a 50% reduction in depression severity from baseline to the end of treatment) in the venlafaxine XR versus placebo control group using intent-to-treat analysis. Secondary outcomes will include changes in pain, health related quality of life depression-related disability and community participation. A successful clinical trial could lead to more aggressive identification and treatment of MDD as well as improved health and quality of life in this important population.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder; Spinal Cord Injuries; Dysthymia
• Intervention / Treatment: Drug: placebo; Drug: venlafaxine XR

Detailed Description

Depression is likely the most prevalent and disabling psychological complication associated with spinal cord injury (SCI). The prevalence of major depression in people with SCI is 22% or two to six times higher than in the general population. Depression is linked to a myriad of adverse outcomes including poor subjective health, poor community integration, higher rates of medical complications and high rates of suicide. Surprisingly there are no randomized controlled trials for treating major depressive disorder (MMD) in people with SCI. Despite the widespread use of antidepressants in this population, the common assumption that antidepressant medications are effective and well-tolerated among people with SCI is uncertain. Multiple factors such as severe stresses, bereavement and loss of rewarding activities may complicate treatment. Treatment trials suggest antidepressants may not be as effective in people with medical/neurological conditions as they are with depression that develops as a primary condition. For almost 20 years clinicians and scientists have called for controlled clinical trials of antidepressants among people with SCI in order to establish evidence-based treatment. The proposed study is a multi-site, randomized, double-blind, placebo controlled trial of venlafaxine XR (Effexor XR) in 133 adults with SCI and MDD or dysthymia who are at least one month post injury. Participants aged 18-64 will be recruited from four SCI Model System sites, the University of Washington, Rehabilitation Institute of Chicago, University of Michigan, University of Alabama, Birmingham and Baylor Institute for Rehabilitation, Dallas TX. The purpose of the study is to examine the efficacy and tolerability of venlafaxine XR as a treatment for MDD. The primary outcome will be the percent of responders (those who report at least a 50% reduction in depression severity from baseline to the end of treatment) in the venlafaxine XR versus placebo control group using intent-to-treat analysis. Secondary outcomes will include changes in pain, health related quality of life and participation. A successful clinical trial could lead to more aggressive identification and treatment of MDD as well as improved health and quality of life in this important population.

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0111
      • University Of Alabama
  • Florida
    • Miami, Florida, United States, 33124
      • University of Miami
  • Illinois
    • Chicago, Illinois, United States, 60611-2654
      • Rehabilitation Institute of Chicago
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0491
      • University of Michigan
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Institute for Rehabilitation
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington/Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Spinal cord injury (ASIA A-D)
• At least one month post injury
• Meets DSM IV criteria for major depression or dysthymia on the SCID
• At least moderately severe depression (PHQ-9 score >= 10)
• Within reasonable travel distance to one of the study sites

Exclusion Criteria:

• Current DSM IV alcohol or drug dependence
• History of bipolar disorder or psychosis
• History of >= 2 suicide attempts or suicide attempt with 5 years
• Current suicidal intent or plan
• Medical contraindications
• Non-English speaker
• Clinically significant cognitive/language impairment
• History of allergic reaction to venlafaxine XR or use of MAO-I with 2 weeks
• Current use of antidepressant medications (will not exclude if on low dose of a tricyclic antidepressant or trazodone for pain, sleep, or bladder), psychotherapy for depression, or electroconvulsive therapy
• Pregnant or lactating women or women of childbearing potential who are not willing to use a reliable form of contraception
• Unstable medical condition, as determined by physical examination, CBC w/ platelets (including hematocrit, hemoglobin, WBC, differential), serum chemistry panel (serum sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose), liver transaminases (AST, ALT), thyroid stimulating hormone (TSH), urinalysis, supine diastolic blood pressure (SDBP) > 90 mm Hg, or near terminal illness (primary care physician estimates that patient has < 1 year to live)
• Anticipated major surgical procedures within the 12 weeks of randomization
• Use of an investigational drug within 30 days
• Use of psychoactive medications, including corticosteroids and anticonvulsants, that have not been at a stable dose for at least 2 weeks
• Use of anxiolytic, sedative-hypnotic, or other psychotropic drug or substance (including St. John's Wort) within 7 days of start of double-blind treatment. If the patient is taking a sedative deemed necessary for sleep induction or spasticity, the dosage must have been stable for at least 2 weeks. Use of anticholinergic, low-dose tricyclic antidepressant, GABAergic or adrenergic medications for spasticity are permitted if at a stable dose for at least 2 weeks.
• Refusal to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; identically encapsulated placebo pills 37.5 - 300 mg/day for 12 weeks	Drug: placebo; Once daily oral dose of placebo ranging from 37.5 mg up to 300 mg; Other Names: identically encapsulated inactive substance
Experimental: venlafaxine XR; venlafaxine XR 37.5 - 300 mg/day for 12 weeks	Drug: venlafaxine XR; Once daily oral dose of venlafaxine XR ranging from 37.5 mg up to 300 mg; Other Names: Effexor XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression Rating Scale-17	The 17-item Hamilton Depression Rating Scale is a clinician rated measure of depression severity (we used a structured interview version (Williams 1988) to improve inter-rater reliability). Scores range from 0-52. Higher scores indicate more severe depression. Scores of 7 or less indicate remission from depression.	0 weeks, 12 weeks
Hamilton Depression Rating Scale-Maier Subscale	The Maier is a 6-item sub scale of the Hamilton derived from Rasch analysis. It is a unidimensional scale with superior sensitivity to change. It excludes somatic items and is therefore especially appropriate for individuals who have substantial physical impairment and medical comorbidity. Scores can range from 0-22 with higher scores indicating more severe depression. Scores of 4 or less indicated in remission from depression.	0 weeks, 12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Symptom Checklist-20 Depression Subscale	Weeks 0, 1, 3, 6, 8, 10, 12, 24
Modified Brief Pain Inventory	Weeks 0, 1, 3, 6, 8, 10, 12
Modified Ashworth Spasticity Scale	Weeks 0, 1, 3, 6, 8, 10, 12
Structured Clinical Interview for DSM IV Depression Module	Weeks 0, 12, 24
SF-12	Weeks 0, 12, 24
Side Effects Checklist	Weeks 0, 1, 3, 6, 8, 10, 12
Craig Handicap and Reporting Technique	Weeks 0, 12
Satisfaction With Life	Weeks 0, 12
Sheehan Disability Scale	Weeks 0, 12
Clinical Global Impression	Weeks 0, 1, 3, 6, 8, 10, 12
Patient Global Impression	Weeks 0, 1, 3, 6, 8, 10, 12
Hamilton Rating Scale for Anxiety	Weeks 0, 12

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: University of Miami; University of Alabama at Birmingham; New York University; University of Michigan; Shirley Ryan AbilityLab; Baylor Health Care System
• Investigators: Principal Investigator: Charles H. Bombardier, PhD, University of Washington School of Medicine, Department of Rehabilitation Medicine; Principal Investigator: Jesse R. Fann, MD, MPH, University of Washington School of Medicine, Department of Psychiatry and Behavioral Science

Publications and helpful links

General Publications

• McCullumsmith CB, Kalpakjian CZ, Richards JS, Forchheimer M, Heinemann AW, Richardson EJ, Wilson CS, Barber J, Temkin N, Bombardier CH, Fann JR; PRISMS Investigators. Novel risk factors associated with current suicidal ideation and lifetime suicide attempts in individuals with spinal cord injury. Arch Phys Med Rehabil. 2015 May;96(5):799-808. doi: 10.1016/j.apmr.2014.12.017. Epub 2015 Jan 19.
• Fann JR, Bombardier CH, Richards JS, Wilson CS, Heinemann AW, Warren AM, Brooks L, McCullumsmith CB, Temkin NR, Warms C, Tate DG; PRISMS Investigators. Venlafaxine extended-release for depression following spinal cord injury: a randomized clinical trial. JAMA Psychiatry. 2015 Mar;72(3):247-58. doi: 10.1001/jamapsychiatry.2014.2482.
• Bombardier CH, Fann JR, Tate DG, Richards JS, Wilson CS, Warren AM, Temkin NR, Heinemann AW; PRISMS Investigators. An exploration of modifiable risk factors for depression after spinal cord injury: which factors should we target? Arch Phys Med Rehabil. 2012 May;93(5):775-81. doi: 10.1016/j.apmr.2011.12.020. Epub 2012 Mar 20.
• Fann JR, Bombardier CH, Richards JS, Tate DG, Wilson CS, Temkin N; PRISMS Investigators. Depression after spinal cord injury: comorbidities, mental health service use, and adequacy of treatment. Arch Phys Med Rehabil. 2011 Mar;92(3):352-60. doi: 10.1016/j.apmr.2010.05.016. Epub 2011 Jan 20.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: January 1, 2008
• First Submitted That Met QC Criteria: January 1, 2008
• First Posted (Estimate): January 14, 2008

Study Record Updates

• Last Update Posted (Estimate): January 1, 2015
• Last Update Submitted That Met QC Criteria: December 31, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: pain; quality of life; anxiety; major depressive disorder; spinal cord injuries; muscle spasticity; dysthymia; community participation; antidepressant agents
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Central Nervous System Diseases; Nervous System Diseases; Mood Disorders; Trauma, Nervous System; Spinal Cord Diseases; Depression; Depressive Disorder; Wounds and Injuries; Depressive Disorder, Major; Spinal Cord Injuries; Dysthymic Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Venlafaxine Hydrochloride
• Other Study ID Numbers: 31665-D; H133A060107; (Other Grant/Funding Number: National Institute on Disability and Rehabilitation Research)