Treatment of Mild to Moderate Depression in Persons with SCI: A Randomized Clinical Trial

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Treatment of Mild to Moderate Depression in
Persons with SCI A Randomized Clinical Trial

• Denise G. Tate Ph.D.
• Martin Forchheimer MPP
• Claire Kalpakjian Ph.D.
• Anthony Chiodo MD
• University of Michigan SCI Model System, Ann
  Arbor, MI
• Vancouver, Canada October 2012

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Acknowledgements

• This research was conducted by the University of
  Michigan Spinal Cord Injury Model System and
  supported by a Grant (H133N060032) from the
  National Institute on Disability and
  Rehabilitation Research, Office of Special
  Education and Rehabilitative Services, U.S.
  Department of Education

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Julie Harrison (1975-2005)

• People living deeply have no fear of death
• Anais Nin, 1934
• The lived experience of SCI throw us into the
  spray of this problem. While she feared neither
  death nor its opposite, such deep intensity
  changed the course of living for Julie Harrison.
  
• Epstein Pettway,
  2006

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Why is Depression a Problem? Three Main Points

• Pain and depression are among the most prevalent
  problems documented as secondary conditions
  following SCI (pain 52 depression30)
• There are high costs associated with both
  conditions in terms of medical/rehabilitation
  care and quality of life impact
• Both conditions are amenable to change with
  effective treatment

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SCI Depression Trials

• The PRISMS (Project to Improve Symptoms and Mood
  After SCI) a collaborative multi-site trial just
  concluded in 2012. Findings highlight the need
  for mental health services for those with SCI
  diagnosed with depression.

Archives of Physical Medicine and
Rehabilitation, 2011.
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Purpose of the Study

• To determine factors relating to symptoms of pain
  and depression among a sample of persons with
  SCI. How can we predict it?
• To examine the effectiveness of Venlafaxine XR, a
  serotonin-norepinephrine reuptake inhibitor -
  SNRI antidepressant, on the management of mild to
  moderate depressive symptoms and pain following
  SCI. How can we treat it?

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Research Hypotheses

• There are significant associations between
  depression, anxiety, stress and pain intensity
  and interference
• Those receiving drug treatment will show greater
  improvement in symptoms across the study period
  compared to those receiving placebo
• 2.1 Decrease in depression symptoms as measured
  by the PHQ-9
• 2.2 Decrease in pain severity and interference as
  measured by the SCIPI

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Methods

• Sample
• Recruitment (e.g. outpatient clinics, hospital,
  SCIMS Database, Ann Arbor Center for Independent
  Living)
• Sample size (Screened gt400 persons 34 enrolled
  18 completed it)
• Statistical Design and Analyses
• Group differences were adjusted at baseline
• Pearson Correlation Coefficient
• RCT Design and analyses
• Double blind randomized placebo controlled trial
• Differences in outcomes were assessed by using
  Linear Mixed Models

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Eligibility Criteria

• Traumatic SCI sustained at least one year prior
  to enrollment
• PHQ-9 score of 5 14 (mild to moderate symptom
  severity range)
• Neurological impairment classified ASIA Grades A
  D
• English speaker age 18 or older
• Able to communicate with study personnel
• Completion of informed, written consent that
  includes an agreement to release protected health
  information (PHI) under the rules established by
  HIPPA.

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Exclusion Criteria

• Cognitive deficits precluding the ability to
  provide informed consent and completion of
  survey-based assessments tools
• Psychiatric contraindications (e.g. suicidal
  ideation, history of suicidal attempts, current
  alcohol or drug dependency, diagnosis of bipolar
  disorder)
• Other medical contraindications (e.g. terminal
  illness, unstable medical condition as determined
  by medical history and examination)
• Symptoms of MDD and taking other anti-depressant
• Pregnancy or unwillingness to use birth control
  if female and sexually active
• Prior use of Venlafaxine XR which was
  unsuccessful or led to an allergic response
• Presence of glaucoma
• Engagement in another experimental drug study
  within 30 days
• Expectation of major surgery within the following
  12 weeks

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Intervention

• Double blind randomized placebo controlled trial
  to assess the effectiveness of Venlafaxine XR for
  managing mild to moderate depression and pain
  symptoms
• Duration 26 week trial with intervention ending
  on week 12th
• Assessments 6 Follow-up interviews conducted
  during the active treatment phase and 6 following
  treatment
• Additional contacts for treatment and safety
  monitoring before medication was tapered down
• Subjects presenting symptoms of MDD during trial
  were considered a case, physician was informed
  and they were removed from trial
• The IRBMED and Data Safety Monitoring Board
  (DSMB) were informed of all adverse events

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Typical Dosing and Dispensing Schedule
Drug Trial Event Prescription Number Total Daily Dose Number of Days at Dose Level Cumulative Days in Drug Trial at End of Dose Level
Starting dose 1 37.5 mg 7 7
Titration, 1st step up 2 75.0 mg 7 14
Titration, 2nd step up to full dosage 3 150.0 mg 7 21
Second supply at full dosage 4 150.0 mg 21 42
Third supply at full dosage 5 150.0 mg 28 70
Fourth supply at full dosage 6 150.0 mg 21 91
Taper, 1st step down 7 75.0 mg 14 105
Taper, 2nd and final step down 8 37.5 7 112
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Study Timeline
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Sample Demographics and Measures

• Demographics
• Mean age 50.4 years 77.4 males 87.1
  Caucasians 58.1 married 100 completed
  High School
• Injury Characteristics
• 45.2 incomplete paraplegia 25.8 complete
  paraplegia 22.6 incomplete tetraplegia 6.5
  complete tetraplegia
• Primary Outcome Measures
• Depression Patient Health Questionnaire-9
  (PHQ-9)
• Pain Severity and Interference SCI Pain
  Inventory (SCIPI)
• Secondary Outcome Measures
• Anxiety Generalized Anxiety Disorder-7 (GAD-7)
• Stress Perceived Stress Scale (PSS)

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Consort Flow Chart
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Study findings
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Depression Scores Across Time1(unadjusted Mean
PHQ-9 scores)
Mean PHQ Scores (SD) Mean PHQ Scores (SD) Mean PHQ Scores (SD)
Group Baseline 13 Wks 26 Wks
Treatment 9.0 (5.1) 5.2 (4.7) 5.0 (4.2)
Placebo 10.1 (5.4) 3.0 (4.0) 2.9 (4.2)
PHQ-9 score ranges 0 4 minimal depression 5 9
mild depression 10 14 moderate depression 15
19 moderately severe depression 20 28 severe
depression
1 No differences were observed between groups at
any time point
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Significant Correlations for Depression and Pain
After SCI1
r0.55 plt0.02
r 0.79 plt0.01
r0.73 plt0.01
1 All other correlations were not significant but
trends were observed. N18 _at_ week 13 of
assessment
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Clinical Trial Depression Results

• PHQ-9 scores declined over time (p lt 0.001)
  irrespective of group assignment and controlling
  for baseline PHQ there were no differences
  between groups (p 0.74)
• Possible placebo effect?
• May explain why there were no group differences
  despite the change in depression scores (the
  lines are close together)
• Possible trial participation or Hawthorne
  effect?
• May explain why both groups changed similarly
  over time (lines are parallel and have the same
  pattern)

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Adjusted Depression Scores Across Time Drug vs.
Placebo

N 18 (189 PHQ measurements) with gt 5
assessments Predicted values control for baseline
PHQ score
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Participants Remaining in Trial by Follow Up Week
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Discussion, Study Limitations and Conclusions

• No drug treatment effects noted. Why?
• Dose issue? Dose was relatively low (max. 150mg)
  for treating depression symptoms or pain
• Sample size too small exclusion criteria too
  broad per IRB and RCT design requirements
• Difficulties in recruitment for clinical trial
• Many placebo subjects withdrew suggesting side
  effects (e.g. sexual side effects,
  rash-unrelated, severe constipation, severe
  sleepiness headaches)
• Possible Hawthorne/placebo effects? both groups
  changed
• Findings suggest a positive effect of trial
  participation
• Treatments using behavioral activation maybe an
  very effective way of treating depression
  symptoms as they are based on motivation and
  engagement in the physical and social
  environments (Carver White, 1994 Dimidjian,
  2006).

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People living deeply have no fear of death
In Memory of Julie Harrison (1975-2006)