Effects of Erythropoietin on Cognition and Neural Activity in Mood Disorders
Condition: Bipolar Disorder; Cognitive Impairment; Unipolar Depression
MeSH terms: Bipolar Disorder; Depressive Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      The present trial consists of 2 sub-studies that investigate important novel aspects of
      treatment with erythropoietin (EPO) on cognitive dysfunction in bipolar disorder (BD) and
      recurrent unipolar depressive disorder (UD) (defined as minimum 2 treatment-requiring
      depressive episodes). The aims of the trial are three-fold. We aim to investigate the effects
      of 12 weekly recombinant human EPO infusions on cognition in (i) healthy people with
      cognitive impairment (substudy 1) and (ii) patients with remitted BD or recurrent UD
      (substudy 2), and (iii) explore early treatment-associated neural activity changes that may
      predict subsequent cognitive improvement.

      It is hypothesized that:

      i. 12 weekly EPO infusions improve cognition in healthy first-degree relatives and remitted
      BD patients in comparison with saline.

      ii. EPO vs. saline-treated participants will display early cognition-related neural activity
      in the frontal lobes, which will correlate with cognitive improvement.
    

Detailed description: 
      This trial will include healthy people (sub-study 1) and patients with bipolar disorder or
      recurrent unipolar depressive disorder in partial or full remission (defined as a score of
      ≤14 on the Hamilton Depression Rating Scale 17-items and the Young Mania Rating Scale,
      respectively (sub-study 2) with objectively-verified cognitive dysfunction. Participants will
      be recruited from Psychiatric Centres in The Mental Health Services in the Capital Region of
      Denmark, consultant psychiatrists in the Capital Region of Denmark, as well as through
      advertisements on relevant websites.

      The study design comprises 4 major assessments (baseline, week 3, week 13, and a 6 month
      follow-up after treatment completion) and weekly safety monitoring and study medication
      infusions during a 12 week treatment period. The baseline assessment is divided into 2 days,
      1-3 days apart for practical reasons and to avoid attrition. On the first day of the baseline
      assessment, participants will perform an fMRI scan. On the second baseline day, participants
      complete an assessment comprising neuropsychological testing, verbal IQ assessment, and
      filling in questionnaires concerning subjective cognitive complaints, quality of life, level
      of functioning, and functional capacity, as well as mood symptom severity ratings. Functional
      capacity is assessed using a clinician-rated interview and a performance-based task. After 2
      weeks of treatment (i.e., 2 doses of EPO or saline) an fMRI scan, neuropsychological testing,
      mood ratings, and questionnaires on subjective cognitive difficulties are repeated. After
      treatment completion (week 13) and at the 6 month follow-up, the neuropsychological tests,
      questionnaires concerning subjective cognitive complaints, quality of life, and functional
      capacity (self-reported and performance-based) are repeated. Sleep quantity and quality in
      the past three days is assessed before each of the 4 major assessment time point. Blood
      samples are collected at baseline, week 3 and 13 for assessment of potential blood-based
      biomarkers of pro-cognitive effects.

      Pharma Consulting Group AB (www.pharmaconsultinggroup.com) has conducted block randomization
      for each sub-study group, stratified for gender and age (sub-study 1: < or >=30 years;
      sub-study 2: < or >=35 years). Power calculation was also carried out by Pharma Consulting
      Group based on findings from a previous RCT in our group assessing the effect of 8 weeks of
      EPO treatment on the same cognitive composite score. In this trial, the clinically relevant
      differential change between EPO and saline groups following 12 weeks of treatment is assumed
      to be at least 0.4 SD (corresponding to a moderate effect size) on the primary outcome with
      SD of the change of 0.5. Assuming a 10% drop-out rate, we plan to recruit up to n=58 for each
      sub-study to achieve complete data sets for n=52 participants per sub-study.

      Data from the primary, secondary, and tertiary outcomes will be analyzed using Mixed Models
      Design and Intention to Treat (ITT) analyses. Functional MRI data are pre-processed and
      analyzed with FMRIB Expert Analysis Tool (FEAT) and the 'randomize' algorithm implemented in
      FSL (FMRIB Software Library; www.fmrib.ox.ac.uk/fsl). Functional MRI data is analysed using
      region of interest (ROI) analyses to assess potential differences in neural activity within
      the dorsal prefrontal cortex and the hippocampi between EPO and placebo groups after 2 weeks
      of treatment. Exploratory whole-brain analyses are conducted to assess treatment-related
      activity change in other brain regions. Any differences in neural activity between treatment
      groups are correlated with potential changes in the primary cognitive composite measure after
      2 weeks of treatment (week 3) and after treatment completion (week 13). If this correlation
      is significant, multiple regression analyses will be performed with adjustment for mood
      symptoms, age, and gender to assess the potential predictive value of early neural activity
      change for potential pro-cognitive efficacy after 12 weeks of EPO treatment.
    

Intervention name(s): Erythropoietin; Saline
Intervention type(s): Drug; Drug
Intervention description(s): 40.000 IU/ml Erythropoietin (Epoetin alpha; Eprex) diluted with 100 ml saline (0.9% NaCl) is administered 12 times as intravenous infusions over 15 minutes.; 1 ml NaCl is administered 4 times as intravenous infusions over 15 minutes
Other intervention name(s): Eprex; EPO; Placebo
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: bipolar disorder; cognition; cognitive dysfunction; erythropoietin; pro-cognitive efficacy; prefrontal cortex; functional magnetic resonance imaging; biomarker; unipolar disorder