Effects of Erythropoietin for Cognitive Side-effects of ECT
Condition: ECT; Cognitive Impairment; Unipolar Depression; Bipolar Depression
MeSH terms: Depression; Depressive Disorder; Bipolar Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      EPO-T aims to investigate (i) whether short-term add-on treatment with erythropoietin (EPO)
      can reduce cognitive side-effects of ECT and (ii) whether such effects are long-lasting.
      Further, structural and functional magnetic resonance imaging (MRI) will be used to explore
      the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines
      whether potential protective effects of EPO on cognition are accompanied by changes in
      markers of oxidative stress, inflammation, and neuroplasticity.

      It is hypothesized that EPO treatment will (i) counteract ECT-induced cognitive decline,
      accompanied by (ii) increased sub-regional hippocampal volume, (iii) greater memory-related
      hippocampal activation and reinforcement of dorsolateral prefrontal activity during memory
      encoding and working memory, and (iv) changes in peripheral markers of inflammation,
      oxidative stress and neuroplasticity. Furthermore, we hypothesize that add-on EPO-treatment
      will produce greater, more sustained mood improvement than ECT treatment alone.
    

Detailed description: 
      The trial will include patients with a diagnosis of major depression (MDD) unipolar disorder
      (UD) or bipolar disorder (BD) with a current moderate to severe depressive episode symptoms
      (a score of >17 on the Hamilton Depression Rating Scale 17-items (HRDS-17) scheduled for ECT
      treatment. Patients will be recruited from Psychiatric Centres in The Mental Health Services
      in the Capital Region of Denmark and will undergo an eligibility assessment prior to
      randomization to 4 intravenous infusions of either recombinant human EPO (40.000 IU/ml;
      Epoetin alpha; Eprex, Janssen-Cilag) or placebo (1 ml NaCl) diluted with 100 ml saline (0.9%
      NaCl).

      Cognitive functions, mood symptoms, and blood- and urine markers of inflammation, oxidative
      stress, and neuroplasticity will be assessed 3 times during the trial. First time at
      baseline, second time 3 days after ECT session 8 (patients skip one ECT session day after 8
      ECTs to minimise the confounding effects of acute side-effects of ECT due to anaesthesia
      etc.), and the third time at a 3 month follow-up after ECT completion. In addition, the
      neuronal substrates for potential effects of EPO on cognition are investigated with
      structural and functional MRI after 8 ECT sessions (after 3 weekly EPO or saline infusions).

      Block randomization and power calculations have been conducted by the independent Pharma
      Consulting Group AB (www.pharmaconsultinggroup.com). Treatment groups are stratified for age
      (>40 or <40) and gender.

      The difference in cognitive change between EPO and saline-treated groups from baseline to
      post-treatment in our previous trial was 0.5 SD. Based on these findings, the sample size of
      N=52 (n=26 per group) in the current trial will reach a >0.8 power to detect a clinically
      relevant difference in the primary outcome measure (the cognitive composite score) between
      the 2 groups at an alpha level of 5% (two-sided test). The study is also powered to
      investigate differences in functional magnetic resonance imaging (fMRI) blood-oxygen
      dependent level (BOLD) response in key neural networks based on previous fMRI studies from
      our group in which sample sizes of 30 age and gender matched participants (n=15 per group)
      had the power of >0.8 to show drug-related effects on task-related neural response at an
      alpha level of p<0.05. In the current trial, inclusion of 52 participants (n=26 per treatment
      group) therefore ensures sufficient statistical power to detect EPO-related effects on neural
      activity.

      Behavioural, mood, and biomarker data will be analysed using Mixed Models Design and
      Intention to Treat (ITT) approaches. Resting state and task-related fMRI data will be
      pre-processed and analyzed using FMRIB Expert Analysis Tool (FEAT) and the 'randomize'
      algorithm integrated in FSL, FMRIB Software Library (www.fmrib.ox.ac.uk/fsl).
    

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 4 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: electroconvulsive therapy; depression; cognition; cognitive side-effects; erythropoietin; functional magnetic resonance imaging