Elsevier

Biological Psychiatry

Volume 78, Issue 4, 15 August 2015, Pages 270-277
Biological Psychiatry

Archival Report
Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders

https://doi.org/10.1016/j.biopsych.2014.12.013Get rights and content

Abstract

Background

Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients’ functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects.

Methods

Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender.

Results

Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change.

Conclusions

EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition.

Section snippets

Study Design and Participants

This article is based on a previously reported double-blind, placebo-controlled, parallel-group study (23, 24). In brief, patients, 18 to 65 years of age, were recruited through the Clinic for Affective Disorders, Psychiatric Centre Copenhagen, and by advertisement on relevant websites and screened with Schedules for Clinical Assessment in Neuropsychiatry to confirm ICD-10 diagnosis. Eligible patients had a diagnosis of major depression and fulfilled the criteria for TRD based on assessment of

Patient Flow and Characteristics

Table 1 and the CONSORT chart in Supplement 1 display patient flow and characteristics, respectively. Of the 84 patients that were randomized to EPO (n = 42) or saline (n = 42), 1 patient withdrew at baseline and data collection was incomplete for 14 patients (for details, see the CONSORT chart in Supplement 1). Six EPO-treated patients (3 TRD, 3 BD) were discontinued from their infusions between weeks 5 and 7 due to increased thrombocyte counts (>4 × 109/L) but continued all assessments.

Discussion

This study is the first to prospectively elucidate the neuroanatomical underpinnings of the cognitive improvement observed in EPO-treated patients with BD or TRD. The study demonstrated that EPO treatment is associated with prevention of brain matter loss in a subfield of the left hippocampus encompassing the CA1-3 region and subiculum and improves verbal memory independent of changes in mood. Across the whole cohort, verbal memory improvement was mediated by structural increase in this left

Acknowledgments And Disclosures

The study was funded by the Danish Ministry of Science, Innovation and Higher Education, Novo Nordisk Foundation, Beckett Fonden, and Savværksejer Juhl’s Mindefond. The sponsors had no role in the planning or conduct of the study or in the interpretation of the results.

We thank A. John Rush, M.D., Professor Emeritus, National University of Singapore, and Martin B. Jørgensen, M.D., DMsc, Professor, for their valuable feedback on the manuscript; David Cole, Ph.D., for statistical advice regarding

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