Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial

Miskowiak KW, Ehrenreich H, Christensen EM, Kessing LV, Vinberg M

J Clin Psychiatry. 2014 Dec;75(12):1347-55.


OBJECTIVE: Available drug treatments for bipolar disorder fail to reverse patients’ cognitive deficits. Erythropoietin has neurotrophic actions and aids neurocognitive function. The aim of the study was to investigate the potential of erythropoietin to treat cognitive dysfunction in bipolar disorder.

METHOD: Patients with an ICD-10 diagnosis of bipolar disorder in remission were randomized, with stratification by age and gender, to receive 8 weekly erythropoietin (40,000 IU) or saline (sodium chloride [NaCl], 0.9%) infusions in a double-blind, parallel-group design. The first patient was randomized in September 2009 and last assessment was completed in October 2012. Patients were assessed at baseline and at weeks 9 and 14. The primary outcome was change in verbal memory indexed by the total words recalled across Rey Auditory Verbal Learning Test learning trials (I-V) from baseline to week 9; secondary outcomes were sustained attention and facial expression recognition; and tertiary outcomes were attention, executive function, subjective cognitive function, and mood. Analysis was by intention to treat, using repeated-measures analysis of covariance adjusted for stratification variables and mood. The statistical threshold for which results were considered significant was P ≤ .05 (2-tailed).

RESULTS: 44 patients were randomized; given 1 dropout after baseline, results were analyzed for 43 patients (erythropoietin: n = 23; saline: n = 20). There was no significant improvement of verbal memory in erythropoietin versus saline groups (P = .10). However, erythropoietin enhanced sustained attention (P = .001), recognition of happy faces (P = .03), and speed of complex information processing across learning, attention, and executive function (P = .01). These effects occurred in absence of changes in simple reaction times or mood (P values ≥ .16) and were maintained after red blood cell normalization.

CONCLUSIONS: This is the first trial investigating erythropoietin to treat cognitive dysfunction in bipolar disorder. The findings highlight erythropoietin as a candidate treatment for deficits in attention and executive function in bipolar disorder.

TRIAL REGISTRATION: identifier: NCT00916552.

Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial

Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, Kessing LV

Neuropsychopharmacology. 2014 May;39(6):1399-408.


Pharmacological treatments for depression have insufficient efficacy in 30-40% of patients and fail to reverse cognitive deficits. Erythropoietin (EPO) has neurotrophic actions and aids neurocognitive function. The aim of this exploratory study was to determine whether recombinant human EPO improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ≥ 17 were randomized to eight weekly EPO (Eprex; 40,000 IU) or saline infusions in a double-blind, placebo-controlled, parallel-group design. Patients were assessed at baseline and at weeks 5, 9, and 14. Primary outcome was reduction in HDRS-17 score. Global assessment of function (GAF) was reported in addition. Secondary outcome was remission rate, and tertiary outcomes were changes in Rey Auditory Verbal Learning Test (RAVLT), Beck Depression Inventory-21 (BDI-21), and World Health Organization Quality of life-BREF (WHOQOL-BREF). Exploratory outcomes were depression and cognition composite scores. HDRS-17, GAF, and remission rates showed no effects of EPO over saline at week 9 (P-value ≥ 0.09). However, EPO improved BDI (P=0.02) and WHOQOL-BREF (P=0.01), and this was maintained at follow-up week 14 (P-values ≤ 0.04). EPO enhanced verbal recall (P=0.02) and recognition (P=0.03), which was sustained at follow-up (P-values ≤ 0.04). Exploratory analysis in patients fulfilling depression severity criteria at trial start revealed ameliorated HDRS-17 in EPO (N=14) vs saline groups (N=17), which was sustained at week 14 (P-values ≤ 0.05). Exploratory analysis in the complete cohort showed that EPO reduced depression composite at weeks 9 and 14 (P-values=0.02). The findings of this exploratory study highlight EPO as an interesting compound for treatment-resistant depression, which deserves further investigation.

Is there a difference in subjective experience of cognitive function in patients with unipolar disorder versus bipolar disorder?

Miskowiak K, Vinberg M, Christensen EM, Kessing LV

Nord J Psychiatry. 2012 Dec;66(6):389-95.


BACKGROUND: Cognitive dysfunction in unipolar disorder (UD) and bipolar disorder (BD) may persist into remission and affect psychosocial function. Executive and memory deficits during remission may be more pronounced in BD than UD. However, patients’ subjective experience of cognitive difficulties is poorly understood, and it is unclear whether BD and UD patients experience different cognitive difficulties.

AIMS: To investigate whether there are differences in the quality and magnitude of subjective cognitive difficulties between UD and BD, and which factors influence the subjective cognitive difficulties in these patients.

METHODS: Patients with BD (n = 54) or UD (n = 45) were referred to the outpatient mood disorder clinic at Department of Psychiatry, Copenhagen University Hospital, following hospital discharge. Affective symptoms and patients’ experience of cognitive symptoms were assessed at their initial consultation at the clinic.

RESULTS: Patients experienced mild to moderate cognitive impairment despite being in partial or full remission, but there were no differences in subjective difficulties between BD and UD. Subjective cognitive dysfunction was predicted by depression severity, anxiety and mania symptoms rather than by diagnosis, age, gender or alcohol misuse.

CONCLUSION: The absence of difference in subjective cognitive difficulties between UD and BD contrasts with evidence of greater objective dysfunction in BD. This highlights a potential discord between subjective and objective measures of cognitive function. Subjective cognitive function was predicted by affective symptoms, perhaps suggesting that this reflects mood symptoms rather than objective deficits. This points to a clinical need for objective assessment of cognitive function in these patient groups.