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Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Depression and Bipolar Disorder

Primary Purpose

Mood Disorders

Status
Completed
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Erythropoietin
Sponsored by
Lars Vedel Kessing, professor, MD, DMSc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mood Disorders focused on measuring Erythropoietin, Epo, depression, bipolar disorder, cognition, cognitive function, antidepressant

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Treatment-resistant depression (defined as failure to respond to at least 2 different types of antidepressants) and an HDRS score of at least 17

OR

  • Bipolar disorder in remission (HDRS score of max 14 and Young Mania Scale score of max 14) and subjective complaints of moderate to severe cognitive problems on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) (Fava et al 2006) (score at least 4 on at least 2 domains)
  • Unchanged antidepressant or mood stabilizing treatment for at least 2 weeks prior to and during the study

Exclusion Criteria:

  • Schizophrenia/ schizoaffective disorder
  • Dependence on or abuse of drugs (including alcohol and benzodiazepines corresponding to more than 22.5 mg Oxazepam daily)
  • Diabetes
  • Renal failure
  • Smoking
  • Major surgery within 4 weeks prior to inclusion
  • Previous Epo-treatment
  • Known allergy or antibodies against Epo
  • Present or past malignancies
  • Epilepsy or epilepsy in first degree family Diagnosis (past or present) of a cardiovascular or cerebrovascular disease
  • Untreated or not sufficiently treated arterial hypertension ("therapy-resistant hypertension")
  • Initial hematocrit > 50% (males) or > 48% (females)
  • Initial platelet count above normal range of laboratory
  • Initial reticulocyte count below norma range of laboratory
  • Past thromboembolic events or thromboembolic events in first degree family (increased thromboembolic risk)
  • Contraindications against prophylactic thrombosis treatment
  • Myeloproliferative disorder, polycythemia
  • Present immunosuppressive treatment with cyclosporin
  • Overweight (BMI > 30) or body weight of less than 45 kg or over 95 kg
  • Acute suicidal risk, present or previous suicide attempts in the past 2 years
  • Pregnancy or breast feeding
  • Women who presently use contraceptive pills
  • Sexually active women with child bearing potential who refuse to use double barrier anticonception methods
  • Unwillingness or inability to comply with the requirements of the protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the protocol
  • Present illness which in investigator's opinion could affect the patient's participation in the study

Sites / Locations

  • Copenhagen University Hospital, Rigshospitalet

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Erythropoeitin

Arm Description

40.000 IU, epoetin alfa; Janssen-Cilag

Outcomes

Primary Outcome Measures

a) For treatment-resistant depressed patients: Antidepressant effect measured with the Hamilton Depression Rating Scale (HDRS); b) For bipolar patients in remission: Memory measured with the Rey Auditory Verbal Memory Test.

Secondary Outcome Measures

a) For treatment-resistant depressed patients: number of remissions measured with the HDRS; b) For bipolar patients in remission: sustained attention measured with the RVIP and facial expression recognition.

Full Information

First Posted
June 8, 2009
Last Updated
November 8, 2012
Sponsor
Lars Vedel Kessing, professor, MD, DMSc.
Collaborators
The Ministry of Science, Technology and Innovation, Denmark, Novo Nordisk A/S, University of Oxford, Max-Planck-Institute of Experimental Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT00916552
Brief Title
Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Depression and Bipolar Disorder
Official Title
The Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Patients With Treatment Resistant Depression and in Patients With Remitted Bipolar Disorder - a Proof of Concept Study
Study Type
Interventional

2. Study Status

Record Verification Date
November 2012
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
October 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lars Vedel Kessing, professor, MD, DMSc.
Collaborators
The Ministry of Science, Technology and Innovation, Denmark, Novo Nordisk A/S, University of Oxford, Max-Planck-Institute of Experimental Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Depression and bipolar disorder (mania and depression) may be related to problems with nerve cells not being regenerated as fast as normal and are accompanied by cognitive difficulties including memory, attention and planning problems. There is thus a need for better, more efficient treatments with effects on cognitive function. Erythropoietin (Epo) is involved in brain repair and may be a candidate for future treatment strategies. The investigators have demonstrated that a single dose of Epo improves mood and reduces the processing of negative emotional information in healthy volunteers similar to effects seen with antidepressants. With the current study the investigators aim to build upon this discovery by investigating whether repeated Epo administration has antidepressant effects and is able to reverse cognitive difficulties in patients with depression or bipolar disorder. It is hypothesized that Epo will improve mood in treatment-resistant depression and improve cognitive function in this group and in patients with bipolar disorder in remission. If the study reveals beneficial effects of Epo, this would highlight Epo as a candidate compound for future treatment of depression and bipolar disorder, with the potential to directly promote brain repair mechanisms.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mood Disorders
Keywords
Erythropoietin, Epo, depression, bipolar disorder, cognition, cognitive function, antidepressant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
83 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Erythropoeitin
Arm Type
Experimental
Arm Description
40.000 IU, epoetin alfa; Janssen-Cilag
Intervention Type
Drug
Intervention Name(s)
Erythropoietin
Other Intervention Name(s)
Eprex, Epo
Intervention Description
40.000 IU/ml epoetin alfa is administered as intravenous infusions over 15 min weekly for 8 weeks.
Primary Outcome Measure Information:
Title
a) For treatment-resistant depressed patients: Antidepressant effect measured with the Hamilton Depression Rating Scale (HDRS); b) For bipolar patients in remission: Memory measured with the Rey Auditory Verbal Memory Test.
Time Frame
a) Baseline and weeks 5, 9 and 14; b) Baseline and weeks 9 and 14
Secondary Outcome Measure Information:
Title
a) For treatment-resistant depressed patients: number of remissions measured with the HDRS; b) For bipolar patients in remission: sustained attention measured with the RVIP and facial expression recognition.
Time Frame
a) Baseline and weeks 5, 9 and 14; b) Baseline and weeks 9 and 14

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Treatment-resistant depression (defined as failure to respond to at least 2 different types of antidepressants) and an HDRS score of at least 17 OR Bipolar disorder in remission (HDRS score of max 14 and Young Mania Scale score of max 14) and subjective complaints of moderate to severe cognitive problems on the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) (Fava et al 2006) (score at least 4 on at least 2 domains) Unchanged antidepressant or mood stabilizing treatment for at least 2 weeks prior to and during the study Exclusion Criteria: Schizophrenia/ schizoaffective disorder Dependence on or abuse of drugs (including alcohol and benzodiazepines corresponding to more than 22.5 mg Oxazepam daily) Diabetes Renal failure Smoking Major surgery within 4 weeks prior to inclusion Previous Epo-treatment Known allergy or antibodies against Epo Present or past malignancies Epilepsy or epilepsy in first degree family Diagnosis (past or present) of a cardiovascular or cerebrovascular disease Untreated or not sufficiently treated arterial hypertension ("therapy-resistant hypertension") Initial hematocrit > 50% (males) or > 48% (females) Initial platelet count above normal range of laboratory Initial reticulocyte count below norma range of laboratory Past thromboembolic events or thromboembolic events in first degree family (increased thromboembolic risk) Contraindications against prophylactic thrombosis treatment Myeloproliferative disorder, polycythemia Present immunosuppressive treatment with cyclosporin Overweight (BMI > 30) or body weight of less than 45 kg or over 95 kg Acute suicidal risk, present or previous suicide attempts in the past 2 years Pregnancy or breast feeding Women who presently use contraceptive pills Sexually active women with child bearing potential who refuse to use double barrier anticonception methods Unwillingness or inability to comply with the requirements of the protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the protocol Present illness which in investigator's opinion could affect the patient's participation in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lars V Kessing, Professor
Organizational Affiliation
Rigshospitalet, Denmark
Official's Role
Principal Investigator
Facility Information:
Facility Name
Copenhagen University Hospital, Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2200
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
31804779
Citation
Miskowiak KW, Forman JL, Vinberg M, Siebner HR, Kessing LV, Macoveanu J. Impact of pretreatment interhemispheric hippocampal asymmetry on improvement in verbal learning following erythropoietin treatment in mood disorders: a randomized controlled trial. J Psychiatry Neurosci. 2020 May 1;45(3):198-205. doi: 10.1503/jpn.180205.
Results Reference
derived
PubMed Identifier
27835716
Citation
Miskowiak KW, Rush AJ Jr, Gerds TA, Vinberg M, Kessing LV. Targeting Treatments to Improve Cognitive Function in Mood Disorder: Suggestions From Trials Using Erythropoietin. J Clin Psychiatry. 2016 Dec;77(12):e1639-e1646. doi: 10.4088/JCP.15m10480.
Results Reference
derived
PubMed Identifier
27259062
Citation
Miskowiak KW, Macoveanu J, Vinberg M, Assentoft E, Randers L, Harmer CJ, Ehrenreich H, Paulson OB, Knudsen GM, Siebner HR, Kessing LV. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders. Acta Psychiatr Scand. 2016 Sep;134(3):249-59. doi: 10.1111/acps.12597. Epub 2016 Jun 3.
Results Reference
derived
PubMed Identifier
26996196
Citation
Miskowiak KW, Vinberg M, Glerup L, Paulson OB, Knudsen GM, Ehrenreich H, Harmer CJ, Kessing LV, Siebner HR, Macoveanu J. Neural correlates of improved executive function following erythropoietin treatment in mood disorders. Psychol Med. 2016 Jun;46(8):1679-91. doi: 10.1017/S0033291716000209. Epub 2016 Mar 21.
Results Reference
derived
PubMed Identifier
26011424
Citation
Vinberg M, Miskowiak K, Hoejman P, Pedersen M, Kessing LV. The effect of recombinant erythropoietin on plasma brain derived neurotrophic factor levels in patients with affective disorders: a randomised controlled study. PLoS One. 2015 May 26;10(5):e0127629. doi: 10.1371/journal.pone.0127629. eCollection 2015.
Results Reference
derived
PubMed Identifier
25641635
Citation
Miskowiak KW, Vinberg M, Macoveanu J, Ehrenreich H, Koster N, Inkster B, Paulson OB, Kessing LV, Skimminge A, Siebner HR. Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders. Biol Psychiatry. 2015 Aug 15;78(4):270-7. doi: 10.1016/j.biopsych.2014.12.013. Epub 2014 Dec 18.
Results Reference
derived
PubMed Identifier
25099079
Citation
Miskowiak KW, Ehrenreich H, Christensen EM, Kessing LV, Vinberg M. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry. 2014 Dec;75(12):1347-55. doi: 10.4088/JCP.13m08839.
Results Reference
derived
PubMed Identifier
20942940
Citation
Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, Kessing LV. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials. 2010 Oct 13;11:97. doi: 10.1186/1745-6215-11-97.
Results Reference
derived

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Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Depression and Bipolar Disorder

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