Clinical trial NCT00916552: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mood Disorders
Keywords: Erythropoietin
Epo
depression
bipolar disorder
cognition
cognitive function
antidepressant
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: The Ministry of Science, Technology and Innovation, Denmark
name: Novo Nordisk A/S
name: University of Oxford
name: Max-Planck-Institute of Experimental Medicine
First posted: 2009-06-09
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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.
timeFrame: a) Baseline and weeks 5, 9 and 14; b) Baseline and weeks 9 and 14
Secondary outcomes:
measure: 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.
timeFrame: a) Baseline and weeks 5, 9 and 14; b) Baseline and weeks 9 and 14
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Lars V Kessing, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.