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Background: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. Aim: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. Methods: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. Results: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. Conclusions: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. Trial registrations: EudraCT no.: 2016–004023-24; ClinicalTrials.gov identifier: NCT03315897. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement.Methods: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library.Discussion: If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment.Trial Registration: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro‐cognitive interventions is the limited insight into the brain correlates of cognitive impairments in these patients. This is the first study investigating the resting‐state neural underpinnings of cognitive impairments in different neurocognitive subgroups of patients with BD. Method: Patients with BD in full or partial remission and healthy controls (final sample of n = 144 and n = 50, respectively) underwent neuropsychological assessment and resting‐state functional magnetic resonance imaging. We classified the patients into cognitively impaired (n = 83) and cognitively normal (n = 61) subgroups using hierarchical cluster analysis of the four cognitive domains. We used independent component analysis (ICA) to investigate the differences between the neurocognitive subgroups and healthy controls in resting‐state functional connectivity (rsFC) in the default mode network (DMN), executive central network (ECN), and frontoparietal network (FPN). Results: Cognitively impaired patients displayed greater positive rsFC within the DMN and less negative rsFC within the ECN than healthy controls. Across cognitively impaired patients, lower positive connectivity within DMN and lower negative rsFC within ECN correlated with worse global cognitive performance. Conclusion: Cognitive impairments in BD seem to be associated with a hyper‐connectivity within the DMN, which may explain the failure to suppress task‐irrelevant DMN activity during the cognitive performance, and blunted anticorrelation in the ECN. Thus, aberrant connectivity within the DMN and ECN may serve as brain targets for pro‐cognitive interventions. [ABSTRACT FROM AUTHOR]

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) 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.Methods/design: The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library.Discussion: If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT.Trial Registration: ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) and major depressive disorder (MDD) are associated with cognitive and functional impairment. Cognitive impairment is often associated with dorsal prefrontal cortex (dPFC) hypo-activity, but the neuronal correlates of functional disability is largely unknown. In this study, 91 patients with affective disorders in full or partial remission (BD, n = 67; MDD, n = 24) with objectively verified cognitive impairment and substantial functional disability underwent neuropsychological assessment and functional magnetic resonance imaging (fMRI) scan during which they completed a strategic picture-encoding task. For comparison, 36 matched healthy controls underwent an identical test protocol. Patients showed encoding-related hypo -activity in the dPFC compared to controls. In patients, lower right dlPFC activity was associated with poorer overall functioning and more antipsychotic drug use. In conclusion, memory impairments were underpinned by failure to recruit the dPFC during task performance which was associated with impaired functioning in fully or partially remitted patients with affective disorders. This aberrant neurocircuitry activity has implications for the design of future pro-cognitive interventions that aim to improve not only cognition but also real-world functioning. • Cognitively impaired patients had lower memory-related dorsal prefrontal response. • Lower dorsal prefrontal activity correlated with poorer daily functioning. • Dorsal prefrontal engagement may reflect ability to recruit executive skills. • Interventions that target dorsal prefrontal hypo-activity may improve functioning. [ABSTRACT FROM AUTHOR]