Search

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]

Cognitive impairment affects many patients with bipolar disorder (BD). No pro-cognitive treatment with robust efficacy exists partly due to limited insight into underlying neurobiological abnormalities. This magnetic resonance imaging (MRI) study investigates structural neuronal correlates of cognitive impairment in BD by comparing brain measures in a large sample of cognitively impaired versus cognitively intact patients with BD or cognitively impaired patients with major depressive disorder (MDD) and healthy controls (HC). Participants underwent neuropsychological assessments and MRI scans. The cognitively impaired and – intact BD and MDD patient groups were compared with each other and HC regarding prefrontal cortex measures, hippocampus shape/volume, and total cerebral white (WM) and grey matter (GM). Cognitively impaired BD patients showed lower total cerebral WM volume than HC, which scaled with poorer global cognitive performance and more childhood trauma. Cognitively impaired BD patients also showed lower adjusted GM volume and thickness in the frontopolar cortex than HC but greater adjusted GM volume in the temporal cortex than cognitively normal BD patients. Cognitively impaired BD patients showed decreased cingulate volume than cognitively impaired MDD patients. Hippocampal measures were similar across all groups. The cross-sectional study design prevented insights into causal relationships. Lower total cerebral WM and regional frontopolar and temporal GM abnormalities may constitute structural neuronal correlates of cognitive impairment in BD, of which the WM deficits scale with the degree of childhood trauma. The results deepen the understanding of cognitive impairment in BD and provide a neuronal target for pro-cognitive treatment development. • Limited insight into neurobiological abnormalities underlying cognitive impairment in bipolar disorder • Participants underwent neuropsychological assessment and magnetic resonance imaging. • Cognitively impaired patients with bipolar disorder show lower cerebral white matter. • Cognitively impaired bipolar disorder patients also show grey matter abnormalities. • Total volume of cerebral white matter correlated with cognitive performance. • Cerebral white matter reduction scaled with higher levels of childhood trauma. [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]