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  • Moisala, Mona; Salmela, Viljami; Salo, Emma; Carlson, Synnove; Vuontela, Virve; Salonen, Oili; Alho, Kimmo (2015)
  • Rantamäki, Tomi; Kohtala, Samuel (2020)
    Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. Significance Statement-Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as N-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.
  • Urrila, Anna S.; Hakkarainen, Antti; Castaneda, Anu; Paunio, Tiina; Marttunen, Mauri; Lundbom, Nina (2017)
    Aim: This study used proton magnetic resonance spectroscopy (H-1 MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. Methods: Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent H-1 MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. Results: Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. Conclusion: Lower frontal cortex ml may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression. (C) 2017 S. Karger AG, Basel
  • Kraus, Christoph; Castrén, Eero; Kasper, Siegfried; Lanzenberger, Rupert (2017)
    Serotonin modulates neuroplasticity, especially during early life, and dysfunctions in both systems likewise contribute to pathophysiology of depression. Recent findings demonstrate that serotonin reuptake inhibitors trigger reactivation of juvenile-like neuroplasticity. How these findings translate to clinical antidepressant treatment in major depressive disorder remains unclear. With this review, we link preclinical with clinical work on serotonin and neuroplasticity to bring two pathophysiologic models in clinical depression closer together. Dysfunctional developmental plasticity impacts on later-life cognitive and emotional functions, changes of synaptic serotonin levels and receptor levels are coupled with altered synaptic plasticity and neurogenesis. Structural magnetic resonance imaging in patients reveals disease-state-specific reductions of gray matter, a marker of neuroplasticity, and reversibility upon selective serotonin reuptake inhibitor treatment. Translational evidence from magnetic resonance imaging in animals support that reduced densities and sizes of neurons and reduced hippocampal volumes in depressive patients could be attributable to changes of serotonergic neuroplasticity. Since ketamine, physical exercise or learning enhance neuroplasticity, combinatory paradigms with selective serotonin reuptake inhibitors could enhance clinical treatment of depression. (C) 2017 Elsevier Ltd. All rights reserved.