Evidence for Impaired Neocortical Synaptic Plasticity in Bipolar II Disorder

Elvsåshagen, Torbjørn; Moberget, Torgeir; Bøen, Erlend; Boye, Birgitte; Englin, Nils Olof Andreas; Pedersen, Per Øystein Heiberg; Andreassen, Ole A.; Dietrichs, Espen; Malt, Ulrik Fredrik; Andersson, Stein

doi:10.1016/j.biopsych.2011.09.026

Cited by 45 publications

(67 citation statements)

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“…Following tetanus, a significant increase in the magnitude of the N1 and N1b components of VEPs were seen in control subjects, in line with previous published data demonstrating this phenomenon. 69,[133][134][135][136] However, no significant enhancement was seen in depressed patients in line with a previous report in non-treatment-refractory depressed patients, 137 patients with bipolar disorder 138 and patients with schizophrenia. 139 This suggests that impaired visual cortical plasticity is a phenomenon shared across a range of psychiatric disorders.…”

Section: Discussionsupporting

confidence: 79%

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

et al. 2015

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BackgroundDepressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. TheAntiglucocorticoid augmentation of antiDepressants inDepression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.ObjectiveTo determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.MethodsA total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.ResultsThe estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.DiscussionThe inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.ConclusionsThe results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.Trial registrationCurrent Controlled Trials ISRCTN45338259.Funding detailsThis study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

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Section: Discussionsupporting

confidence: 79%

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

et al. 2015

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“…It persists into adulthood, is frequently NMDAR dependent, and has been observed at subcortical and sensory cortex synapses (1-6). Although classical LTP studies used high-frequency electrical stimulation to induce LTP, HFvS also induces lasting potentiation of neural responses (8)(9)(10)(11)(12)(13)(14), and potentiated neural responses following HFvS show cardinal features of synaptic LTP (7,8). In the current study, participants who received DCS showed greater potentiation of the VEP following HFvS compared with participants who received placebo.…”

Section: Discussionmentioning

confidence: 52%

“…C1 is the first major visual event-related potential component and is generated by neurons in primary visual cortex (40). Although one study using a similar LTP paradigm in humans found that C1 was potentiated up to 22 min following HFvS (13), additional studies found no change or a trend toward reduced C1 amplitude up to 28 min following HFvS (11,12). Given that VEPs measured by EEG capture the electrical discharge of populations of neurons, this variable direction of C1 plasticity may reflect interactive effects of homosynaptic LTP and heterosynaptic LTD across visual cortex synapses, where homosynaptic synapses are those synapses that are directly activated by electrical stimulation and heterosynaptic synapses are nearby synapses that are not directly activated by stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Forsyth

Bachman

Mathalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-D-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using D-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activitydependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.D-cycloserine | NMDA receptor | neuroplasticity | long-term potentiation | learning E xperience-dependent neuroplasticity is the capacity of the brain to change in response to environmental input, learning, and use. It is a fundamental property of the brain and is critical for everyday functioning. It allows us to learn and remember patterns, predict and obtain reward, and refine and accelerate response selection for adaptive behavior (1). During development, experience-dependent plasticity interacts with genetic programming to organize neurons into the structurally and functionally connected circuits that characterize a mature brain. Although this basic circuitry is established by early adulthood, experience-dependent plasticity continues to shape connectivity within these circuits such that important inputs and action outputs are represented by larger and more coordinated populations of neurons. Given that these changes are the primary means through which the adult brain enables new behavior and that such plasticity is impaired in a range of neurological and psychiatric disorders (2), identifying manipulations that can harness experiencedependent plasticity offers exciting possibilities. Here, we tested whether augmenting N-methyl-D-aspartate receptor (NMDAR) activity could enhance experience-dependent plasticity in the adult human brain.The ...

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“…However, other attempts to measure human brain plasticity in the course of MDD have demonstrated functional alterations such as those observed at LTP level. For example, visual-evoked potential amplitudes in the visual pathway were, compared to matched control subjects, decreased in patients with depression (Normann et al 2007; Bubl et al 2015) and also in bipolar disorder patients (Elvsashagen et al 2012). …”

Section: Neuroplasticity Changes In Mdd and The Effects Of Antidepresmentioning

confidence: 99%

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

et al. 2018

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Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory.

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Evidence for Impaired Neocortical Synaptic Plasticity in Bipolar II Disorder

Cited by 45 publications

References 45 publications

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

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