Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine.

Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 06/2010; 35(7):1415-22. DOI: 10.1038/npp.2010.24
Source: PubMed

ABSTRACT Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl-D-aspartate receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally arousing tasks. This study tested the hypothesis that during the N-back task, a widely used working memory paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement after ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance 1 to 3 days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r=-0.73, p=0.0021, FDR <0.05).These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Ketamine has been available for approximately 50 years as an anesthetic agent. It is known to have potent effects on the central nervous system glutamatergic system, in particular blockade of n-methyl-d-aspartate (NMDA) receptors. Based upon pre-clinical evidence of involvement of the glutamatergic system in mood disorders, studies have been undertaken to test the antidepressant properties of ketamine. Several well-controlled studies, along with open-label case series, have established that ketamine can have rapid antidepressant effects. Additionally, data exist showing benefits of ketamine in post-traumatic stress disorder as well as obsessive compulsive disorder. However, improvements in these conditions tends to be short-lived with single infusions of ketamine. Of concern, ketamine has been associated with neurotoxicity in pre-clinical rodent models and is well-known to cause psychotomimetic effects and addiction in humans. While ketamine has proven safe for use in sub-anesthetic doses administered once or a few times, the safety profile of prolonged use has not been established. Aspects of safety, possible mechanisms of action, and future directions of ketamine research are discussed in addition to the clinical literature on its use in psychiatric conditions.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; DOI:10.1016/j.pnpbp.2015.01.002 · 4.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This literature review begins with a rationale for the development of new therapeutic approaches for the treatment of depressive disorder. In the following sections the history of the finding of ketamine‘s antidepressant effect, its pharmacological properties and application routes are summarized. The following is an overview of the existing scientific evidence of ketamine’s efficacy in patients with unipolar and bipolar depression, suicidality and the adjuvant use in electroconvulsive therapy. Finally, the author discusses acute and chronic side effects, safety of repeated administration of ketamine and possibilities of extending the antidepressant effect. The last section summarizes recent findings on the mechanism of the antidepressant effect of ketamine on the molecular level and its effect on neuronal plasticity.
    Psychiatrie 01/2014; 18(4):193-205.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of depression has been shown to be increased with the presence of chronic inflammatory and/or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, type II diabetes mellitus and cardiovascular diseases. It has been well documented in the last decade that inflammation in the periphery could interact within the central nervous system. Once an inflammatory stimulus reaches the brain, microglial cells serve as fundamental sensory complements by playing an important role in neuroinflammation which is a necessary process required for brain development. However, the process itself, if excessive or prolonged, can turn into a pathological condition and become a causative factor of the disease, for example, in the case of chronic stress or depression. The association between high plasma levels of pro-inflammatory cytokines and depression has been shown by several clinical and experimental studies. In addition, current antidepressant therapies reduce high cytokine levels of depressive patients and antidepressant-like effects are observed with the use of immunosuppressant drugs acting on cytokine-mediated mechanisms. On the other hand, inflammatory cytokines are known to mediate the activity of the hypothalamic-pituitary axis (HPA) which is well known to be elevated in depression and stress, resulting in a further contribution to the inflammatory state. At present, approximately of patients with depression do not respond to current antidepressant therapies. Thus, great efforts have been made in many studies to provide novel therapeutic approaches for depression. At this point, targeting initiator molecular mechanisms of cytokine-mediated inflammatory responses has become an intriguing approach for preventing the process before the production and release of these inflammatory mediators. Herein, we have aimed to draw attention to a novel aspect of the cytokine hypothesis of depression that may serve as a novel target mechanism and provide further understanding of the disease, namely NLRP3 inflammasome, a multi protein complex formed in macrophage and microglia cells which is responsible for initiating the inflammatory responses mediated with IL-1 beta and IL-18.
    Bulletin of Clinical Psychopharmacology 09/2013; 23(3):1. DOI:10.5455/bcp.20130927070724 · 0.37 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014