Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
NeuroImage (Impact Factor: 6.36). 05/2011; 57(4):1317-23. DOI: 10.1016/j.neuroimage.2011.05.051
Source: PubMed

ABSTRACT Studies have revealed abnormalities in resting-state functional connectivity in those with major depressive disorder specifically in areas such as the dorsal anterior cingulate, thalamus, amygdala, the pallidostriatum and subgenual cingulate. However, the effect of antidepressant medications on human brain function is less clear and the effect of these drugs on resting-state functional connectivity is unknown.
Forty volunteers matched for age and gender with no previous psychiatric history received either citalopram (SSRI; selective serotonergic reuptake inhibitor), reboxetine (SNRI; selective noradrenergic reuptake inhibitor) or placebo for 7 days in a double-blind design. Using resting-state functional magnetic resonance imaging and seed based connectivity analysis we selected the right nucleus accumbens, the right amygdala, the subgenual cingulate and the dorsal medial prefrontal cortex as seed regions. Mood and subjective experience were also measured before and after drug administration using self-report scales.
Despite no differences in mood across the three groups, we found reduced connectivity between the amygdala and the ventral medial prefrontal cortex in the citalopram group and the amygdala and the orbitofrontal cortex for the reboxetine group. We also found reduced striatal–orbitofrontal cortex connectivity in the reboxetine group.
These data suggest that antidepressant medications can decrease resting-state functional connectivity independent of mood change and in areas known to mediate reward and emotional processing in the brain. We conclude that hypothesis-driven seed based analysis of resting-state fMRI supports the proposition that antidepressant medications might work by normalising the elevated resting-state functional connectivity seen in depressed patients.

Download full-text


Available from: Ciara Mccabe, Jul 28, 2015
  • Source
    • "Cognitive dysfunction might therefore be regarded as both, a state-and a trait-marker of depression. Conversely, since it has been suggested that SSRI and SNRI treatments can decrease the resting-state functional connectivity independent of mood change and in areas known to mediate reward and emotional processing in the brain (McCabe and Mishor, 2011), antidepressant treatment may also decrease cognitive function. For this reason, the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medicationnaïve state before the administration of antidepressants has been recently highlighted in a study by Herzallah et al. (2013a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cognitive dysfunction is of clinical significance and exerts longstanding implication on patients׳ function. Pharmacological and non-pharmacological treatments of cognitive dysfunction are emerging. This review evaluates pharmacological and non-pharmacological treatments of cognitive impairment primarily in the domains of memory, attention, processing speed and executive function in clinical depression. A total of 35 studies were retrieved from Pubmed, PsycInfo and Scopus after applying inclusion and exclusion criteria. Results show that various classes of antidepressants exert improving effects on cognitive function across several cognitive domains. Specifically, studies suggest that SSRIs, the SSRE tianeptine, the SNRI duloxetine, vortioxetine and other antidepressants such as bupropion and moclobemide may exert certain improving effects on cognitive function in depression, such as in learning and memory and executive function. Class-specific cognitive domains or specific dose–response relationships were not identified yet. The few non-pharmacological studies conducted employing cognitive orientated treatments and cognitive remediation therapy show promising results for the improvement of cognitive impairment in depression. However, several methodological constraints of studies limit generalizability of the results and caution the interpretation. Future direction should consider the development of a neuropsychological consensus cognitive battery to support the discovery, clinical assessment, comparison of studies and registration of new agents in clinical depression.
    Psychiatry Research 09/2014; 219(1):25–50. DOI:10.1016/j.psychres.2014.05.013 · 2.68 Impact Factor
  • Source
    • "Opposing effects have been reported for the OFC (Del-Ben et al., 2005; McCabe et al., 2010; McKie et al., 2005). On a brain systems level, decreased functional connectivity between ventral medial prefrontal cortex and amygdala has been found under SSRI treatment in healthy subjects (McCabe & Mishor, 2011). In the context of MDD, an initial reduction of amygdala-ACC functional coupling (Anand et al., 2005) has been reported to be reversible by chronic SSRI treatment (Chen, C.H. et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A vast number of imaging studies have demonstrated the impact of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) on emotion and memory-related networks in the context of Major Depressive Disorder (MDD). Underlying molecular mechanisms that affect the functionality of these networks have been examined in detail in animals and corroborate imaging findings. The crucial role of 5-HT and BDNF signaling in the context of MDD is reflected in the etiologic models of MDD such as the monoamine or neuroplasticity hypothesis as well as in pharmacological models of antidepressant response. While antidepressant drug treatment has been primarily linked to the modulation of emotion-related networks, cognitive behavioral therapy has been implicated in a top-down control of limbic structures. Initially, a simple lack of monoamines or BDNF has been proposed as causal factor of MDD etiology. However, recent findings suggest a much more complex neurobiology emphasizing epistatic and epigenetic mechanisms responsible for structural and functional changes observed in emotion and memory-related brain regions of healthy subjects and MDD patients. In this review, which focuses on neuroimaging studies in the context of MDD, the authors will provide a comprehensive overview of these networks as well as on the specific role of 5-HT and BDNF in their development and function.
    04/2013; 32(1). DOI:10.3233/RNN-139005
  • Source
    • "Here regions showing increased connectivity were the right visual, intraparietal and superior frontal cortex (Grefkes et al., 2010). McCabe and Mishor (2011) investigated the effects of reboxetine within a resting state condition and focused their analysis on regions of the limbic system. Their data provides evidence that reboxetine reduced the striatal–orbitofrontal cortex connectivity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies document that cholinergic and noradrenergic drugs improve attention, memory and cognitive control in healthy subjects and patients with neuropsychiatric disorders. In humans neural mechanisms of cholinergic and noradrenergic modulation have mainly been analyzed by investigating drug-induced changes of task-related neural activity measured with functional magnetic resonance imaging (fMRI). Endogenous neural activity has often been neglected. Further, although drugs affect the coupling between neurons, only a few human studies have explicitly addressed how drugs modulate the functional connectome, i.e., the functional neural interactions within the brain. These studies have mainly focused on synchronization or correlation of brain activations. Recently, there are some drug studies using graph theory and other new mathematical approaches to model the brain as a complex network of interconnected processing nodes. Using such measures it is possible to detect not only focal, but also subtle, widely distributed drug effects on functional network topology. Most important, graph theoretical measures also quantify whether drug-induced changes in topology or network organization facilitate or hinder information processing. Several studies could show that functional brain integration is highly correlated with behavioral performance suggesting that cholinergic and noradrenergic drugs which improve measures of cognitive performance should increase functional network integration. The purpose of this paper is to show that graph theory provides a mathematical tool to develop theory-driven biomarkers of pro-cognitive drug effects, and also to discuss how these approaches can contribute to the understanding of the role of cholinergic and noradrenergic modulation in the human brain. Finally we discuss the "global workspace" theory as a theoretical framework of pro-cognitive drug effects and argue that pro-cognitive effects of cholinergic and noradrenergic drugs might be related to higher network integration.
    Frontiers in Behavioral Neuroscience 08/2012; 6:53. DOI:10.3389/fnbeh.2012.00053 · 4.16 Impact Factor
Show more