Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford OX3 7JX, United Kingdom.
Biological psychiatry (Impact Factor: 10.26). 03/2010; 67(5):439-45. DOI: 10.1016/j.biopsych.2009.11.001
Source: PubMed


Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans.
We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment.
Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key "punishment" areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect.
Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.

Download full-text


Available from: Ciara Mccabe
  • Source
    • "Furthermore, anhedonia in MDD is a predictor of proximal (within 1 year) suicide completion (Fawcett et al., 1990). Additionally, mounting evidence suggests that standard antidepressants may possess minimal efficacy in relieving anhedonia (Nutt et al., 2007) and may even induce emotional blunting (McCabe et al., 2010; Opbroek et al., 2002; Price et al., 2009) and sexual dysfunction (Hindmarch, 1998). Despite the importance of this symptom in psychiatry, and particularly in MDD, there is currently no approved medication specifically targeting anhedonia. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC. © The Author(s) 2015.
    Full-text · Article · Feb 2015 · Journal of Psychopharmacology
    • "Clinically, SRIs are less effective in managing the anhedonic symptoms of depression (Nutt et al., 2007; Lane, 2014) and in fact provoke cognitive and emotional blunting (Sansone and Sansone, 2010). These SRI-associated effects have been ascribed to 5-HT 2C -mediated suppression of frontal DA function (Barnhart et al., 2004; Wongpakaran et al., 2007; McCabe et al., 2010; Sansone and Sansone, 2010) (Figure 2). By not promoting 5-HT release, agomelatine will bolster and/ or sustain DA function (by limiting 5-HT 2C activation of GABA inhibitory neurons), or it can temper DA release via NA activation of α 2 -heteroreceptors on DA neurons (Figure 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology.DesignThe relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS.ResultsAltered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems.Conclusions This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd.
    No preview · Article · Nov 2014 · Human Psychopharmacology Clinical and Experimental
  • Source
    • "Research has primarily examined serotonin reuptake inhibitors (SSRIs) and serotonergic–noradrenergic reuptake inhibitors (SNRIs) indicating that SNRIs are superior to SSRIs at improving certain cognitive functions (Herrara-Guzman et al., 2009). In contrast, SSRI antidepressants such as citalopram have been suggested to diminish neural processing of aversive and rewarding stimuli in healthy individuals (McCabe et al., 2010), suggesting the possibility that antidepressants may exert negative effects on neuropsychological function during antidepressant treatment of depressed patients. Other antidepressants that have been examined and seem to have improving effects on neuropsychological functioning in depression include selective serotonin reuptake enhancers (SSREs), tricyclic antidepressants (TCAs), and other specific drugs (Allain et al., 1992; Nickel et al., 2003; Gallassi et al., 2006; Holtzheimer et al., 2008; Katona et al., 2012; Levkovitz et al., 2012); however, their mechanisms of action on cognitive processes remain to be fully understood. "
    [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.
    Full-text · Article · Sep 2014 · Psychiatry Research
Show more