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Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
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2017 (English)In: EBioMedicine, E-ISSN 2352-3964, no 24, p. 179-188, article id S2352-3964(17)30385-7Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

METHODS: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

FINDINGS: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(2)(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

INTERPRETATION: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

FUNDING RESOURCES: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).

Place, publisher, year, edition, pages
2017. no 24, p. 179-188, article id S2352-3964(17)30385-7
Keywords [en]
Expectancies, Neuroimaging, Placebo effect, SSRI, Social anxiety disorder, fMRI
National Category
Psychology General Practice
Identifiers
URN: urn:nbn:se:uu:diva-331755DOI: 10.1016/j.ebiom.2017.09.031ISI: 000414392900030PubMedID: 29033138OAI: oai:DiVA.org:uu-331755DiVA, id: diva2:1150255
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-1368Swedish Research Council, 421-2013-1366Riksbankens Jubileumsfond, P13-1270:1
Note

Vanda Faria and Malin Gingnell contributed equally

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2022-10-28Bibliographically approved
In thesis
1. Imaging serotonin and dopamine transporters in social anxiety disorder: Characterization, treatment and expectancy effects
Open this publication in new window or tab >>Imaging serotonin and dopamine transporters in social anxiety disorder: Characterization, treatment and expectancy effects
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The monoamines serotonin and dopamine are likely to be involved in the pathophysiology of social anxiety and other affective disorders, but their respective contributions and putative interactions in the causes and cures of these disorders are still not well understood. It is also largely unknown if and how expectations of treatment success affect brain neurochemistry and neural activations, and if expectations interact with antidepressants like selective serotonin reuptake inhibitors (SSRIs). In this thesis some of these issues were addressed by use of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Using the highly selective radiotracers [11C]DASB and [11C]PE2I to characterize the availability of serotonin (SERT) and dopamine (DAT) transporter proteins, study I compared non-displaceable binding potentials (BPND), probing the transporters, between patients with social anxiety disorder and healthy controls. Increased SERT binding was observed in the reward related region nucleus accumbens (NAcc), in the social anxiety group. Moreover, increased DAT binding was associated with severity of the disorder and social anxiety was also associated with higher SERT-DAT co-expression in fear- and reward-related areas, including the amygdala and NAcc. Study II showed that verbal instructions regarding expected treatment efficacy strongly affected the clinical outcome of SSRI-treatment. Overt treatment, when patients with social anxiety disorder were correctly informed, was vastly superior to covert SSRI treatment, when patients expected an ineffective placebo. Groups were also differentiated on objective brain activity measures. Study III further demonstrated different SERT and DAT binding changes in limbic and striatal areas with overt as compared to covert SSRI-treatment. Decreased DAT BPND in the striatum, as assessed with PET, correlated with improvement in the overt group, suggesting increased dopaminergic signalling. Study IV compared treatment-induced changes in SERT and DAT binding after cognitive-behavior therapy (CBT) combined with an SSRI or placebo in patients with social anxiety disorder. Both groups showed initial co-expression similar to study I. The SSRI+CBT and placebo+CBT combinations yielded dissimilar transporter change patterns. Higher SERT occupancy in the NAcc correlated with reduced symptoms and this relationship was moderated by the change in DAT BPND. The results of this thesis support that functional interactions between serotonin and dopamine modulate social anxiety symptomatology and are important brain targets for successful treatment. Further it demonstrates that the treatment success of SSRIs in social anxiety disorder depends on how the treatment is presented. These results can be informative for the practice of clinicians, but also highlights an ethical dilemma because a large portion of the total treatment effects is elicited by processes within the patient itself.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences, ISSN 1652-9030 ; 176
Keywords
PET, serotonin, dopamine, placebo, SSRI, CBT, MRI
National Category
Psychiatry Radiology, Nuclear Medicine and Medical Imaging Psychology
Research subject
Psychology; Psychiatry; Radiology
Identifiers
urn:nbn:se:uu:diva-406312 (URN)978-91-513-0895-1 (ISBN)
Public defence
2020-04-24, Sal XI, Universitetshuset, Biskopsgatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2020-04-02 Created: 2020-03-06 Last updated: 2020-05-19

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Faria, VandaGingnell, MalinM. Hoppe, JohannaHjorth, OlofAlaie, ImanFrick, AndreasEngman, JonasMånsson, Kristoffer N.T.Larsson, Elna-MarieFredrikson, MatsFurmark, Tomas
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