1. Modulation pharmacoMRI to investigate the neural effects of SSRIs on emotional face processing A. E. ÉDES 1,2, D. KOVÁCS 1,2, D. PAP 1,2, X. GONDA 1,2,3, G. BAGDY 1,2, G. JUHÁSZ 1,2,4 1 Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary 2 MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary 3 Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary 4 Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, UK and Manchester Academic Health Sciences Centre

2. Introduction Many common psychiatric disorders such as depression and anxiety disorders are due to the dysfunction of monoamine neurotransmission in the central nervous system We are far from completely understanding the background of this disorders Drugs commonly used to treat these diseases are the selective serotonin reuptake inhibitors (SSRIs), which may increase intracellular serotonin levels The functional magnetic resonance imaging (fMRI) is a non-invasive method for the examination of brain activity With modulation pharmacological magnetic resonance imaging (phMRI) we can investigate the immediate effect of a single dose of the medication on face processing or we can observe the long-term effect of an antidepressant 1 Methods Literature search concerning examination of neurological responses to emotional faces and the effects of SSRIs on face processing

3. Results ArticleParticipantsAntidepressantTreatment duration Results Harmer et al. 200624 healthy subjects Citalopram vs placebo 7 days↓ activity by citalopram in medial prefrontal cortex, bilateral amygdala, hippocampal area with fearful stimuli Anderson et al. 2007 12 healthy subjects Citalopram i.v. vs placebo Single dose↓ activity by citalopram in right amygdala with fearful stimuli ↓ activity by citalopram in the left amygdala to disgusted faces ↑ activity by citalopram in the left posterior insula to disgusted faces Arce et al. 200813 healthy subjects S-citalopram vs placebo 21 daysNo difference in activation Murphy et al. 200926 healthy subjects Citalopram vs placebo Single dose↓ activity by citalopram of amygdala with fearful stimuli Norbury et al.200928 healthy subjects Citalopram vs placebo 7-10 days↑ activity by citalopram of amygdala with happy stimuli Windischberger et al. 2010 18 healthy subjects Citalopram vs s- citalopram vs placebo 10 days↓ activity by citalopram and S-citalopram in right amygdala and left middle temporal gyrus compared to placebo Henry et al 201324 healthy subjects Citalopram vs s- citalopram vs placebo 14 days↓ activity by citalopram and S-citalopram in bilateral lingual gyrus, bilateral occipital cortex and occipital fusiform gyrus, and left frontal orbital cortex (happy in comparison with fearful stimuli)

4. ArticleParticipantsAntidepressantTreatment duration Results Fu et al. 200719 patients and 19 healthy controls Fluoxetine8 weeks↓ activity with happy faces in patients in cerebellum, lingual gyrus, cuneus, posterior cingulate gyrus and precuneus at baseline, reversed at follow-up Chen et al. 2008 19 patients and 19 healthy controls Fluoxetine8 weeks↑ amygdala-anterior cingulate cortex functional coupling in patients at baseline, reversed after treatment Fales et al. 2009 23 patients and 18 healthy controls S-citalopram or sertraline or paroxetine 8 weeks↑ activity in patients in amygdala and ↓ activity in dorsolateral prefrontal cortex with fearful faces, reversed at follow-up Anderson et al. 2011 14 remitted depressed subjects and 12 never depressed healthy controls CitalopramSingle dose↑ activity by citalopram in left anterior cingulate with happy faces and right posterior insula and right lateral orbitofrontal with sad faces ↓ activity by citalopram in amygdala bilaterally to fearful faces ↑ activity by citalopraIn in controls in bilateral hippocampus to happy faces and in right anterior insula to sad faces Arnone et al. 2012 32 depressed subjects Citalopram8 weeks ↑ activity with sad faces in patients in bilateral amygdala at baseline, reversed at follow-up Results

5. According to the reviewed literature the SSRI treatment changes the fMRI responses most to aversive stimuli in healthy subjects The amygdala activation decreases by SSRI treatment At baseline there are many differences between healty and depressed patients, which can be important biomarkers of depression 2 In depressed patients the increased amygdala activity to sad or fearful faces gets improved after SSRI treatment 2 In contrast, there are inconsistentes in the scientific literature which can be explained by the different patient samples and study designs Results Conclusion The modulation phMRI is an effective way to investigate the role of serotonin in emotional face processing and to monitor the changes in brain activity during antidepressant treatment The SSRI treatment leads to the improvement of the enhanced amygdala activity to negative stimuli in depressed patients The application of this method may help deepen our understanding of serotonergic function in the living human brain as well as of diseases related to serotonergic neurotransmitter system dysfunction

6. 1.Jenkins BG. Pharmacologic magnetic resonance imaging (phMRI): imaging drug action in the brain. Neuroimage. 2012 Aug 15;62(2):1072-85. 2.Elliott R, Zahn R, Deakin JF, Anderson IM. Affective cognition and its disruption in mood disorders. Neuropsychopharmacology. 2011 Jan;36(1):153-82. References Acknowledgement Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary This study has been supported by National Development Agency (KTIA_NAP_13-1-2013-0001), Hungarian Brain Research Program - Grant No. KTIA_13_NAP-A-II/14.