Introduction: The mechanisms of action of antidepressants at the system level remain mainly unresolved. Antidepressants rapidly modulate emotional processing, enhancing processing of positive versus negative information, but this has been mostly demonstrated in healthy subjects and using fairly simple, controlled emotional stimuli such as emotional faces. Aim of the study: The aim of the studies of this thesis was to shed light on early antidepressant effects on emotional processing both in healthy subjects, avoiding the confounding effect of depressed mood, and in treatment-seeking depressed patients at an early stage of treatment, to elude the confounding effect of improved mood. The studies specifically aimed to reveal antidepressant effects on self-referential processing, a core factor in psychopathology of depression, and to investigate whether/how antidepressants modulate processing of complex, dynamic emotional stimuli resembling daily-life emotional situations. Methods: In Study 1 (experiments I and II), an open-label study of 30 healthy volunteers, half of the subjects received mirtazapine 15 mg two hours prior to functional magnetic resonance imaging (fMRI), and the other half was scanned without medication as a control group. Study 2 (experiments III and IV) was a double-blind, placebo-controlled study where 32 treatment-seeking depressed patients were randomized to receive escitalopram 10 mg or placebo for one week, after which fMRI was performed. In experiments I and III, neural responses to positive and negative self-referential adjectives as well as a neutral control task were assessed. In experiments II and IV participants listened to spoken emotional narratives and neural responses to the emotional content of the narratives were assessed. Results: Both mirtazapine in healthy subjects and escitalopram in depressed patients modulated self-referential processing. Mirtazapine attenuated responses to both positive and negative self-referential words in the anterior cortical midline structures (CMS, including the medial prefrontal cortex and the anterior cingulate), whereas escitalopram increased processing of positive relative to negative self-referential words. When comparing the placebo group and the escitalopram group from Study 2 separately with the healthy controls from Study 1, depressed patients receiving placebo had decreased responses of the anterior CMS to positive versus negative self-referential words, whereas no differences were found between the escitalopram group and healthy controls, implicating normalization of the negative bias in depressed patients receiving escitalopram. Both mirtazapine and escitalopram also modulated brain responses to spoken emotional narratives. Mirtazapine was found to modulate dynamic functional connectivity (measured with seed-based phase synchronization) of large-scale brain circuits, particularly potentiating functional connectivity of the anterior CMS and the limbic regions during positive parts of the narratives. Escitalopram increased synchronization of brain responses (measured with inter-subject correlation, ISC), specifically during positive parts of the narratives. Conclusions: A single dose of mirtazapine in healthy subjects and a one-week treatment with escitalopram in treatment-seeking depressed patients modulated neural responses to emotional information without any concurrent changes in mood. Both antidepressants modulated self-referential processing, a core psychological process in developing and maintaining depression. Escitalopram normalized the negatively biased self-referential processing of depressed patients in the anterior CMS. Both mirtazapine and escitalopram modulated brain responses to spoken emotional narratives, extending the previous findings of antidepressant effects based on simple emotional stimuli to complex, dynamic, every-day like emotional situations. Specifically, potentiated processing measured with novel methods of dynamic functional connectivity and ISC was found in the anterior CMS among other regions during positive emotional content of the narratives. These results suggest that antidepressants rapidly modulate processing of particularly positive emotional and self-referential information in the anterior CMS. This may be important for their later therapeutic effect.
|Myöntöpäivämäärä||1 maalisk. 2019|
|Tila||Julkaistu - 2019|
|OKM-julkaisutyyppi||G5 Tohtorinväitöskirja (artikkeli)|
LisätietojaM1 - 141 s. + liitteet
- 3124 Neurologia ja psykiatria