**2.1 Antidepressant drugs and mechanisms of neuroplasticity**

Current national and international guidelines recommend serotonin reuptake inhibitors (SSRIs) as first-line treatment for most patients with major depression, and the use of serotonin—norepinephrine reuptake inhibitors (SNRI) in patients resistant to the former [4, 5]. Although novel, better tolerated and more selective inhibitors of serotonin and norepinephrine reuptake are continuously being developed, the efficacy of tricyclic antidepressants such as amitriptyline for severe depression, has never been surpassed [6].

Most of currently licensed antidepressants act to enhance monoamine neurotransmission, where they are believed to achieve therapeutic effects by increasing availability of serotonin or/and norepinephrine, at least initially [7]. On the neural level, antidepressants normalize aberrant neural activity patterns underlying negative bias in affective information processing, posited to play central role in the etiology and maintenance of depressed state [8]. Thus, antidepressants were shown to attenuate hyperactivity in limbic areas of the brain (amygdala, insula, anterior cingulate), and enhance regulatory activity in the dorsolateral and medial prefrontal cortex as measured by functional magnetic resonance imaging [9, 10]. It was demonstrated that 7 days treatment with SSRI, citalopram, SNRI, and reboxetine reversed abnormal patterns of neural response to affective information, and induced a similar direction of change in healthy individuals [11, 12]. Noteworthy, short-term SSRI administration normalized amygdala hyperactivity in response to negative emotional stimuli prior to clinical changes in mood ratings in placebo-controlled

studies [13]. These findings allow to speculate that treatment-induced early reversal of negative emotional bias sets the scene for therapeutic recovery over time by reducing the influence of this key maintaining factor [14].
