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    • The diverse set of mechanisms by which neural activity leads

    2018-11-13

    The diverse set of mechanisms by which neural activity leads to changes in blood flow is termed neurovascular coupling, and involves neuronal- and glial-mediated release of several molecules which can increase or decrease blood vessel diameter (Attwell et al., 2010). If any component of a neurovascular coupling pathway is affected by antidepressants, the BOLD signal could be altered even in the absence of a difference in neural activity. Similarly, any difference in EZ Cap Reagent AG (3\' OMe) metabolism and oxygen use could directly alter the BOLD signal. In order to ascribe between-group differences in the BOLD signal to differences in neural activity, it is important to be able to assume that the same set of processes is linking neural activity to oxygen use and blood flow in each group (Harris et al., 2011; Reynell and Harris, 2013). Is this a safe assumption in the case of antidepressants? We turn to this question after briefly reviewing what is known about the neurophysiology of depression and the pharmacology of antidepressants (Section 3), and then looking at some of the ways that fMRI is being used to study the effects of antidepressants on the adolescent brain (Section 4).
    Depression and antidepressant treatment in adolescents As mentioned above, major depression is a highly prevalent lifetime disorder, with its onset commonly occurring during adolescence. It is considered an episodic illness, although depression in adolescence is often associated with a chronic course, persisting into adulthood (Mueller et al., 1999; Solomon et al., 2000; Dunn and Goodyer, 2006). It is still unclear what causes depression, although we are increasingly aware of risk factors, such as early adverse experiences and childhood anxiety (Reinherz et al., 2003; Beesdo et al., 2007), substance abuse (Currie et al., 2005), and genetics (Sanders et al., 1999). Over the past several decades, research involving human patients and animal models has helped to build a picture of the neurobiological basis of depression (reviewed comprehensively in Nestler et al., 2002; Maletic et al., 2007). Our knowledge is far from complete, but many lines of evidence point towards structural and functional abnormalities in several brain areas including the prefrontal cortex, cingulate cortex, amygdala, striatum, hippocampus, hypothalamus and thalamus (Nestler et al., 2002; Maletic et al., 2007). Perhaps the most well known neuropathological aspect of depression is the “chemical imbalance” in the depressed brain. Depression is associated with impairments in neurotransmission, particularly in the transmission of monoamines including, dopamine, noradrenaline and serotonin (Nestler et al., 2002; Maletic et al., 2007), although the exact ways in which these neurotransmitters contribute to depressive episodes is still under debate (see Dunlop and Nemeroff, 2007; Cowen, 2008; Cowen and Browning, 2015). Interestingly, monoaminergic systems undergo significant functional changes over adolescence (Goldman-Rakic and Brown, 1982; reviewed in Harris et al., 2011). Augmenting the function of aminergic signalling is one of the most effective ways to treat the symptoms of depression. The most common antidepressants are selective serotonin reuptake inhibitors (SSRIs) and, of this diverse class, only one is officially recommended for use in adolescents in the UK: fluoxetine (NHS guidelines, 2014; NICE guidelines, 2015). In practice, many adolescents are prescribed other SSRIs “off-label”, such as sertraline and citalopram, particularly in cases where adolescents do not respond well to fluoxetine. Recent meta-analyses show, however, that fluoxetine most effectively treats depressive symptoms in children and adolescents, with fewer adverse side-effects than other pharmacological antidepressant treatments (Hetrick et al., 2010; Cipriani et al., 2016). Fluoxetine is also prescribed as a treatment for other affective and anxiety disorders that show adolescent onset, including obsessive compulsive disorder, panic disorder, and bulimia nervosa (Hoffman and Mathew, 2008). Like other SSRIs, fluoxetine is thought to produce its antidepressant effect primarily by increasing the extracellular concentration of serotonin in the brain. Fluoxetine does this by blocking the reuptake of serotonin into cells by selectively binding to the serotonin transporter (SERT; Stahl, 1998). Several studies have shown that fluoxetine can also interact with serotonin receptors, in both agonistic (Peng et al., 2014) and antagonistic (Palvimaki et al., 1996) capacities.