Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain

The effects of six-day SSRI administration on diurnal cortisol secretion in healthy volunteers.

Rationale Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in depression, and evidence suggests that selective serotonin reuptake inhibitors (SSRIs) might exert their therapeutic effects through altering cortisol secretion. Objective This study assessed the effects of SSRI administration on diurnal cortisol secretion in healthy volunteers. Methods Sixty-four healthy men and women were randomised to receive either 10 mg escitalopram or placebo for six days in a double-blind fashion. On day six of medication, saliva samples were obtained at home for measurement of diurnal cortisol parameters (cortisol slope, cortisol awakening response, total daily cortisol output). Results Women receiving escitalopram had significantly steeper cortisol slopes across the day compared with those receiving placebo (F(1, 36) = 7.54, p = 0.009). This alteration in cortisol slope was driven by increases in waking cortisol levels (F(1, 35) = 9.21, p = 0.005). Escitalopram did not have any significant effect on the cortisol awakening response or the total daily cortisol output. Conclusions Flattened cortisol slopes have been seen in depression. The results of this study suggest that escitalopram might exert its therapeutic effect in women in part through correction of a flattened diurnal cortisol rhythm.This work was supported by the British Heart Foundation (grant number RG/10/05/28296 and FS/13/40/30343)