Effect of pharmacological treatment of serotonergic function in depression

Since its identification in raphe neurons of the central nervous system (CNS), the biogenic amine serotonin (5-hydroxytryptamin, 5-HT) has been implicated in the etiology and pathophysiology of affective disorders, such as depression. It has been proposed that enhancement of central serotonergic transmission may underlie the therapeutic response to different types of antidepressant drugs. Furthermore, dysfunction of the hypothalamicpituitary-adrenal (HPA) axis has been documented repeatedly in patients with major depression. The overall aim of this thesis was to investigate the effects of pharmacological treatment with different agents on central serotonergic mechanisms and indices of endocrine activity in depression. The 5-HT parameters studied in this work were the active 5-HT uptake, the [H]paroxetine binding to the 5-HT transporter and the [H]LSD binding to 5-HT2A receptors. Since direct studies of the living human brain are associated with great methodological difficulties, blood platelets, which share several biochemical and pharmacological properties with serotonergic nerve endings, provide useful peripheral model systems in the investigations of certain central serotonergic neuron dynamics. Additionally, plasma levels of cortisol, prolactin and dehydroepiandrosterone (DHEA) were measured in order to assess some aspects of the HPA axis. Medication-free depressed patients showed significantly lowered platelet 5-HT uptake and elevated plasma cortisol concentrations than healthy controls. However, no differences were noted in the density of 5-HT transporters and 5-HT2A receptors or in plasma levels of prolactin and DHEA between these two groups. Lowered 5-HT uptake and hypercortisolemia found in depressive illness may reflect a reduced central serotonergic activity during the state of illness or represent a biological marker of vulnerability and postulate hyperactivity of the HPA system. Interestingly, lowered velocity and affinity of platelet 5-HT uptake and higher basal values of plasma cortisol and DHEA were observed in patients who had suffered from multiple depressions compared to patients with first depressive episodes. These differences may be explained by a persisting modulation of the 5-HT uptake, caused by earlier use of antidepressant drugs with 5-HT inhibiting properties or the possibility that repeated depressive illness may cause some alterations in the serotonergic machinery. They may also postulate the existence of an association between a past history of depressive episodes with dysregulation of the HPA axis. Administration of the mood stabilizing agent lithium seems to affect calcium metabolism in patients with bipolar affective disorder inducing mild hypercalcemia and a dose dependent normalized calcium mobilization. Furthermore, lithium appears to have a net ameliorating impact on the 5-HT uptake and, when kept at a steady state at recommended plasma levels, it may counteract any changes in this mechanism. Additionally, the ability of lithium to stimulate an increase in the density and a modulation in the sensitivity of platelet 5-HT2A receptors may be particularly relevant to its mode of action in order to enhance the 5-HT neurotransmission in patients undergoing prophylactic lithium treatment. Six months of treatment with the two selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline caused a significant decrease in the velocity and affinity of the 5-HT uptake, but did not alter the density of platelet 5-HT transporters and 5-HT2A receptors. The dual effect on 5-HT uptake parameters indicates that both compounds act as noncompetitive inhibitors of the 5-HT uptake. Depressed patients who all responded to six months of treatment with the selective noradrenaline reuptake inhibitor (NRI) reboxetine, showed no changes in the density and affinity of platelet 5-HT transporters or 5-HT2A receptors. Our results indicate that effects on these aspects of the serotonergic system may not in fact be relevant to the antidepressant activity of reboxetine. Medication with lithium, SSRIs and reboxetine caused a significant decrease in plasma cortisol concentration. Since these changes occur in association with the improvement of the patient s clinical state, it is tempting to postulate that changes of the HPA-axis in depressive illness may be in pace with the mood-normalizing effects of antidepressant treatment. The finding of lowered plasma prolactin levels in long-term lithium treated patients may be explained by the net inhibitory impact of lithium s augmentative effects on dopaminergic activity and serotonergic neurotransmission in the CNS. Furthermore, there was a significant decrease in plasma DHEA levels but no alterations in the cortisol/DHEA ratio in depressed patients following treatment with citalopram and reboxetine. Changes in DHEA appear to be parallel to those in cortisol and could be partly explained by the action of DHEA as an antagonist to glucocorticoids. The work presented here supplies further evidence for the involvement of disturbances in the serotonergic system and the HPA axis in depressive illness. Furthermore, multiple depressive episodes appear to be associated with some alterations in the serotonergic machinery and the function of the HPA system. These changes, which may be caused by repeated depressive illness or earlier antidepressant treatment, provide additional aspects to the complexity of depressive illness. Finally, pharmacological inhibition of central serotonin uptake appears to be an effective antidepressant treatment and alterations of the HPA axis may be in pace with the moodnormalizing effects of antidepressant therapy.