Delayed pharmacological effects of antidepressants

Abstract

Although antidepressants may not be primary mood stabilizers, they are efficacious in the prophylaxis of recurrent depressive illnesses, as well as in the treatment of acute episodes. Pharmacological effects that may contribute to the prophylactic effects of these drugs are not understood. Studies have been carried out in which antidepressants have been given to laboratory animals, such as rats, for periods of up to 3-4 weeks. Data obtained in such studies are thought to be important for their beneficial effects in depressive episodes, but also may be relevant to their prophylactic effects. Results are presented showing that when selective inhibitors of serotonin or norepinephrine uptake are given for such time periods, they still produce selective effects on serotonergic or noradrenergic parameters. For example, longterm administration of selective norepinephrine reuptake inhibitors causes a down-regulation of ␤ 1 adrenoceptors. Selective serotonin reuptake inhibitors do not produce this effect. Longterm administration of selective serotonin reuptake inhibitors causes down-regulation of the serotonin transporter, but not the norepinephrine transporter. In contrast, selective norepinephrine reuptake inhibitors down-regulate the norepinephrine transporter but not the serotonin transporter. Substantial loss of serotonin transporter binding sites takes 15 days to occur and is accompanied by a marked reduction of serotonin transporter function in vivo. Molecular Psychiatry (2002) 7, S23-S28.

siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain

“…Infusion of citalopram i.c.v., for 2 weeks, produced a significant downregulation of SERT, by a magnitude equivalent to that previously reported with subcutaneous infusions of SSRIs. 6,7 Further, citalopram-induced downregulation of SERT was independent of any changes at the mRNA level, consistent with previous studies using other SSRIs. 5,6 In contrast, 2-week infusion of SERT-siRNA specifically reduced the mRNA levels of SERT in the dorsal and median raphe nuclei.…”

“…20 The same infusion period is also required by SSRIs in order to produce a substantial downregulation of SERT. 6,7 Therefore, mice were infused with the SERT-targeting siRNA, a corresponding mmRNA, citalopram or vehicle for 2 weeks into the ventricular system. In situ hybridization analysis revealed a significant downregulation of SERT mRNA in the dorsal as well as median raphe of mice receiving siRNA (Figure 1a).…”

“…3,4 Emerging studies reveal downregulation of SERT as an adaptive consequence of sustained and high occupancy by chronically administered SSRIs. [5][6][7][8] The downregulation of SERT favorably potentiates the SSRI-mediated increase in the brain serotonergic neurotransmission. [6][7] Further, the lag time required by SSRIs to produce a substantial downregulation of SERT correlates well with the time needed for eliciting a full therapeutic response.…”

“…[5][6][7][8] The downregulation of SERT favorably potentiates the SSRI-mediated increase in the brain serotonergic neurotransmission. [6][7] Further, the lag time required by SSRIs to produce a substantial downregulation of SERT correlates well with the time needed for eliciting a full therapeutic response. Therefore, downregulation of SERT has been implicated in the antidepressant action of SSRIs.…”

“…Therefore, downregulation of SERT has been implicated in the antidepressant action of SSRIs. 7 Recently, SERT-deficient mice were used to ascertain the role of SERT in the etiology of depression vs the antidepressant action of SSRIs. 9,10 Consequently, the depression-related behavior illustrated by these mice has been attributed to the developmental changes that result from early-life absence of SERT.…”