Fluvoxamine transporters

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Smeraldi, E., Zanardi, R. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3(6), 508-11. Wang, S. L., Huang, J. D. et al. (1993). Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther., 53(4), 410-18. 

Yoshida, K., Ito, K. etal. (2002). Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog. Neuropsychopharmacol. Biol. Psychiatry, 26(2), 383-6. 

Ito, K. et al. (2002). A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine. Psychiatry Res, 111, 235-9. 

Smeraldi, E. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3, 508-11. 

Serretti, A., Zanardi, R., Rossini, D. etal. (2001b). Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressants activity. Mol. Psychiatry, 6, 586-92. 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ (2002) Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 7 1115-1119 Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E (2000) Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 20 105-107 Zanardi R, Serretti A, Rossini D, et al (2001) Factors affecting fluvoxamine antidepressant activity influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 50 323-330... 

Initial pharmacogenetic studies of serotonin transporter gene (HTT) variants used case-control methods and have generated disparate results in different populations. Positive association of the promoter VNTR polymorphism (5-HTTLPR) with clinical response to fluvoxamine was seen in Italian patients with bipolar or unipolar delusional depression subjects with one or... 

Dick DAT, Naylor GJ, Dick EG Effect of lithium on sodium transport across membranes, in Dthium in Medical Practice. Edited by Johnson EN, Johnson S. Lancaster, England, MTP Press, 1978, pp 183-192 Dick P, Eerrero E A double-blind comparison study of the clinical efficacy of fluvoxamine and chlorimipramine. Br J Chn Pharmacol 15 [suppl 3) 419S-425S, 1983... 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Fluoxetine Highly selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET) Acute increase of serotonergic synaptic activity slower changes in several signaling pathways and neurotrophic activity Major depression, anxiety disorders panic disorder obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia) Half-lives from 15-75 h oral activity Toxicity Well tolerated but cause sexual dysfunction Interactions Some CYP inhibition (fluoxetine 2D6, 3A4 fluvoxamine 1A2 paroxetine 2D6)... 

Takano A, Suhara T, Yasuno F, Ichimiya T, Inoue M, Sudo Y, Suzuki K. Characteristics of clomipramine and fluvoxamine on serotonin transporter evaluated by PET. Int Clin Psychopharmacol 2002 17(Suppl 2) S84—5. 

St John s wort 1. TCAs (e.g. amitrypty-line, nortryptiline, clomipramine) 2. SSRIs (e.g. fluvoxamine, fluoxetine) 3. Venlafaxine Low blood amitriptyline levels (<20%). May potentially 1 therapeutic effects. Nortriptyline levels may be i by 50%. St John s wort t sedative effects (weakness, lethargy, fatigue, slow movements, incoherence) of SSRIs Due to induction of metabolizing CYP3A4 enzyme and P-gp transport proteins St John s wort inhibits uptake of serotonin and thereby t serotonin levels Avoid concomitant use... 

Kato M, Ikenaga Y, Wakeno M, et al. Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism. Int Clin Psychopharmacol 2005 20(3) 151—6. 

Serotonin transporter (5-HTT) Antidepressants (e.g., clomipramine, fluoxetine, paroxetine, fluvoxamine) Clozapine effects, 5-HT neurottansmission, antidepressant response... 

The affinity data for the SSRIs show that the SSRIs, as a group, are very potent and selective inhibitors for SERT compared with their affinity for NE and dopamine reuptake transporters (Fig. 21.6) and are more potent inhibitors of 5-HT reuptake than are the tertiary amine TCAs, with the exoeption of clomipramine. None of the SSRIs has substantial effeot on the NET or dopamine transporter. Of the SSRIs, sertraline exhibits the most potent inhibition of dopamine reuptake transporter, although it is still 100 times less potent in terms of inhibiting the dopamine versus the SERT. Therefore, the plasma oonoentration of sertraline would have to be increased by as much as 100 times to inhibit the dopamine reuptake transporter. When drugs are this selective for the reuptake transporters, differences in potency become olinioally irrelevant, because the plasma concentration oan be dose-adjusted to achieve inhibition of the desired transporter without affecting the other transporters. Clomipramine displays less affinity for SERT than oitalopram, fluvoxamine, paroxetine, or sertraline does and is more potent than fluoxetine. In terms of the ability to inhibit the NET, the SSRIs are two to three times less potent than the SNRI TCA, desipramine. 

Their in vitro potenoy for selectively inhibiting the 5-HT transporter more or less mirrors their clinical efficacy as SSRIs (11) paroxetine> sertraline> clomipramine> fluoxetine> citralopram> fluvoxamine> imipramine> amitriptyline> roboxetine> venlafaxine = milnacipran> desipramine. Clinically, however, all the SSRIs are equally effective over time, suggesting that these variations in potency do not affect efficacy or adverse effects. The SSRIs have less affinity for ai, 02, Hi, and musoarinic receptors, which may explain the adverse-effect profile differences between TCAs and SSRIs. 

Furthermore the authors showed that the dissociation kinetics of H-citalopram in membrane preparations of human platelets and human brain (putamen) both appeared to be affected differently by different 5-HT uptake inhibitors at 200 micromolar concentration. For instance 5-HT, clovoxamine and fluvoxamine had no effect on the dissociation half life while indalpine shortened and other 5-HT uptake inhibitors prolonged the dissociation half life of H-citalopram in both transporter preparations [24],... 

Fluvoxamine and clovoxamine are nontricyclic monoamine uptake inhibitors structurally related to the tricyclic smtidepressant noxiptiline (fig. 3). Both fluvoxamine and dovoxamine are trans isomers. Clovoxamine is a potent but nonselective inhibitor of the 5-HT and NE transporter in a synaptosomal preparation of the rat brain frontal cortex (Kj=5.9 and 7.0 nM respectively) and a weak (KjS 720 nM) inhibitor of the DA transporter in synaptosomes of the corpus striatum [26]. 

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