Selective inhibition of the serotonin transporter in the treatment of depression: Sertraline, fluoxetine and citalopram (original) (raw)
Related papers
Antidepressants Targeting the Serotonin Reuptake Transporter Act via a Competitive Mechanism
Journal of Pharmacology and Experimental Therapeutics, 2008
Although several antidepressants (including fluoxetine, imipramine, citalopram, venlafaxine and duloxetine) are known to inhibit the serotonin transporter (SERT), whether or not these molecules compete with serotonin (5-HT) for binding to SERT has remained controversial. We have performed radioligand competition binding experiments and found that all data can be fitted via a simple competitive interaction model, employing Cheng-Prusoff analysis (Cheng & Prusoff, 1973). Two different SERTselective radioligands, [ 3 H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenyl thio)-benzylamine) and [ 3 H]S-citalopram were used to probe competitive binding to recombinantly expressed human SERT (hSERT), or native SERT in rat cortical membranes. All the SERT inhibitors that we tested were able to inhibit [ 3 H]DASB and [ 3 H]S-citalopram binding in a concentration-dependent manner with unity Hill coefficient. In accordance with the Cheng-Prusoff relationship for a competitive interaction, we observed that test compound concentrations associated with 50% maximal inhibition of radiotracer binding (IC 50) increased linearly with increasing radioligand concentration for all ligands: 5-HT, S-citalopram, Rcitalopram, paroxetine, clomipramine, fluvoxamine, imipramine venlafaxine, duloxetine, indatraline, cocaine and 2-beta-carboxy-3-beta-(4-iodophenyl)tropane (β-CIT). The equilibrium dissociation constant of 5-HT and SERT inhibitors were also derived using Scatchard analysis of the dataset, and were found to be comparable to the data obtained using the Cheng-Prusoff relationship. Our studies establish a reference framework that will contribute to ongoing efforts to understand ligand binding modes at SERT by demonstrating that 5-HT and the SERT inhibitors tested bind to the serotonin transporter in a competitive manner. This article has not been copyedited and formatted. The final version may differ from this version.
Current understanding of the mechanism of action of classic and newer antidepressant drugs
Depression, 1994
Until 1980, the two major classes of antidepressant drugs were the tricyclics (TCAs) and the monoamine oxidase inhibitors (MAOIs). During the 1980s several additional classes of drugs appeared. Among these, selective serotonin reuptake inhibitors (SSRIs) have a distinct and well-characterized mechanism of action, and have become among the most widely prescribed antidepressant drugs.A common factor in the action of antidepressants with different chemical structures is the ability to increase the synaptic availability of one or more neurotransmitters, as a result either of blockade of the reuptake process or inhibition of metabolic degradation. However, the delay in clinical response to antidepressants suggests that, even if the acute pharmacologic effects of antidepressants may be essential for efficacy, symptom resolution requires some adaptive changes in neurotransmission. More recent studies, therefore, have focused on the signal transduction process beyond the receptor level, and on the regulation of gene expression of specific proteins.The side-effect profiles of antidepressants are related to their acute mechanisms of action. TCAs lack specificity of their pharmacological action, and are associated with antimuscarinic, antihistaminic, and alpha-adrenergic blocking actions, that account for many unwanted side effects but do not contribute to their therapeutic profile. The SSRIs, as a result of their selective action to inhibit serotonin reuptake, appear to have more tolerable side effects than TCAs and are less likely to be lethal when taken in overdose. SSRIs have little or no affinity for neurotransmitter receptors. The most common side effect is gastrointestinal discomfort. Depression 2:119–126 (1994/1995). © 1995 Wiley-Liss, Inc.
Innovative approaches for the development of antidepressant drugs: Current and future strategies
NeuroRX, 2005
Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2C , ␣-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT 2C , 5-HT 6 ) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands
International Journal of Molecular Sciences, 2015
Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors has for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre-and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic
Serotonin is a Common Thread Linking Different Classes of Antidepressants
Research Square (Research Square), 2023
Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (synaptic plasticity and neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of antidepressants. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis and the monoamine hypothesis).
European Neuropsychopharmacology, 2005
The interaction of the S-and R-enantiomers (escitalopram and R-citalopram) of citalopram, with high-and low-affinity binding sites in COS-1 cell membranes expressing human SERT (hSERT) were investigated. Escitalopram affinity for hSERT and its 5-HT uptake inhibitory potency was in the nanomolar range and approximately 40-fold more potent than R-citalopram. Escitalopram considerably stabilised the [ 3 H]-escitalopram/SERT complex via an allosteric effect at a low-affinity binding site. The stereoselectivity between escitalopram and Rcitalopram was approximately 3:1 for the [ 3 H]-escitalopram/hSERT complex. The combined effect of escitalopram and R-citalopram was additive. Paroxetine and sertraline mainly stabilised the [ 3 H]-paroxetine/hSERT complex. Fluoxetine, duloxetine and venlafaxine have only minor effects. 5-HT stabilised the [ 125 I]-RTI-55, [ 3 H]-MADAM, [ 3 H]-paroxetine, [ 3 H]-fluoxetine and [ 3 H]-venlafaxine/SERT complex to some extent. Thus, escitalopram shows a unique interaction with the hSERT compared with other 5-HT reuptake inhibitors (SSRIs) and, in addition to its 5-HT reuptake inhibitory properties, displays a pronounced effect via an affinity-modulating allosteric site. D