Serotonin-selective reuptake inhibitors SSRIs

Beginning in the 1960s, ben2odia2epiae anxiolytics and hypnotics rapidly became the standard prescription dmg treatment. In the 1980s, buspkone [36505-84-7] (3), which acts as a partial agonist at the serotonin [50-67-9] (5-hydroxytryptamine, 5-HT) type lA receptor, was approved as treatment for generali2ed anxiety. More recently, selective serotonin reuptake inhibitors (SSRIs) have been approved for therapy of panic disorder and obsessive—compulsive behavior. 

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. 

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. 

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. 

The main focus of pharmacoeconomic studies of antidepressants has inevitably fallen on comparisons between tricyclic antidepressants (TCAs) and the more expensive selective serotonin reuptake inhibitors (SSRIs). Few data are available for comparisons within the SSRIs or for newer antidepressants. 

Schuldiner, S (1998) Vesicular neurotransmitter transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 215-240. Stanford, SC (1995) Central noradrenergic neurones and stress. Pharmac. Ther. 68 297-342. Stanford, SC (1999) SSRI-induced changes in catecholaminergic transmission. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austin, TX, pp. 147-170. 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Stanford, SC (1999) SSRI-induced changes in catecholaminergic transmission. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future, Ron Landes Bioscience, Austin, TX, pp. 148-170. 

Figure 20.5 The chemical structure of the selective serotonin reuptake inhibitors (SSRIs)...

Selective serotonin reuptake inhibitors (SSRIs) are considered the drugs of choice based on their tolerability and efficacy for social anxiety disorder as well as comorbid disorders. 

The first-line therapeutic options for PMDD include the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram. These agents can be given either continuously or only during the luteal phase of the menstrual cycle, i.e., initiated at the time of ovulation and discontinued on the first day of menses. 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

FDA, Combined Use of 5-Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Life-Threatening Serotonin Syndrome , FDA Public Health Advisory (2006) http //www.fda.gov/Cder/Drug/advisory/ S SRI S S200607.htm... 

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