Serotonin reuptake enhancers

The behavioural effects of two antidepressants with opposite molecular actions, ie. tianeptine (a serotonin reuptake enhancer) and fluoxetine (a serotonin reuptake blocker) have been assessed and it was concluded that, apart from the effects on serotonin reuptake, these dmgs have other mechanisms playing an important role in the anti-depressant action <00AF5>. 

Sertraline is a potent and selective inhibitor of neuronal serotonin (5-HT) reuptake. It has only a weak effect on neuronal uptake of norepinephrine and dopamine. Sertraline s inhibition of serotonin reuptake enhances serotonergic transmission. 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

Electrophysiological studies in the hippocampus also support enhanced al responses after chronic antidepressant treatments. Recent data indicate that the novel antidepressant tianeptine, which may increase serotonin reuptake when given chronically, also increases responsiveness of the al-adrenergic system (Rogoz et al. 2001). 

Enhances Serotonin Synthesis Increases Serotonin Release Serotonin agonist Inhibits Serotonin Catabolism Inhibits Serotonin Reuptake... 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

The delay in onset of anxiolytic and antipanic effects of serotonin reuptake inhibitors and related compounds is still an issue of much speculation. It appears paradoxical that serotonin reuptake inhibitors block serotonin uptake immediately, whereas it takes weeks before their therapeutic effects become apparent. Recently, the idea was advanced that the tentative enhanced serotonin neurotransmission caused by short-term administration of serotonin reuptake inhibitors is offset by negative feedback in the raphe nuclei (Artigas 1993 Blier and de Montigny 1994). The increased level of serotonin in the somatodendritic area, resulting from serotonin uptake inhibition, reduces serotonin neuronal firing through activation of the 5-HTj, autoreceptors. Alterations in the feedback regulation upon repeated administration may... 

The clinical implications of such data point to a relationship between abnormalities in the central serotonin system and self-injurious behavior. These findings have led to an interest in developing specific drugs that alter 5-HT activity to treat suicidality, impulsivity, and aggressivity independent of any specific psychiatric disorder. Central serotonin function can be enhanced by agents such as lithium and various serotonin reuptake inhibitors. Recent studies have found that the use of such agents is associated with reductions in the likelihood of suicide attempts and completions in both patients with major depression and those with cluster... 

Tramadol has about one tenth the pain-relieving ability of morphine.53 There are two enantiomers, and both contribute to pain relief, but via different mechanisms. (+)-Tramadol and the metabolite (+)-0-desmethy 1-tramadol, which is referred to as Ml, are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine re uptake.25 This latter action enhances the inhibitory effects on pain transmission in the spinal cord. Because the actions of the two enantiomers are complementary, they are usually supplied as a racemic mixture. However, because it is a serotonin-reuptake blocker, interaction with other medications can lead to the occurrence of serotonin syndrome.54... 

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