Selective serotonin reuptake inhibitors enhanced

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,... 

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. 

Deletion of the 5-HT1A receptor leads to enhanced extracellular 5-HT levels in response to systemic administration of selective serotonin reuptake inhibitors... 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

Paroxetine is a selective serotonin reuptake inhibitor that blocks reuptake of serotonin, enhancing serotonergic function. It is used to treat panic disorder or social anxiety disorder (except Pexeva), as defined in the DSM-IV major depressive disorder, as defined in DSM-111 (immediate release) orDSM-lV (controlled release). Immediate release only for obsessive-compulsive disorder (OCD) generalized anxiety disorder (GAD) (except Pexeva) posttraumatic stress disorder (PTSD), as defined in the DSM-IV (except Pexeva). 

When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. Mirtazapine has been shown to be effective in the treatment of panic disorder, social phobia, and post-traumatic stress disorder. In one study, mirtazapine combined with citalopram in obsessive-compulsive patients induced an earlier response when compared with citalopram plus placebo. It was suggested that antagonism of presynaptic a2-adrenergic receptors does not enhance serotonin neurotransmission directly, but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. 

Most prominent among the psychotropics that enhance serotonergic transmission are the selective serotonin reuptake inhibitors (SSRIs), which may induce sexual dysfunction in as many as 50-75% of patients, in part by activation of central 5-HT2 receptors. Antidepressants that antagonize the 5-HT2 receptor, such as mirtazapine and trazodone, cause fewer sexual side-effects compared with the SSRIs. Stimulation of the 5-HTia receptor facilitates sexual functioning, while activation of the 5-HTib,id and 5-HTic receptors inhibits... 

Seizures have been reported in patients receiving tramadol. The risk of seizure is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking tricyclic antidepressants, selective serotonin reuptake inhibitors, or other opioids. Tramadol may enhance the seizure risk in patients taking MAO inhibitors, neuroleptics, or other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). 

Serotonin, also known as 5-hydroxytryptamine (5-HT) is biosynthesized from tryptophan and is a neurotransmitter. Serotonin plays an important role in many behaviors including sleep, appetite, memory, and mood [52]. People with depressive disorders exhibit low levels of serotonin in the synapses. Protonated serotonin binds to a serotonin reuptake transporter protein, sometimes referred to as the serotonin transporter (SERT) and is then moved to an inward position on the neuron and subsequently released into the cjdoplasm. Selective serotonin reuptake inhibitors (SSRI) bind with high affinity to the serotonin binding site of the transporter. This leads to antidepressant effects by increasing extracellular serotonin levels which in turn enhances serotonin neurotransmission [53]. The SSRI class of antidepressants has fewer side effects than the monoamine oxidase inhibitors. 

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