The clinical use of tricyclic antidepressants (TCAs) is often complicated by toxicity and safety problems due to their effects on multiple mechanisms of action, many of which are unnecessary for therapeutic effect. The development of the selective serotonin reuptake inhibitors (SSRIs), with their selective mode of action, has resulted in a class of antidepressant drugs possessing an improved side-effect profile, while retaining good clinical efficacy. Their introduction into clinical practice has led to enhanced patient compliance with antidepressant therapy and the ability to maintain treatment over longer periods of time at an adequate therapeutic dose. Although, as a result of their selective action, side-effects associated with SSRI therapy are minimised, distinct variations between individual SSRIs in terms of their tolerability profiles have been observed. The wealth of clinical data now available has revealed differences in their potential to cause psychiatric and neurological side-effects, dermatological reactions, anticholinergic side-effects, changes in body weight, sexual dysfunction, cognitive impairment, discontinuation reactions and drug-drug interactions. Patients who suffer from concomitant depression and physical illness may experience different tolerability profiles, in addition to the greater likelihood that they will be receiving concomitant medications with the potential for pharmacokinetic drug-drug interactions with coadministered SSRI therapy. In addition, the safety margin of SSRIs in overdose may vary within the group. Knowledge of the differences that exist among the SSRIs in respect of tolerability and safety will aid physicians in the selection of the most beneficial treatment strategy for their patients. A successful clinical outcome leads to a reduced economic burden for the patient, their family and the healthcare services. Thus, pharmacoeconomic considerations are also important in choosing antidepressant therapy. The SSRIs, despite relatively higher prescription costs, have been demonstrated to be a more cost-effective option than the TCAs. Furthermore, there is evidence that the emerging clinical differences between SSRIs may translate into significantly different economic outcomes within the group.

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT 2c , also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs.

Accelerator MS (AMS) provides a novel method for obtaining and analyzing pharmacokinetics and pharmacodynamics in children. This paper reviews the scientific and ethical rationale for AMS in pediatric trials, the regulatory framework and general considerations with some specific examples of pediatric clinical trials using AMS. Microdosing in the context of this article refers to studies using a negligible amount (nanocuries) of (14)C as tracer, and AMS as a quantitative technique. The technology is by no means a panacea for the deficiency in pediatric clinical research; however, it lessens the challenges and provides the most quantitative tool for pediatric pharmacology studies.

Since their introduction, the selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely used classes of medication in psychiatry. Their popularity is based on apparent efficacy over a wide range of disorders and a favorable side-effect profile. However, as with any psychotropic medication, considerable data are required to define where a drug works and where it does not. There is now a wealth of evidence demonstrating that SSRIs may differ in their efficacy profiles in certain depressive symptoms, in different subtypes of depression, with respect to their ability to maintain efficacy over time, on broader outcomes such as quality of life, and in the consistency of the usually effective minimum therapeutic dose across the age spectrum and across indications. Although this review includes data on all SSRIs, it focuses on fluoxetine and sertraline, which in addition to being the most widely used SSRIs are also the most widely studied. The relative quantity and quality of data on these two SSRIs means that it is possible to make relatively firm inferences regarding their differential effects on affective symptoms and quality of life.

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