Some Unanswered Questions

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Although the monoamine uptake inhibitors have proved very successful in the treatment of depression and anxiety states many questions remain unanswered. How can drugs that are selective norepinephrine reuptake inhibitors be equally effective as those that selectively target serotonin reuptake? In reality none of the antidepressants is completely selective for NET or SERT. In some cases the formation of active metabolites alters the drug selectivity profile. Thus the non-selective compound imipramine and the partially NET-selective compound lofepramine are extensively metabolized to desipramine, a highly potent and selective NE reuptake inhibitor. Similarly whereas amitriptyline has little selectivity for NET or SERT, the metabolite nortriptyline is a selective NET inhibitor. Alternatively some have suggested that the SSRI's act indirectly to modulate noradrenergic function [21,22].

The long term changes in the brain that are triggered by the antidepressants, remain obscure. Although inhibition of monoamine uptake is an immediate effect, all antidepressant drugs require a period of several weeks before they become fully effective. Many theories have been proposed to explain this delayed action, including alterations in the expression of monoamine receptors, changes in transcription factors and neurotrophic factors, and morphological alterations in the connectivity of monoaminergic nerves and the promotion of new nerve cell formation [23].

The mechanisms underlying the prominent placebo effect seen in all clinical trials of antidepressant drugs also remain obscure. It is not uncommon for the placebo effect to be so large as to obscure any significant effect attributable to the active drug in clinical trials. An analysis of 74 Phase III clinical trials for 12 antidepressants submitted to the Food and Drug Administration USA between 1987 and 2004 revealed that only half of these trials succeeded in demonstrating a statistically significant benefit from drug treatment [24].

Other Medical Uses of Inhibitors of Monoamine Uptake

Amphetamines represent another important group of compounds that act on monoamine transporters. They act by promoting the release of dopamine in the brain by virtue of their high affinity for the dopamine transporter and the vesicular monoamine transporter. They displace endogenous dopamine by a combination of a depletion of vesicular stores and counter transport of dopamine outwards via the transporter [25]. Amphetamine itself and the related drug methylphenidate ("RitalinĀ®") are widely used in the treatment of children with attention deficit hyperactivity disorder (ADHD). A norepinephrine-selective NET inhibitor, atomoxetine is also used for the treatment of ADHD.

The older antidepressant bupropion, acts as a weak inhibitor of norepinephrine and dopamine uptake, with little effect on serotonin uptake. Bupropion had little success as an antidepressant, but is approved in the USA and Europe as an aid to smoking cessation [26].

The anti-obesity drug sibutramine acts as a non-specific inhibitor of NET, SERT and DAT [27].

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