Antidepressants mechanism

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

Stahl, S.M. (1997) Are two antidepressant mechanisms better than one Journal of Clinical Psychiatry 58(8), 339—41. 

Mennini T, Gobbi M. The antidepressant mechanism of Hypericum perforatum. Life Sci. 2004 75 1021-1027. 

In addition to the presumed antidepressant mechanism of these drugs, they exert a multiplicity of effects on other neurotransmitters and neuron receptors, both in the areas that control mood symptoms and elsewhere in the central and peripheral nervous systems. Because medications have effects not only in the areas thought to be related to the disorder being treated but also in other areas in the brain and peripheral nervous system,... 

Laifenfeld D, Klein E, Ben-Shachar D. Norepinephrine alters the expression of genes involved in neuronal sprouting and differentiation relevance for major depression and antidepressant mechanisms. J Neurochem 2002 83 1054-1064. 

This book was written to provide facts about antidepressant basic research and clinical studies. Each chapter will discuss a particular family of antidepressants and call attention to pertinent scientific papers that describe antidepressant mechanisms, side effects, and epidemiology. We will also investigate some of the controversy surrounding antidepressant use, evaluating pros and cons for each drug family. 

The catecholamine hypothesis was then modified to include 5-HT in the etiology of depression (9,10). It should be noted, however, that not all Inhibitors of monoamine reuptake are antidepressants, because cocaine, a potent inhibitor of NE and dopamine reuptake, is not an antidepressant but, rather, an addictive stimulant. Subsequent studies with inhibitors of monoamine biosynthesis appear to confirm Kielholz s opinion and Schiidkraut s modified theory that clinical depression is the result of a deficiency in both 5-HT and NE and that the antidepressive mechanism of action most likely affects levels of both. 

Maprotiline exhibits the highest affinity and selectivity for the NE transporter (Fig. 21.6). Its antidepressant mechanism of action is similar to that of desipramine, with an onset of action of up to 2 to 3 weeks. 

Of these, the low level of SERTs in depressed patients has received the most attention in the development and synthesis of the SSRIs. The precise antidepressant mechanism of action for the SSRIs eludes neuroscientists, but the SSRIs have been shown to alleviate depression and are the most commonly used drugs in the therapy for depression. Claims of decreased adverse effects (adverse drug reactions) and less toxicity in overdose than both the MAOIs and the TCAs, together with increased safety, have led to their extensive use, and several are ranked in the Top 50 prescription drugs dispensed in the United States during the year 2005. 

Clomipramine is different from the other TCAs, exhibiting preferential selectivity for inhibiting the reuptake of 5-HT at the presynaptic neuronal membrane. Its antidepressant mechanism of action as an inhibitor of the 5-HT transporter is reduced in vivo, however, because of the formation of its active metabolite, N-desmethylclomipramine, which inhibits the reuptake of NE. As a result of its common structure with the other TCAs, clomipramine shares the pharmacological and adverse-effect profile of the other TCAs. 

Stewart, C.A. and Reid, l.C. 2002. Antidepressant mechanisms functional and molecular correlates of excitatory amino acid neurotransmission. Mol. Psychiatry 7(Suppl. 1) S15-S22. 

The search for antidepressant test methods, unrelated to the monoamine hypothesis, has become more and more important. In order to find new antidepressant mechanisms of action, new experiments are being devised which either demonstrate the effectiveness of known antidepressants or suggests a relation to the human depressed state. 

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