Mechanisms antidepressant activity

While such models of depression are quite useful in conceptualizing the mechanisms behind antidepressant activity, they are assuredly an oversimplification of the actual pathophysiologic process of the disorder. Depression probably involves a complex dysregulation of monoamine systems, and these systems, in turn, modulate and are modulated by other neurobio-logic systems. Thus, the underlying cause of depression may well extend beyond dysfunction of the monoamine system.10... 

Malcolm MacCoss, Christopher J. Swain, Timothy Harrison, Raymond G. Hill, Franz Hefti, Edward M. Scolnick, Margaret A. Casderi, Gary G. Chicchi, Sharon Sadowski, Angela R. Williams, Louise Hewson, David Smith, Emma J. Carlson, Richard J. Hargreaves and Nadia M. J. Rupniak, Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors , Science 281 (1998) 1640-45 Kuhn, Roland, Artistic Imagination and the Discovery of Antidepressants , Journal of Psychopharmacology 4, no. 3 (1990) 127-30... 

Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998 281 1640-1645. 

Subarnas A, Tadano T, Nakahata N, Aral Y, Kinemuchi H, Oshima Y, Kisara K, Ohizumi Y. (1993b). A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia inflata leaves In the forced swimming test. Life Sci. 52(3) 289-96. 

The kidney brush border also possesses a carnosine transport system and there is evidence that kidney also contains an active carnosinase (Sauerhoefer et al., 2005). There is also evidence that carnosine can influence sympathetic nervous activity in kidney (Tanida et al., 2005) as well as brown (Tanida et al., 2007) and white adipose tissue (Shen et al., 2008). Other studies have shown that carnosine has antidepressant activity in rats (Tomonaga et al., 2008). In chicks, carnosine induces hyperactivity (Tsuneyoshi et al., 2007) whereas its reverse structure (L-histidinyl-13-alanine) has sedative and hypnotic effects (Tsuneyoshi et al., 2008). The mechanisms involved in remain obscure however. 

Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snovely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, HiU RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Rupniak NMJ (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281 1640-1645 Landgraf R (1995) Intracerebrally released vasopressin and oxytocin measurement, mechanisms and behavioral consequences. J Neuroendocrinol 7 243-253 Landgraf R, Neumann I (2004) Vasopressin and oxytocin release within the brain a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25 150-176... 

The mechanisms by which thyroid hormones enhance antidepressant activity are still unknown. It is of interest that thyroid hormone increases net activity of several neurotransmitters that are putatively involved in the pathophysiology of depression in a way that is descriptively similar to that of estrogens. Receptors for the two hormones belong to the same superfamily. As was previously mentioned [Pfaff 1996], these issues are currently being explored, and clarifications are expected shortly. 

Partly reduced counterparts of the indole nucleus provide the basis for several agents with varied biological activities. A pair of closely related A-phenyl derivatives have both shown antidepressant activity in test systems. The apparent preference for the monomethyl amine suggests that these act by the same mechanism as the classical tricyclic antidepressants, where the secondary amine is the more active species. The first step in the preparation of the common intermediate (27-3) to these compounds consists of acylation of diphenylamine (27-1) with chloroacetyl chloride. 

However, its relative weak affinity for these uptake pumps has raised questions as to whether either of these mechanisms is relevant to its antidepressant activity. The combined plasma concentration of bupropion and its three active metabolites are consistent with the conclusion that the inhibition of both of these uptake pumps likely occurs under clinically relevant dosing conditions. For comparison purposes, the combined levels of bupropion and its metabolites are in microgram per milliliter range versus the nanogram per milliliter range for almost all other antidepressants (163). The only other antidepressant that achieves plasma concentration comparable with bupropion is nefazodone and its metabolites (164). That observation is also consistent with the relatively weak in vitro affinity of nefazodone and its metabolites for 5-HT2,a receptors and the serotonin uptake pump. 

Mirtazapine has been on the market in the United States since August 1996, and it is available in several other countries. The putative mechanism of action mediating antidepressant activity is the blockade of several serotonin receptors (i.e., 5-HT 2a and 5-HT2c) and a2-adrenergic receptors (172). The latter effect increases NE... 

The benefit of having different classes to choose from includes the apparent difference in their mechanisms of action (which may lead to differences in their range of antidepressant activity), as well as differences in tolerability and safety. Knowledge about these differences can then be used to tailor drug treatment for a given patient, thus optimizing outcome. 

The pharmacological activity of SJW extracts has recently been reviewed (55-58). Recent reports have shown that the antidepressant activity of Hypericum extracts can be attributed to the phloroglucinol derivative hyperforin (59-62), to the naphthodianthrones hypericin and pseudohypericin (18,63-65), and to several flavonoids (66-69). The role and the mechanisms of action of these different compounds are still a matter of debate. But, taking these previous findings together, it is likely that several constituents are responsible for the clinically observed antidepressant efficacy of SJW. 

Mueller WE, Singer A, Wonnemann M. Hyperforin—antidepressant activity by a novel mechanism of action. Pharmacopsychiatry 2001 34 S98-S102. 

EGb in vitro modifies the [3H]5-HT uptake by synaptosomes prepared from mice cerebral cortex in a biphasic manner. As mentioned above, the uptake of [3H]5-HT is inhibited by a high concentration of EGb [174]. On the other hand, low concentrations of EGb (4-16 pg/ml) significantly increase [3H]5-HT uptake. A similar increase was also obtained when synaptosomes were prepared from the cortices of mice treated orally with EGb, either acutely (100 mg/kg, 14 hours and 2 hours before death) or semi-chronically (2 x 100 mg/kg/day, for 4 days). Furthermore, such an increment in the [3H]5-HT uptake is attributed to the flavonoid constituents of EGb [175], and may be associated with the mechanism of its antidepressant activity. 

A variety of different chemical structures have been found to have antidepressant activity. With the possible exception of bupropion, however, the core antidepressant action of even the newest agents derives from mechanisms engaged by antidepressants introduced 4 decades ago. 

Tricyclic antidepressants block neuronal uptake of norepinephrine and variably serotonin (those with tertiary amine side chains), and the degree of inhibition seems to correlate with antidepressant activity. However, the block in amine uptake occurs shortly after drug administration, whereas the antidepressant effects generally require several weeks to develop. Thus the mechanism of action is incompletely understood and may involve changes in presy-naptic and postsynaptic neurogenic amine receptor response. In addition to their mood-elevating actions, tricyclic antidepressants also have sedative effects that may be... 

Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy, but cannot be used in a substantial number of patients. St. John s Wort (Hypericum perforatum) is a herbal antidepressant which may act via mechanisms similar to tricyclics. Clinical trials have extensively reported the ability of Hypericum perforatum extracts to exert a significant antidepressant activity [224-226], Hypericins, Fig. (13) are considered to be one of the compounds contributing to the activity of the extract [227], These... 

Ferris RM, Cooper BR. Mechanism of antidepressant activity of bupropion, j Clin Psychiatry 1993 11 2-14. 

Extracts of the flowers of St. John s wort contain chemicals with possible antidepressant activity. In vitro studies have shown that these chemicals interfere with the neuronal reuptake of amine neurotransmitters in a fashion similar to the proposed mechanism of antidepressant actions of tricyclics and SSRIs. The answer is (B). 

---