Reference

Mechanism of action of antidepressants: New data from Escitalopram

Mechanism of action of antidepressants: New data from Escitalopram. Fabre, V.; Hamon, M. (INSERM U288, Neuropsychopharmacologie, CHU Pitie-Salpetriere, Paris F-75634/13, Fr.). Encephale, 29(3, Cahier 1), 259-265 (French) 2003 ETICOM.In this study，128196-01-0 is also used. CODEN: ENCEAN. ISSN: 0013-7006. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review. A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, wt. gain, dry mouth, etc., mainly caused by their capacity to block a1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approx. 30 % of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 wk of treatment, like that obsd. with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addn., the potency of Escitalopram to inhibit serotonin reuptake (Ki = 2, 1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is esp. relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such ad fluoxetine)to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 wk of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 wk with any other antidepressant drug. These unique properties led to further investigations of the pharmacol. profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further expts. showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addn., behavioral studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant and anxiolytic - like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary mol. targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (Ki=180 nM) and a1-adrenergic (Ki=560 nM) receptors than Escitalopram (resp. Ki=560 nM) receptors than Escitalopram (resp. Kis32000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (Ki=200-430 nM) for both subtypes of sigma receptors. (s1 and s2) is higher than that of R-citalopram (and of the racemate citalopram; K1=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioral studies showed that selective s1 and s2 agonists are endowed with both antidepressant - and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiol. mechanisms underlying antidepressant therapy, and, possibly, depression itself. .

Combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mood disorders

Some chemicals with cas registry numbers like 128196-01-0 and 820225-60-3 are also used. Combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mood disorders. Gupta, Sandeep (Forest Laboratories, Inc.; Samoriski, Gary, USA). PCT Int. Appl. WO 2005000216 A2 6 Jan 2005, 54 pp. DESIGNATED STATES: W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW; RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, CY, DE, DK, ES, FI, FR, GA, GB, GR, IE, IT, LU, MC, ML, MR, NE, NL, PT, SE, SN, TD, TG, TR. (English). (World Intellectual Property Organization). CODEN: PIXXD2. CLASS: ICM: A61K. APPLICATION: WO 2004-US16959 27 May 2004. PRIORITY: US 2003-2003/PV473639 27 May 2003. DOCUMENT TYPE: Patent CA Section: 1 (Pharmacology) Section cross-reference(s): 63 The present invention provides a method for the treatment of depression, including treatment-resistant depression, and other mood disorders using a combination of an NMDA receptor antagonist and a SSRI that is citalopram or escitalopram. It has unexpectedly been shown that the combination has a synergistic and potentiated effect of either compd. as monotherapy, resulting in an enhanced therapeutic effect at lower doses. For example, an i.p. injection contained memantine and escitalopram was found to have synergistic effect against recurrent depression. .