Depressive disorders inhibitors

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

Kirwin JL, Goren JL. Duloxetine a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder. Pharmacotherapy 2005 25 396-410. 

Fleischhacker, W.W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R., Gerlach, W., Jaklitsch, H., Sastre-y-Hernandez, M., Schmedlng-Wlegel, H., Sperner-Unterweger, B., Voet, B., and Schubert, H. (1992) A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 26 59-64. 

Fava M, Judge R, Hoog SL, et al Fluoxetine versus sertraline and paroxetine in major depressive disorder changes in weight with long-term treatment. J Clin Psychiatry 61 863-867, 2000 Fava M, Thase ME, DeBattista C A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 66 85-93, 2005... 

Reimherr FW, Byerley WF, Ward MF, et al. Sertraline, a selective inhibitor of serotonin uptake, for the treatment of outpatients with major depressive disorder. Psychopharmacol Bull 1988 24 200-205. 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

Ruhe HG et al Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder A systematic review. J Clin Psychiatry 1996 67(12) 1836. 

Treatment of cerebral stroke patients with selective serotonin reuptake inhibitor antidepressant showed difference in improvement with respect to laterality. The post-stroke major depressive disorder improved much more in right stroke subjects in comparison with the left stroke ones (Spalletta el al., 2003). In case of unilateral brain injury due to stroke or parkinsonism, the intact hemisphere plays an important role in recovery and compensation for the lost motor function (Schallert el al., 2003). A well-selected homeopathic potency may facilitate recovery by acting on the intact hemisphere. It has been demonstrated that the brain can asymmetrically... 

Papakostas, G. I., Petersen, T. J., Kinrys, G., Bums, A. M., Worthington, J. J., Alpert, J. E., Fava, M. Nierenberg, A. A. (2005). Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J. Clin. Psychiatry, 66, 1326-1330. 

Ramasubbu, R. (2001). Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders. Acta Psychiatrica Scan-dinavica, 104, 236—239. 

Phenylazepan derivatives, (V), prepared by Wu (5) were effective as both NK antagonists and selective serotonin reuptake inhibitors and used in treating major depression disorders. 

Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE. Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. Int Clin Psychopharmacol 2003 18 151-6. 

Committee on Safety of Medicines. Selective Serotonin Reuptake Inhibitors (SSRIs) overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data. http /medicines.mh-ra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ ssrioverview 101203.htm, updated 8.10.2004. 

In eight patients with major depressive disorder without psychotic features, who did not respond to serotonin re-uptake inhibitors therapy when risperidone was added, all improved within 1 week. Furthermore, risperidone also seemed to have beneficial effects on sleep disturbance and sexual dysfunction (47). In an open study in 30 healthy subjects who took risperidone 1 mg orally... 

Psychodynamic supportive psychotherapy (n = 107) has been compared with psychotherapy plus medication (n = 101) in patients with major depressive disorder (93). The medications included venlafaxine, selective serotonin reuptake inhibitors, nortriptyline, and nortriptyline plus lithium. Lithium was used as an augmentation strategy in the patients who took lithium and nortriptyline (number not given). There were no differences in outcomes between the two treatment groups. No adverse effects specific to lithium were reported. 

In eight patients with major depressive disorder without psychotic features, who did not respond to serotonin reuptake inhibitors therapy when risperidone was added, all improved within 1 week. Furthermore, risperidone also seemed to have beneficial effects on sleep disturbance and sexual dysfunction (272). In an open study in 30 healthy subjects who took risperidone 1 mg orally before and after venlafaxine dosing to steady state, the oral clearance of risperidone fell by 38% and the volume of distribution by 17%, resulting in a 32% increase in AUC renal clearance of 9-hydroxyrisperidone also fell by 20% (273). The authors concluded that these small effects were consistent with the fact that venlafaxine is unlikely to alter the clearance of risperidone, which is mainly by CYP2D6. 

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