Antidepressant efficacy

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Smeraldi, E., Zanardi, R. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3(6), 508-11. Wang, S. L., Huang, J. D. et al. (1993). Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther., 53(4), 410-18. 

Smeraldi, E. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3, 508-11. 

Dozens of clinical trials plus decades of clinical practice plus millions of content patients can t be that wrong. Whatever the bias in whatever the study, common sense clearly says the sum of the parts attesting antidepressants efficacy blatantly outnumbers the evidence showing the opposite. The use of these antidepressants is now deeply rooted and well-established in medical society worldwide, it s safe, it works, and there s no shadow of doubt about it.2... 

Posternak, Michael A., Mark Zimmerman, Gabor I. Keitner and Ivan W. Miller, A Reevaluation of the Exclusion Criteria Used in Antidepressant Efficacy Trials , American Journal of Psychiatry 159 (2002) 191-200... 

Lithium is effective for acute mania, but it may require 6 to 8 weeks to show antidepressant efficacy. It may be more effective for elated mania and less effective for mania with psychotic features, mixed episodes, rapid cycling, and when alcohol and drug abuse is present. Maintenance therapy is more effective in patients with fewer episodes, good functioning between episodes, and when there is a family history of good response to lithium. It produces a prophylactic response in up to two-thirds of patients and reduces suicide risk by eight- to 10-fold. 

Considerable effort in the field of monoamine reuptake inhibitors is focused on improving antidepressant efficacy since 30-40% of patients do not respond to treatment with currently available agents [6,7], An additional major objective is to enhance the onset of action. Current antidepressants typically require 2-6 weeks of treatment before clinical efficacy is seen [6]. Clinical trials exploring augmentation strategies, in which a DA reuptake inhibitor or a dual NE/DA reuptake inhibitor is combined with an SSRI, have resulted in improved efficacy in depressed patients refractory to SSRI treatment alone [4,5]. The improved results from clinical trials such as these serve to justify the considerable focus on the development of inhibitors that simultaneously block the reuptake of 5-HT, NE and DA. 

Structurally related to venlafaxine, PRC025 (29) and PRC050 (30) were reported to be triple reuptake inhibitors. Both exhibited antidepressant efficacy at 5 mg/kg in the rat FST [91]. 

Schatzberg AF. Pharmacological principles of antidepressant efficacy. Hum Psychopharma-col 2002 17(Supplement 1) S17-S22. 

With regard to the specific action of antidepressants on the dopaminergic system, there is evidence that buproprion (not marketed in most countries in Western Europe as an antidepressant but available in North America), amineptine and nomifensin (withdrawn because of the rare occurrence of haemolysis) owed their antidepressant efficacy to their ability to increase central dopaminergic function. There are also open label studies to suggest... 

Administer once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of olanzapine/fluoxetine has not been studied. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine/fluoxetine in a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. The safety of doses above 18 mg/75 mg has not been... 

Behavioral alterations induced by stressful experiences frequently include increased anxiety-related behavior. Accordingly, anxiety has been hypothesized to play a role in stress-coping behavior (Ferre et al. 1994). The most regularly used tests for stress-coping behavior is the so-called forced swim test, which has been developed by Porsolt et al. (1977) as a behavioral paradigm to identify compounds with antidepressant efficacy in humans Mice or rats are forced to... 

Antidepressant Efficacy Tolerability Safety Discontinuation syndrome... 

There is a large evidence base for the antidepressant efficacy of venlafaxine, but fewer studies have been carried out in anxiety disorders. The best evidence is for GAD (Allgulander et al. 2001) and anxiety symptoms associated with depression (Silverstone and Ravindran 1999). Side-effects on initiation of therapy are similar to those of SSRIs, with nausea being the most common. Higher doses can cause raised blood pressure. A discontinuation syndrome similar to that seen with SSRIs has been reported. Toxicity causes cardiac conduction problems, seizures and coma, and venlafax-... 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Clomipramine (Anafranil) also a member of the tricyclic family, possesses similar pharmacology and antidepressant efficacy. This agent, however, has Food and Drug (FDA) approval only for use in the treatment of obsessive-compulsive disorder and is not included in this discussion of antidepressant drugs. 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

E.D. Hendley, S.H. Snyder, The relationship between the action of monoamine oxidase inhibitors on the noradrenaline uptake system and their antidepressant efficacy. Nature 220 (1968) 1330-1331. 

Similar to the discovery of other psychiatric medications, the mood-enhancing effects of monoamine oxidase inhibitors (MAOIs) were identified serendipi-tously mood improvements were observed in patients with tuberculosis treated with iproniazid (Bloch et ah, 1954) The early enthusiasm for the MAOIs was based on significant and unprecedented antidepressant effects and the link between antidepressant efficacy and their... 

Mann, J.J., Aarons, S.R, Wilner, P.J., Keilp, J.G., Sweeney, J.A., Pearl-stein, T, Frances, A.J., Kocsis, J.H., and Brown, R.P. (1989) A controlled study of the antidepressant efficacy and side effects of ( —)-deprenyl. A selective monoamine oxidase inhibitor. Arch Gen Psychiatry 46 45-50. 

Topiramate, a sulfamate-substituted derivative of the monosaccharide cf-fructose, is an anticonvulsant agent (AHFS, 2000). The spectrum of topiramate s anticonvulsant activity resembles that of CBZ and phenytoin (Shank et ah, 2000). Topiramate has shown preliminary antimanic (McElroy et al., 2000) and possibly antidepressant efficacy in treatment-refractory, manic patients with BD type I (Calabrese et ah, 1998). 

Pseudorandomized to Li versus CBZ and Li greater antimanic and antidepressant efficacy in first year versus Li alone. 

Lambert 1984 McElroy et al. 1988b] suggested that valproate may be a much better antimanic than antidepressant agent. In a study of 78 consecutively recruited patients with rapid-cycling bipolar disorder treated with open-label valproate alone or in combination with other psychotropic agents, Calabrese and colleagues [Calabrese and Delucchi 1990 Calabrese et al. 1992] reported a 54% valproate response in acute mania, an 87% response in acute mixed states, and a 19% response in acute depression. However, they did observe a prophylactic antidepressant effect in patients subsequently. Additional controlled studies are needed to clarify valproate s antidepressant efficacy. 

Finally, traditional electrode placements have also been reexamined. Letemendia et al. [1993] compared the efficacy of unilateral ECT, standard bilateral ECT [i.e., bifrontotemporal electrode placement], and bilateral ECT using a bifrontal placement. Both forms of bilateral ECT had superior antidepressant efficacy compared with that of unilateral ECT, and the bifrontal condition was somewhat superior to the standard bilateral placement. This finding further challenges the idea that the elicitation of a generalized seizure in and of itself is both necessary and sufficient for the antidepressant effect of ECT. Rather, the site or sites of seizure initiation, and perhaps propagation, may be critical determinants of therapeutic efficacy. 

ECT is unique in creating numerous biochemical and physiological changes in the brain. At the theoretical level, research into mechanisms of action has received new impetus from advances in fields such as neuroimaging. At the practical level, the use of techniques such as the EEG is leading to the ability to separate effective forms of ECT from those that lack antidepressant efficacy. 

Evidence on the potential antidepressant efficacy of L-dopa is more voluminous, but also discouraging [Kapur and Mann 1992 Oren et al. 1994). Despite the definite effects of L-dopa on mood, its antidepressant efficacy, given with or without a peripheral decarboxylase inhibitor, is not established even in the subset of patients with psychomotor retardation and low pretreatment CSF HVA who are supposed to be particularly sensitive to its effects. Standard antidepressants or electroconvulsive therapy are the methods of choice in treating depression in patients with Parkinson s disease, in whom L-dopa appears to have limited or no antidepressant efficacy and has been suspected of producing depression [Cummings 1992). Furthermore, pro-... 

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