Antidepressants development

Bolden-Watson C, Richelson E. (1993). Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci. 52(12) 1023-29. 

In contrast to the widespread interest in 5-HT in depression research and in the development of antidepressants, there would appear to be little interest in developing antidepressants that selectively modulate the noradrenergic system. At the present time, there do not appear to be any drugs of this type in development. 

Clearly, more research is needed to elucidate the precise mechanisms of action of antidepressants and the psychopathology of the condition. Only then may it be possible to develop antidepressants that show a clear therapeutic superiority over those available today. 

Besides sertraline (no. 10, see Section 3.10) other recently developed antidepressants have become very popular, including two fluorinated compounds, fluoxetine (Prozac , no. 13) and paroxetine (Paxil , no. 14). 

F. P. Bymaster, R. K. McNamara, P. V. Tran (2003). New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opin. Invest. Drugs 12 531-543. 

Finally, perhaps the most convincing line of evidence supporting the monoamine hypothesis is the fact that (at the time of this writing) all available antidepressants appear to have significant effects on the monoamine system. All classes of antidepressants appear to enhance the synaptic availability of 5-HT, norepinephrine, or dopamine. Attempts to develop antidepressants that work on other neurotransmitter systems have not been effective to date. 

Note the specific references to irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, a virtual prescription for violence. This new addition to the label, the implications of which having been largely overlooked, refers to children and adults. By indicating that nonpsychiatric patients can develop these reactions, the FDA class label challenges the commonly held belief that only patients with a bipolar history or vulnerability are at risk for developing antidepressant overstimulation. 

Second-Generation Antidepressants. The frequency of adverse effects associated with first-generation antidepressants and the lack of patient compliance arising from such adverse effects led to the development of a number of second-generation antidepressants. 

Reversible Inhibitors of Monoamine Oxidase. Selective MAO-A inhibitors, which aie leveisible (so-called RIMAs), have also been developed, theiefoie substantially leduciag the potential foi food and dmg iateiactions. Indeed, the tyiamine-potentiating effects of these dmgs is much reduced compared with the irreversible MAO inhibitors. The RIMAs represent effective and safer alternatives to the older MAO inhibitors. The only marketed RIMAs ate toloxatone [29218-27-7] and moclobemide (55). The latter is used widely as an effective, weU-tolerated antidepressant. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Tricyclic Antidepressants. Imipramine [50-49-7] (32), which was the first tricycHc antidepressant to be developed, is one of many useful psychoactive compounds derived from systematic molecular modifications of the antihistamine prometha2ine [60-87-7] (see Histamine and histamine antagonists). The sulfur atom of prometha2ine was replaced with an ethylene bridge and the dimethylamino group attached to an / -propyl group, rather than to an isopropyl one, of the side chain. The actual synthesis of (32) is typical of the compounds in this class (37). 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Potential antidepressant activity of lusaperidone (14) and its derivatives were investigated on al, q 2A, q 2B and q 2C receptor binding tests (00BMCL71). Hydrophilic controlled release formulations of 14 were developed and patented (00MIP8). 

Schechter Lee E, Robert H, Ring Chad E, et al (2005) Innovative approaches for Hie development of antidepressant drags. Curr Future Strat NeuroRx 2(4) 590-611... 

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