**7.1 History of antidepressants**

In the late 1940s two scientist Hafliger & Schindler were synthesized a series of more than 40 iminodibenzyl derivatives which are possibly used as antihistamine, sedatives, analgesics and anti-parkinsonism drugs. Out of this imipramine was found to be a dibenzazepine compound, which is different from the phenothiazines because of replacement of the sulfur with an ethylene bridge to produce a seven membered central ring analogous to the benzepine antipsychotic agents [73]. During clinical investigation of these phenothiazenes analogs, Kuhn was found to be imipramine relatively ineffective for the treatment of psychosis but it had a remarkable effect for the treatment of depression [74]. Tricyclic antidepressants showed quinidine like effect on cardiac conduction that can be harmful at overdose and these are used limited for the heart patients. This is the main reason that TCAs only limited used to the patient at any given time. The research of chemically related compound to imipramine was found to be multiple analogs that are common in clinical use in the United States. There were also yielded diabenzazepines, imipramine and its secondary metabolite desipramine, as well as its 3-chloro derivative cloimipramine, amitriptyline and its N-demethylated metabolite nortriptyline, doxepin (dibenzoxepine) and protriptyline. Dibenzazepines are similar to the phenothiazines chemically. The ethylene group of middle of imipramine is responsible for the dissimilar stereochemical properties and prevents conjugation among the rings. Secondary metabolite (desipramine) of imipramine is similar to imipramine as an antidepressant while it is also showing some dissimilarity from imipramine. It might be possible that desipramine responsible for therapeutic responses to imipramine but it is no more effective or rapidly acting than imipramine [75].
