example of a non-hydrazine maoi that was introduced. the maois work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. this leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. the fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. the problem with maois is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. although selective maois can reduce, if not eliminate these risks, their efficacy tends to be lower. maois may preferentially treat tca-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. this may be a function of the ability of maois to increase synaptic levels of da in addition to 5-ht and ne. the maois also seem to be effective in the treatment of fatigue associated with fibromyalgia (fm) or chronic fatigue syndrome (cfs). although a substantial number of maois were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. the reason for this is that they were hepatotoxic and could cause jaundice. tcas the first tricyclic antidepressant (tca), imipramine (tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. imipramine is an iminodibenzyl (dibenzazepine). the tcas such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine. it is the histaminiergic (h1), muscarinic acetylcholinergic (m1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of tcas. these include somnolence and lethargy, anticholinergic side-effects, and hypotension. due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the tcas could be lethal. tcas were, for 25 years, the leading cause of death from overdoses in many countries. patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications. another example of a tca is amineptine which is the only one believed to function as a dri. it is no longer available. failure of sndris for depression sndris have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials. in addition, the augmentation of a selective serotonin reuptake inhibitor (ssri) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase iii clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued. these occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. as such, skepticism has been cast on the promise of the remaining sndris that are still being trialed, such as ansofaxine (currently in phase ii trials), in the treatment of depression. nefazodone a weak sndri has been successful in treating major depressive disorder which makes it unique.