maoi in conjunction with tryptophan (precursor of 5-ht) elevated mood in control patients and potentiated the antidepressant effect of maoi. set against this, combination of an maoi with dopa did not produce a therapeutic benefit. inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more sert selective than the parent compound. clomipramine was a predecessor to the development of the more recent ssris. there was, in fact, a time prior to the ssris when selective nris were being considered (c.f. talopram and melitracen). in fact, it is also believed that the selective nri nisoxetine was discovered prior to the invention of fluoxetine. however, the selective nris did not get promoted in the same way as did the ssris, possibly due to an increased risk of suicide. this was accounted for on the basis of the energizing effect that these agents have. moreover, nris have the additional adverse safety risk of hypertension that is not seen for ssris. nevertheless, nris have still found uses. further support for the monoamine hypothesis came from monoamine depletion studies: alpha-methyl-p-tyrosine (ampt) is a tyrosine hydroxylase enzyme inhibitor that serves to inhibit catecholamine synthesis. ampt led to a resurgence of depressive symptoms in patients improved by the ne reuptake inhibitor (nri) desipramine, but not by the ssri fluoxetine. the mood changes induced by ampt may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine. dietary depletion of the da precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication. administration of fenclonine (para-chlorophenylalanine) is able to bring about a depletion of 5-ht. the mechanism of action for this is via tryptophan hydroxylase inhibition. in the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today. although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants. dopaminergic there appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings. several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression: mood disorders are highly prevalent in pathologies characterized by a deficit in central da transmission such as parkinson's disease (pd). the prevalence of depression can reach up to 50% of individuals with pd. patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression. data from clinical studies have shown that da agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties. amineptine, a tca-derivative that predominantly inhibits da re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. a number of studies have suggested that amineptine has similar efficacy to the tcas, maois and ssris. however, amineptine is no longer available as a treatment for depression due to reports of an abuse potential. the b-subtype selective maoi selegiline (a drug developed for the treatment of pd) has now been approved for the treatment of depression in the form of a transdermal patch (emsam). for some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine. taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity. when users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. this is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also. for these drugs to be reinforcing, they must block more than 50% of the dat within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration. in addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans. the rate of clearance from the body is faster for ritalin than it is for regular amphetamine. noradrenergic the decreased levels of na proposed by schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ect) decrease β-adrenoceptor density in the rat forebrain. this led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. however, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density. another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. this supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of na in the central nervous system, cns) na activity leading to depression. in addition to enhancing na release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-ht nerve terminals. serotonergic 5-hydroxytryptamine (5-ht or serotonin) is an important cell-to-cell signaling molecule found in all animal phyla. in mammals, substantial concentrations of 5-ht are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-ht is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-ht receptor subtypes have been cloned and characterized. with the exception of the 5-ht3 receptor subtype, which is a transmitter-gated ion channel, 5-ht receptors are members of the 7-transmembrane g protein-coupled receptor superfamily. in humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. in accordance with this, drugs that affect 5-ht-containing cells or 5-ht receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine. because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. this is accounted for by the lethargic feel that some ssris can produce, although tcas and antipsychotics can also cause lethargy albeit through different mechanisms. appetite suppression is related to 5-ht2c receptor activation as for example was reported for pal-287 recently. activation of the 5-ht2c receptor has been described as "panicogen" by users of ligands for this receptor (e.g., mcpp). antagonism of the 5-ht2c receptor is known to augment dopaminergic output. although ssris with 5-ht2c antagonist actions were recommended for the treatment of depression, 5-ht2c receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. nevertheless, the 5-ht2c is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized. azapirone-type drugs (e.g., buspirone), which act as 5-ht1a receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. the hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-ht1a receptors. systemic administration of a 5-ht1a agonist also induces growth hormone and adrenocorticotropic hormone (acth) release through actions in the hypothalamus. current antidepressants most antidepressants on the market today target the monoaminergic system. ssris the most commonly prescribed class of antidepressants in the usa today are the selective serotonin reuptake inhibitors (ssris). these drugs inhibit the uptake of the neurotransmitter 5-ht by blocking the sert, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side-effects that result in discontinuation of treatment. although many patients benefit from ssris, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. even in remitters, a relapse is often observed following drug discontinuation. the major limitation of ssris concerns their delay of action. it appears that the clinical efficacy of ssris becomes evident only after a few weeks. ssris can be combined with a host of other drugs including bupropion, α2 adrenergic antagonists (e.g., yohimbine) as well as some of the atypical antipsychotics. the augmentation agents are said to behave synergistically with the ssri although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. it is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. in addition, single compounds are more likely to be approved by the fda than are drugs that contain greater than one pharmaceutical ingredient (polytherapies). a number of sris were under development that had auxiliary interactions with other receptors. particularly notable were agents behaving as co-joint ssris with additional antagonist activity at 5-ht1a receptors. 5-ht1a receptors are located presynaptically as well as post-synaptically. it is the presynaptic receptors that are believed to function as autoreceptors (cf. studies done with pindolol). these agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-ht relative to baseline than was the case for ssris as measured by in vivo microdialysis. nris norepinephrine reuptake inhibitors (nris) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. however reboxetine is no more effective than the ssris in treating depression. in addition, atomoxetine has found use in the treatment of adhd as a non-addictive alternative to ritalin. the chemical structure of atomoxetine is closely related to that of fluoxetine (an ssri) and also duloxetine (snri). ndris bupropion is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (ndri). it prevents the reuptake of na and da (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. this drug does not cause sexual dysfunction or weight gain like the ssris but has a higher incidence of nausea. methylphenidate is a much more reliable example of an ndri (the action that it displays on the dat usually getting preferential treatment). methylphenidate is used in the treatment of adhd, its use in treating depression is not known to have been reported, it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. there are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter. snris serotonin–norepinephrine reuptake inhibitors (snris) such as venlafaxine (effexor), its active metabolite desvenlafaxine (pristiq), and duloxetine (cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the ssris. sibutramine is the name of an snri based appetite suppressant with use in the treatment of obesity. this was explored in the treatment of depression, but was shown not to be effective. both sibutramine and venlafaxine are phenethylamine-based. at high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. the inhibition of da reuptake is unlikely to be relevant at clinically approved doses. maois monoamine oxidase inhibitors (maois) were the first antidepressants to be introduced. they were discovered entirely by serendipity. iproniazide (the first maoi) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity. isoniazid also displayed activity as an antidepressant, even though it is not a maoi. this led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the maoi activity could be a secondary side-effect. however, with the discovery of tranylcypromine (the first non-hydrazine maoi), it was shown that maoi is thought to underlie the antidepressant bioactivity of these agents. etryptamine is another