Discovery and theories of drug action

Table..,! gives a brief chronology of antidepressant drug discoveries and theories of drug action. Prior to 1954, except for the use of electroconvulsive therapy, there were few effective drug treatments for depression. In 1954, the antidepressant era was initiated with the observation that some patients with tuberculosis displayed mood elevations following treatment with the antituberculosis agent iproniazid.(2) Following this initial serendipitous observation, the antidepressant effect of iproniazid was confirmed/3) and its action of inhibiting monoamine oxidase was reported. Iproniazid had significant toxicity and other monoamine oxidase inhibitors ( MAOIs) were subsequently introduced. Independent from the work on MAOIs, imipramine, which has a chemical structure similar to the phenothiazines, was assessed as an agent to treat agitation in psychotic patients where it was found to be ineffective. However, it was noticed (again serendipitously) that imipramine produced an improvement of mood in the subset of patients who had symptoms of depression. Kuhn then reported in 1958 that imipramine was an effective antidepressant.(4)

Table 1 History of discovery of antidepressants and pharmacological theories of antidepressant drug action

One of the earliest theories of antidepressant drug action was that the antidepressant effect was produced by an increase of serotonin (5-hydroxytryptamine ( 5-HT)) in brain. This was supported by an initial study showing that an MAOI plus tryptophan, the precursor of 5-HT, was a more effective antidepressant treatment than an MAOI alone.(5) Subsequently, the discovery that imipramine and desipramine had effects in inhibiting the reuptake of noradrenaline (norepinephrine) and adrenaline (epinephrine) into the synapse led to the catecholamine theory of depression, which proposed that antidepressant treatments act by increasing the level of catecholamines at brain synapses.'67) Ten years later it was reported that in laboratory animals most antidepressant treatments lead to downregulation of b-adrenergic receptors. This supported the proposal that antidepressants act by reducing b-adrenergic receptor sensitivity. (8) However, the reduction in b-adrenergic receptor sensitivity occurred within hours and antidepressant effect requires 1 to 3 weeks. In addition, not all effective antidepressant treatments produce reductions in b-adrenergic receptor sensitivity.

In the 1970s and 1980s a large number of studies on antidepressants were conducted in laboratory animals which demonstrated that they produced a number of changes in monoamine receptor sensitivity.(9) In the late 1980s a number of neurophysiological studies provided evidence that the delay in onset of antidepressant effects could be accounted for by a slow decrease in sensitivity at presynaptic serotonergic autoreceptors which has the overall result of increasing serotonergic function after days and weeks of treatment/1..10 An elaboration on the receptor sensitivity theory was the discovery that most antidepressants produce alterations in the sensitivity of a specific glycine-sensitive site on the M-methyl-D-aspartate receptor.(11) There have not, however, been direct tests of whether new drugs acting on this site are antidepressants. An additional receptor sensitivity change thought to be important in the mechanism of action of antidepressants involved changes in the sensitivity of receptors for glucocorticoids where it was found that antidepressants produce an overall improvement of inhibitory feedback on the hypothalamic-pituitary-adrenal axis.(1, !,,3)

A more recent theory of antidepressant drug action involves findings that antidepressant treatments affect intracellular pathways and neurotrophins. It was found that many antidepressants, in spite of b-adrenergic receptor downregulation, continue to produce sustained activation of the cAMP system and that this is related to increases of neurotrophic factors in brain. (14) Neurotrophins reverse the effects of stress in some brain areas and this raises the possibility that antidepressants act by increasing neurotrophins which reverse the effects of stress in important brain areas of depressed patients.

Throughout the 1980s and 1990s a number of compounds that do not fit the standard monoamine theories of depression have been found to be effective clinical antidepressants. One of these drugs, tianeptine, actually increases the uptake of 5-HT into nerve endings, an effect that is opposite to the standard selective serotonin reuptake inhibitors (SSRIs)/15 An important report that has implications for theories of antidepressant action is the discovery that an antagonist of a substance P receptor which does not interact with monoamine systems is as effective an antidepressant treatment as the widely used SSRI paroxetine.(16)

Although no single mechanism has been discovered that will account for the antidepressant effects of all effective antidepressant treatments, it is clear that initial effects on monoamine metabolism with subsequent effects of intracellular pathways is important. In addition, to date there have been no clear demonstrations of immediate antidepressant efficacy (clear clinical changes in hours or days) as all drugs currently studied require 7 to 21 days to begin to show antidepressant effect. Pharmacology and types of compounds available

Antidepressant drugs fall into a wide variety of chemical classes and they have a wide range of neuropharmacological effects. They are grouped in Table.2, Xa.ble.3, and Ta.b.le.4 based on the presumed primary action that leads to an antidepressant effect. Table.2. lists the drugs that inhibit the uptake of the monoamines noradrenaline, 5-HT, and dopamine into nerve endings which in turn is thought to increase the function of the respective monoamine systems in brain. Table.3. lists the drugs that inhibit monoamine oxidase and thereby increase the concentration of many amines in brain. Table..4. lists the drugs with other primary actions that do not primarily involve inhibition of monoamine uptake or monoamine oxidase inhibition.

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Table 3 Pharmacological actions of antidepressant drugs that inhibit monoamine oxidase

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Table 4 Pharmacological actions of antidepressants: drugs that do not act by strong inhibition of monoamine uptake or inhibition of monoamine oxidase

In Table.2. the first 11 compounds are inhibitors of noradrenaline uptake with a variable potency of inhibiting 5-HT uptake also. The drugs with secondary amine structures, desipramine, nortriptyline, protriptylene, amoxapine, and maprotiline are predominantly noradrenaline uptake inhibitors with little effect on 5-HT uptake. (.1Z> It can be seen in Table..? that clomipramine, in addition to inhibiting noradrenaline uptake, is also a strong 5-HT uptake inhibitor. Venlafaxine, a relatively new drug, inhibits both noradrenaline and 5-HT uptake,(18) as do the older drugs imipramine and amitriptyline. A key issue in the pharmacology of all antidepressant drugs is the relative specificity of their action. Drugs with a tertiary amine structure tend to produce more antagonism of a 1-adrenergic receptors which can produce hypotension, histamine receptors which can produce sedation, and muscarinic cholinergic receptors which can produce blurred vision, dry mouth, and urinary retention. This leads to more side-effects for these compounds than the drugs with a secondary amine structure. Venlafaxine has relatively less effect on these receptors and thus fewer side-effects(l8> (see Table.6, below).

One of the more recent important advances in antidepressant treatments is the development of the SSRIs. Unlike the tricyclics they each have different chemical structures. The five drugs listed in Table...2 have a relatively specific effect in inhibiting 5-HT uptake, (1Z> and because of their relatively specific effect on this monoamine system and the lack of antagonism of many other receptors, they have been found to have fewer side-effects.

MAOIs are listed in .T.able...,3.. Two isoenzymes, monoamine oxidases A and B, are present in many discrete cell populations within the central nervous system, and glial cells also express monoamine oxidases A and B. The main substrates for monoamine oxidase A include adrenaline, noradrenaline, and 5-HT. The breakdown of dopamine in striatal regions of the brain is preferentially by monoamine oxidase B, but it can also be broken down by monoamine oxidase A. Since monoamine oxidase is located on the outside of the plasma membrane of the mitochondria in neurones, it is not able to eliminate amines that are stored inside vesicles. MAOI produces an increase in monoamines in the cytoplasm. It is thought that the increase in monoamine content is the primary mechanism of action of MAOIs, and other secondary changes including b-adrenergic receptor downregulation and other receptor changes are secondary to the increased amine levels. (1§>

Four of the six drugs listed in Ta.b.le.,.3 are irreversible inhibitors. The two reversible inhibitors are essentially inert substrate analogues, and there is usually a correlation between their plasma concentration and the reversible inhibition of monoamine oxidase A. Since isocarboxazid, phenelzine, and tranylcypromine are irreversible inhibitors of monoamine oxidases A and B, there can be serious side-effects when foods that are high in tyramine or other amines are ingested. In addition, these three drugs have strong interactions with other drugs that alter monoamine metabolism and therefore their use as antidepressants is much more limited than the tricyclics, SSRIs, or other antidepressant compounds. Tranylcypromine, which has a structure similar to amphetamine in addition to being an MAOI, is also thought to have a stimulant-type action of rapid onset. With the reversible MAOIs moclobemide and brofaromine the recovery of monoamine oxidase back to normal levels after the drug is stopped is much shorter than with the irreversible MAOIs. These drugs increase concentrations of 5-HT, noradrenaline, and adrenaline that are short and parallel the time course of the monoamine oxidase A inhibition. These two drugs are more easily displaced by the pressor amines such as tyramine, and therefore are thought to be safer than the irreversible inhibitors. (20)

Selegiline is selective at lower doses for monoamine oxidase B but at higher doses it becomes non-selective. It has been primarily used for the treatment of Parkinson's disease and the doses for treating depression need to be much higher. (21) Since monoamine oxidase B is not involved in the intestinal tyramine interaction, selegiline interactions with ingested monoamines have been minimal.

In addition to inhibiting monoamine oxidase, these compounds have other effects on monoamine systems that can produce side-effects. However, the major concerns are the interactions with dietary amines and other drugs that influence amine function. The combination of dietary interactions and slow recovery of monoamine oxidase following with the irreversible inhibitors makes these drugs one of the more difficult treatments to administer. They are generally reserved for patients not otherwise responding to the other less toxic antidepressants.

In Table...4 compounds that are effective antidepressants but do not inhibit monoamine oxidase or have strong monoamine uptake inhibition are listed. Trazodone has shown receptor antagonist activity at several 5-HT receptor subtypes although its active metabolite m-chlorophenylpiperazine is a potent direct serotonin agonist. This leads to trazodone being classified as a mixed 5-HT agonist/antagonist. It also has relatively weak 5-HT uptake inhibiting properties but with no effect on noradrenaline or dopamine uptake. Trazondone is devoid of anticholingeric activity and therefore it has few side-effects in this area. However, it does produce considerable sedation and hypotension secondary to antagonism of a -,-adrenergic receptors and histamine receptors.(22)

Nefazodone is an analogue of trazodone. Like trazodone it is a 5-HT receptor antagonist with weak monoamine uptake inhibition activity. (23) It has less affinity for the a-adrenergic receptors and is inactive on many other receptors. It too is metabolized to m-chlorophenylpiperazine which is an active serotonergic agonist. Although the initial effects of nefazodone involve alterations of 5-HT neurotransmission, these effects are complex and depend on the biological test used. (24)

Bupropion resulted from focused research to find antidepressant compounds that would have fewer side-effects than traditional tricyclics. Bupropion is a mild inhibitor of noradrenaline uptake and also has some effects on inhibiting dopamine uptake. There is no effect on 5-HT uptake. (25) These effects are not associated with b-adrenergic receptor downregulation as is seen with many other antidepressants. One of the active metabolites is hydroxybupropion which also has an antidepressant profile in laboratory animals. It is of interest that bupropion is one of the few drugs that reduces REM latency since most other treatments increase it. Although the specific mechanisms of bupropions antidepressant effects are not known, its unique profile has led to its use in the treatment of bipolar disorder (26) as well as its use in the treatment of smoking cessation/27)

Mianserin and mirtazapine both have potent effects on antagonizing a 2-adrenergic auto- and heteroreceptors. (28> They also antagonize other 5-HT receptors but have minimal effects on monoamine uptake or monoamine oxidase activity/29' Since a2 receptors inhibit noradrenaline release, their antagonism leads to an increase in noradrenaline release in many brain areas. In addition, antagonism of a 2-adrenergic heteroreceptors located on serotonergic neurones results in an enhanced 5-HT release. With mirtazapine, since 5-HT2 and 5-HT3 receptors are blocked, this could result in selective enhancement of 5-HT -,-receptor-mediated neurotransmission.

These drugs have low affinity for muscarinic, cholinergic, and dopamine receptors and this is related to a reduced side-effect profile. (3 ,3D The combination of increased noradrenaline release and increased 5-HT release resulting from the a 2-antagonism on auto- and heteroreceptors is hypothesized to be the central mechanism of action.

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