Antidepressants
Zubin Bhagwagar
George R. Heninger
Introduction
Major depressive disorder is a serious, recurrent illness which levies a crippling toll on individuals, families, and society in general. The importance of depression as a major public health problem is emphasized by findings from the World Health Organization Global Burden of Disease survey in showing that in 1990 it was the fourth largest cause of burden of disease (i.e. years of life lost due either to premature mortality or to years lived with a disability). It has been estimated that by the year 2020 it is expected to be the second largest cause of burden of disease.(1) Depression is underdiagnosed and frequently under-treated, and depressed individuals have a much higher risk for suicide. The primary treatment for depression involves the use of antidepressant drugs, and it is therefore important that clinicians become familiar with and adept in utilizing this important group of compounds. Although primarily used for the treatment of depression, drugs within this category also have a number of other important uses. A thorough understanding of the pharmacology of antidepressants will aid the clinician in the selective use of these drugs for patients with depression as well as patients with a number of other disorders.
A brief history of antidepressant discovery and theories of action
Table 6.2.3.1 gives a brief chronology of antidepressant drug discoveries and theories of drug action. It is a comment on our understanding of the illness that some of the major advances in the pharmacotherapy of depression have been serendipitous. 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 6.2.3.1 History of discovery of antidepressants and pharmacological theories of antidepressant drug action | ||||||||||||||||||||||||||||||||||||
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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.(6,7) Ten years later, it was reported that in laboratory animals most antidepressant treatments lead to downregulation of β-adrenergic receptors. This supported the proposal that antidepressants act by reducing β-adrenergic receptor sensitivity.(8) However, the reduction in β-adrenergic receptor sensitivity occurred within hours and antidepressant effect requires 1 to 3 weeks and futher not all effective antidepressant treatments produce reductions in β-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.(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 N-methyl-d-aspartate (NMDA) receptor.(11) A subsequent study showed that an NMDA antagonist may have antidepressant actions(12)and this line of thought has borne fruit recently in a possible novel mechanism of action for antidepressant treatment. 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. It was found that antidepressants produce an overall improvement of inhibitory feedback on the hypothalamicpituitary-adrenal axis(13) and that specific corticotrophin releasing hormone (CRH) antagonists have antidepressant properties.(14)
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.(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 N-methyl-d-aspartate (NMDA) receptor.(11) A subsequent study showed that an NMDA antagonist may have antidepressant actions(12)and this line of thought has borne fruit recently in a possible novel mechanism of action for antidepressant treatment. 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. It was found that antidepressants produce an overall improvement of inhibitory feedback on the hypothalamicpituitary-adrenal axis(13) and that specific corticotrophin releasing hormone (CRH) antagonists have antidepressant properties.(14)
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 β-adrenergic receptor downregulation, continue to produce sustained activation of the cAMP system and that this is related to increases of neurotrophic factors in brain.(15) Neurotrophins reverse the effects of stress in some brain areas and this raise 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).(16) Similarly, while there was intense interest in a report of possible antidepressant efficacy of a substance P receptor antagonist,(17) which does not interact with monoamine systems, clinical trials for this specific compound were disappointing.
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. While clinical wisdom and data suggest that there is a lag of 7-21 days to antidepressant action, recent reports question this notion of delayed onset of efficacy.(18) Recently ketamine, an NMDA antagonist has been shown to have an onset of action much faster than that traditionally seen with conventional antidepressants(19,20) suggesting that the pursuit of novel mechanisms may indeed result in advances in the pharmacotherapy of depression. Using preclinical models, it has been suggested that both nonselective NMDA antagonists as well as NR2B selective antagonists exert their antidepressant effects by regulating the functional interplay between AMPA and NMDA throughput.(21)
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 Tables 6.2.3.2, 6.2.3.3, and 6.2.3.4 based on the presumed primary action that leads to an antidepressant effect. Table 6.2.3.2 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 6.2.3.3 lists the drugs that inhibit monoamine oxidase and thereby increase the concentration of many amines in brain. Table 6.2.3.4 lists the drugs with other primary actions that do not primarily involve inhibition of monoamine uptake or monoamine oxidase inhibition.
In Table 6.2.3.2, the first 12 compounds are inhibitors of noradrenaline uptake with a variable potency of inhibiting 5-HT uptake. The drugs with secondary amine structures, desipramine, nortriptyline, protriptyline, amoxapine, and maprotiline are predominantly noradrenaline uptake inhibitors with little effect on 5-HT uptake.(22) It can be seen in Table 6.2.3.2 that clomipramine, in addition to inhibiting noradrenaline uptake, is also a strong 5-HT uptake inhibitor. There are currently three selective serotonin and noradrenaline reuptake inhibitor (SNRI) drugs available; milnacipran (not licensed in the US), venlafaxine and duloxetine. Venlafaxine, inhibits both 5-HT and noradrenaline and 5-HT reuptake,(23) as do milnacipran and duloxetine though in varying proportions. While affinities vary depending on the system studied, milnacipran blocks 5-HT and norepinephrine reuptake with relatively equal affinity, while duloxetine has been suggested to have a slightly greater selectivity for 5-HT and venlafaxine a much greater selectivity for 5-HT.(24) Reboxetine (not licensed in the US) is a highly selective and potent inhibitor of noradrenaline reuptake.(25) It has only a weak effect on the 5-HT reuptake and does not affect the uptake of dopamine.
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 α1-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(23) (see Table 6.2.3.6).
SSRIs are probably the most widely prescribed antidepressants and represent a class of drugs that selectively inhibit 5-HT reuptake from the synapse. Unlike the tricyclics, they each have different chemical structures. The drugs listed in Table 6.2.3.2 have a relatively specific effect in inhibiting 5-HT uptake,(22) 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. Escitalopram was introduced following the discovery that all of the inhibitory activity of citalopram on 5-HT reuptake resides in the S-(+)-enantiomer (S-citalopram),(26) with S-citalopram being 167 times more potent than R-citalopram at inhibiting 5-HT reuptake into rat brain synaptosomes.
MAOIs are listed in Table 6.2.3.3. Two isozymes, 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 β-adrenergic receptor downregulation and other receptor changes are secondary to the increased amine levels.(27)
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 β-adrenergic receptor downregulation and other receptor changes are secondary to the increased amine levels.(27)
Table 6.2.3.2 Pharmacological actions of antidepressants: drugs that inhibit monoamine reuptake at the synapse | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Four of the six drugs listed in Table 6.2.3.3 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 amfetamine 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.
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 amfetamine 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.
Table 6.2.3.3 Pharmacological actions of antidepressants: drugs that inhibit monoamine oxidase | |||||||||||||||||||||||||||||||||||||||||||||
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Table 6.2.3.4 Pharmacological actions of antidepressants: drugs that do not act by strong inhibition of monoamine uptake or inhibition of monoamine oxidase | ||||||||||||||||||
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Selegiline, which has recently become available as a transdermal patch,(28) is selective at lower doses for monoamine oxidase B but at higher doses it becomes non-selective.(29) It has been primarily used for the treatment of Parkinson’s disease and the doses for treating depression need to be much higher (note: selegiline is not licensed in the UK for depression). 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 6.2.3.4, 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 (mCPP) is a potent direct serotonin agonist. It is a weak but relatively selective inhibitor of 5-HT reuptake, is an antagonist at 5-HT1A and 5-HT2 receptors in addition to its active metabolite mCPP being a potent 5-HT agonist.(30) 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. Trazodone is virtually 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 α1-adrenergic receptors and histamine receptors.
Nefazodone is an analogue of trazodone that was developed to overcome the orthostatic hypotension and sedation caused by the latter. Like trazodone it is a 5-HT receptor antagonist with weak monoamine uptake inhibition activity.(31) It has less affinity for the α-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. Bupropion resulted from focussed research to find antidepressant compounds that would have fewer side-effects than traditional tricyclics (note: buproprion is not licensed in the UK for depression).
Bupropion is a mild inhibitor of noradrenaline uptake, has some effects on inhibiting dopamine uptake but has no effect on 5-HT uptake.(32) These effects are not associated with β-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 reduce 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(33) as well as its use in the treatment of smoking cessation.(34)
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