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Most antidepressant drugs prescribed today have been available for decades. Nonetheless, their mechanism of action in treating depression has remained elusive. On the basis of neurochemical studies in laboratory animals, hypotheses explaining their therapeutic effects have been formulated. The most attractive of these theories involves antidepressant-induced changes in the sensitivity of certain catecholamine and serotonergic receptors in the brain. Support for this hypothesis from clinical studies has been difficult to obtain. Pharmacologic studies of antidepressant drugs, however, indicate the involvement of blockade of neuronal uptake systems for norepinephrine and serotonin and blockade of many receptors for neurotransmitters. These properties of antidepressants can explain some of their adverse effects and certain interactions with other drugs.
BACKGROUND
Antidepressants are drugs that have been shown to be effective in treating depression in controlled clinical trials. In general, they are used as adjuncts to other types of therapy for depression, such as brief psychotherapy, supportive therapy, and electroconvulsive therapy. These drugs represent a diverse group of chemical structures, some of which are shown in Figure 1.
Fig. 1Chemical structures of some antidepressant drugs.
Researchers introduced the first antidepressants in the late 1950s to treat this disorder of mood. Today, we have a wealth of knowledge about the pharmacologic and biochemical effects of these drugs; however, their mechanism of action remains speculative. In addition, their efficacy for treating psychiatric disorders other than depression (for example, panic disorder) belies explanation of their therapeutic action as simply mood-elevating drugs.
Depression afflicts about 5% of the adult population in the United States at any given time. About 65 to 70% of patients respond to antidepressant drug therapy and can experience a complete recovery from their depression. Improvement is not immediate. It usually begins about 10 days after initiation of therapy and is complete by about 8 weeks. Electroconvulsive therapy is effective in another 10 to 15% of patients. Therefore, about 20% of depressed patients are resistant to all known forms of therapy. Untreated, depression can lead to death by suicide. During a lifetime, the probability of this type of death is 25 to 30% for persons with untreated depression.
The introduction of antidepressants into the clinical practice of medicine has primarily been by chance. The use of imipramine began early in the 1950s, when chlorpromazine was found to be an effective antipsychotic agent. Researchers then searched for look-alike compounds with which to treat psychosis. Kuhn,
in Switzerland, found that imipramine had antidepressant but no antipsychotic properties.
Around the same time, reports were published of occasional euphoric patients with tuberculosis who had been treated with iproniazid, a monoamine oxidase inhibitor. In addition, pharmaceutical firms were screening monoamine oxidase inhibitors in an animal model of depression. In this model, animals received reserpine, the active ingredient in Rauwolfia serpentina, which causes ptosis in laboratory animals and depression in about 10 to 12% of patients who receive it for treatment of hypertension. The candidate antidepressant was tested in the laboratory for a reversal of the ptosis caused by this ancient drug.
Immediate Presynaptic Effects of Antidepressants.
Taking their cue from the clinical results, Axelrod
showed that imipramine-like drugs blocked the uptake of norepinephrine and serotonin into nerve endings. Thus, these two biogenic amine neurotransmitters were implicated in the pathogenesis of depression and the mode of action of antidepressants.
Other investigators concurrently showed that reserpine depleted brain levels of the biogenic amines norepinephrine, serotonin, and dopamine, whereas monoamine oxidase inhibitors increased their levels by preventing their degradation. Thus, the cornerstones of the so-called biogenic amine hypothesis of affective illness were laid. In the simplest of terms, this theory stated that a deficiency of certain biogenic amines (for example, norepinephrine) at functionally important synapses causes depression, and an excess produces mania.
Neurotransmitters, most of which are stored in vesicles at the nerve ending, are released during neurotransmission (Fig. 2). The propagation of electrical impulses along the nerve to the nerve ending causes an influx of calcium ions. This influx results in the release of the neurotransmitter and the initiation of chemical transmission across the synapse to the next nerve cell. The neurotransmitter diffuses across the synapse to interact with a highly specialized protein, called a receptor, on the outside surface of the postsynaptic cell. Within the cell, a biologic change occurs as a result of a neurotrans-mitter-receptor-effector complex. Examples of effectors are ion channels or an enzyme such as adenylate cyclase. In nerve cells, receptor stimulation often results in an electrical impulse or action potential.
Fig. 2Diagram of components of a synapse. See text for complete discussion.
Neurons regulate their own activity by feedback mechanisms that involve receptors on the nerve ending (autoreceptors). An example of an autoreceptor is the α2-adrenergic receptor on noradrenergic nerve endings. When stimulated, this presynaptic receptor inhibits further release of norepinephrine, an action that regulates the amount of chemical neurotransmitter in the synapse.
Biogenic amine neurotransmitters such as norepinephrine, dopamine, and serotonin are inactivated at the synapse. This result occurs in part by their being taken back into the nerve endings from which they were released.
Antidepressant blockade of the uptake of norepinephrine and serotonin into the presynaptic nerve ending thus potentiates neurotransmission involving these compounds by increasing the levels of free neurotransmitter in the synapse. In recent years, researchers have identified sites of uptake in binding assays with the use of [3H]desipramine
Inhibition of monoamine oxidase in the nerve ending also potentiates neurotransmission at some synapses by preventing degradation of catecholamines and serotonin by this enzyme. Another important effect of antidepressants that occurs shortly after a patient is treated with such a drug is antagonism of many different receptors.
proposed the “permissive hypothesis of affective disorders.” This theory was formulated to accommodate results in the literature that implicated both norepinephrine and serotonin in the action of antidepressants and to explain their own research findings. In a carefully controlled trial,
these researchers showed that l-tryptophan, a precursor of serotonin, reduced mania, the clinical opposite of depression. Other clinical researchers showed that an antidepressant response to a monoamine oxidase inhibitor could be reversed by a drug that depletes brain levels of serotonin (p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin).
Thus, a low level of serotonin “permits” the expression of the affective state that is governed by the level of norepinephrine. A low concentration of norepinephrine causes depression; a high norepinephrine level produces mania. Hypothetically, correcting the low serotonin level will alleviate the affective disease.
Postsynaptic Effects of Antidepressants With Long-Term Treatment.
A perplexing problem about the known effects of antidepressants has been the considerable difference in time course for the effects seen in the laboratory and those seen clinically. Several days elapse before the first clinical effects of antidepressants are evident. In animals and in patients, however, blockade of uptake of neurotransmitters occurs in the brief time needed to achieve sufficient body concentrations of the drug. In the test tube, this inhibition is an almost instantaneous phenomenon.
A possible common mechanism of action of antidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.
presented data that explained this observation. Long-term but not short-term treatment of rats with antidepressant agents caused desensitization (loss of sensitivity) of norepinephrine-stimulated synthesis of cyclic adenosine monophosphate in slices from limbic forebrain of treated animals. β-Adrenoceptor down-regulation, the loss of binding sites for a receptor, accompanies this desensitization for most, but not all, antidepressants. This down-regulation is selective for the β-adrenoceptor.
Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered I-isoproterenol.
Thereafter, researchers changed their focus on the site of action of antidepressants from the presynaptic to the postsynaptic side of the synapse. Nonetheless, this postsynaptic effect of antidepressants clearly resulted from actions at the presynaptic nerve ending. Thus, by removing the presynaptic nerve endings with “lesioning” techniques,
researchers showed that antidepressants lost their postsynaptic effects.
Most antidepressants, from many different chemical classes, can increase the level of catecholamines at postsynaptic receptor sites by inhibiting reuptake or monoamine oxidase degradation of these biogenic amines. This result may also lead to desensitization of the presynaptic autoreceptors and thereby further increase the release of norepinephrine. Increasing the level of an agonist at its receptor site for prolonged periods is the classic mechanism used to desensitize and down-regulate receptors.
Although not all antidepressants have been studied for these long-term postsynaptic effects, most of those that have been tested cause these adaptive changes. In animal studies, many diverse types of antidepressants and electroconvulsive therapy—but not psychiatric drugs of other classes (with the possible exception of the neuroleptic agent chlorpromazine)—cause either desensitization or down-regulation of catecholamine receptors with a clinically appropriate time course.
Thus, these effects suggest an attractive hypothesis for the delayed mechanism of action of antidepressant drugs.
The desensitization hypothesis assumes that certain catecholamine receptors are supersensitive in patients with depression. Antidepressant treatment would return them to a normal level of sensitivity. Clinical studies to show the presence of such supersensitive receptors have not yet yielded data to support this hypothesis.
A possible common mechanism of action of antidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.
more than a decade ago, the hypothesis that antidepressants work by desensitizing certain critical catecholamine receptors in the brain remains in vogue today. Researchers, however, have added certain refinements.
In support of the permissive hypothesis of Prange and associates,
investigators have found that the postsynaptic effects of antidepressants require normal levels of brain serotonin. For example, Janowsky and colleagues
showed that selective lesions of the serotonergic system in rats created by injection of the neurotoxin 5,7-dihydroxy-tryptamine prevent the down-regulation of β-adrenoceptors caused by desipramine.
Studies of whether such chemical lesions also prevented the desensitization of the cyclic adenosine monophosphate response to an agonist, however, yielded conflicting results. Both previously mentioned groups used almost the same experimental paradigms and achieved similar reductions in brain serotonin levels. Nonetheless, Janowsky and associates
A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action of parachlorophenylalanine by 5-hydroxytryptophan.
reproduced their results obtained with the neurotoxin when they depleted serotonin levels with p-chlorophenylalanine. These results have yet to be confirmed in another laboratory.
Adding an interesting detail to all these studies and perhaps explaining some discrepancies in the literature on whether a particular antidepressant can down-regulate β-adrenoceptors are the results reported by Asakura and colleagues.
These workers presented evidence to show that the level of serotonin affects the rate of reversibility of the β-adrenoceptor down-regulation.
When levels of serotonin are normal in rat brain, this down-regulation reverses completely within 24 hours after discontinuing administration of the antidepressant. With high levels of serotonin, no change in the degree of down-regulation is found at this time. Usually, researchers have waited for at least 24 hours before sacrifice of animals to assay β-adrenoceptors. This period provides time for a washout of the administered drug whose presence in the tissue could interfere with the binding assay. For those drugs that do not increase the synaptic levels of serotonin, however, the 24-hour washout period would make it appear as if no down-regulation had occurred.
In other studies, long-term treatment with antidepressants has consistently decreased the number of binding sites for a subtype of serotonin receptors called 5-hydroxytryptamine—serotonin-2(5-HT2).
These changes were found in rat cerebral cortex, as measured in binding studies with [3H]spiperone. In addition, imipramine has decreased [3H]ketanserin binding sites.
5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.
5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.
Enhancement of responsiveness of the central serotonergic system and serotonin-2 receptor density in rat frontal cortex by electroconvulsive treatment.
Thus, evidence for antide-pressant-induced changes in serotonin receptors in the brain is conflicting. In addition, the classic mechanism to explain down-regulation—that is, through increased levels of neurotransmitter—seems not to explain the down-regulation of 5-HT2 receptors.
Down-regulation of serotonin2 but not of beta-adrenergic receptors during chronic treatment with amitriptyline is independent of stimulation of serotonii2 and beta-adrenergic receptors.
In support of some of these results in animals are the reports of increased 5-HT2 and catecholamine receptor binding sites in postmortem brains of persons who committed suicide.
These studies are complicated, however, because they included persons who committed suicide by violent means and would not necessarily have fulfilled the criteria for the diagnosis of depression before death. Indeed, in a study of suicide victims with definite evidence of depression, researchers found no increase in 5-HT2 binding sites.
Pharmaceutical companies are now screening for potential new antidepressant agents by testing drugs for their ability to down-regulate β-adrenoceptors. It is too soon to know whether this is a fruitful approach for discovery of antidepressant agents. These data on adaptive changes in brain receptor systems have generated considerable excitement in the research community. Nonetheless, the clinician responsible for the treatment of depressed patients must continue to await the potential benefits of this research.
In Vitro Studies.
A more practical approach that has an immediate effect on the care of depressed patients relates to the use of some in vitro data on the acute effects of antidepressants. These include blockade of neurotransmitter uptake and antagonism of certain neurotransmitter receptors.
Unlike the previously mentioned research that has as its aim the elucidation of the mechanism of action, this line of research has the objectives of predicting their adverse side effects and determining drug-drug interactions. A more in-depth discussion of the clinical application of these data has recently been published.
Early research on uptake blockade by antidepressants was misinterpreted. Most antidepressants are more potent at blocking uptake of norepinephrine than serotonin
Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.
(Table 1). Newer antidepressants are generally more selective than the older compounds at blocking uptake of one neurotransmitter over another. Some antidepressants—such as bupropion, iprindole, and trimipramine—weakly block uptake of all these neurotransmitters. Bupropion and trimipramine, two effective antidepressants, may not cause desensitization or down-regulation of catecholamine receptors. In general, antidepressants are weak blockers of dopamine uptake and would not enhance dopamine neurotransmission.
Data can be compared both vertically and horizontally to find the most potent drug for a specific property and to find the most potent property of a specific drug. In each column, the highest and lowest numbers are emphasized for the antidepressants.
of Antidepressants at Blockade of Uptake and Some Neurotransmitter Receptors
10−7 × 1/KD, in which KD = equilibrium dissociation in molarity. Data from Richelson and Nelson.8
Drug
NE
5-HT
H1
Muscarinic
5-HT2
D2
Antidepressants
Amitriptyline
4.2
1.5
91
5.5
3.4
0.10
Amoxapine
23
0.21
4.0
0.1
170
0.62
Bupropion
0.043
0.0064
0.015
0.0021
0.0011
0.00048
Desipramine
110
0.29
0.91
0.50
0.36
0.030
Doxepin
5.3
0.36
420
1.2
4.0
0.042
Fluoxetine
0.36
8.3
0.016
0.050
0.48
0.015e
Imipramin
7.7
2.4
9.1
1.1
1.2
0.050
Maprotiline
14
0.030
50
0.18
0.83
0.28
Nortriptyline
25
0.38
10
0.67
2.3
0.083
Protriptyline
100
0.36
4.0
4.0
1.5
0.043
Trazodone
0.020
0.53
0.28
0.00031
13
0.026
Trimipramine
0.20
0.040
370
1.7
3.1
0.56
Reference compounds
d-Amphetamine
2.0
…
…
…
…
…
Diphenhydramine
…
…
7.1
…
…
…
Atropine
…
…
…
42
…
…
Methysergide
…
…
…
…
15
…
Haloperidol
…
…
…
…
…
26
* Data can be compared both vertically and horizontally to find the most potent drug for a specific property and to find the most potent property of a specific drug. In each column, the highest and lowest numbers are emphasized for the antidepressants.
† D2 = dopamine; H1 = histamine; 5-HT and 5-HT2 = 5-hydroxytryptamine (serotonin-1 and serotonin-2); NE = norepinephrine.
‡ 10−7 × 1/Ki, in which Ki = inhibitor constant in molarity. Data from Richelson and Pfenning.
Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.
Selectivity cannot be equated with potency because selectivity is derived from a ratio of potencies. For example, although maprotiline is more selective (that is, more specific) at blocking uptake of norepinephrine than is desipramine, it is much less potent than desipramine at this blockade (Table 1).
No strict dichotomy exists between tertiary amine tricyclic antidepressants (for example, amitriptyline and imipramine) and secondary amine compounds (for example, desipramine and protriptyline) in their selectivity for blockade of catecholamine uptake. All tertiary amine tricyclic compounds except trimipramine are reasonably potent at blocking uptake of norepinephrine (Table 1). Some secondary amine compounds are more potent than tertiary amine compounds at blocking uptake of serotonin (Table 1).
Neurotransmitter Receptor Blockade.
On the basis of radioligand binding studies with animal
brain tissue, researchers have determined that antidepressant agents are antagonists of many different receptors. Some of these data for a series of antidepressants and human brain receptors are presented in Table 1.
In general, the most potent interaction of antidepressants is at the histamine H1 receptor (Table 1). Their next most potent effect is at the muscarinic receptor. It is important to recognize that of all the known pharmacologic effects of antidepressants, including blockade of uptake of biogenic amines, histamine H1-receptor blockade is their most potent effect. Monoamine oxidase inhibitors have weak effects on these two receptors and are almost devoid of clinically significant pharmacologic activity on them.
Some antidepressants are exceedingly potent histamine Hx antagonists (Table 1). Therefore, clinicians are using them to treat allergic and dermatologie problems.
Histamine is a putative neurotransmitter in the brain. At least two types of histamine receptors are present in the brain, as elsewhere in the body: histamine H1 and histamine H2. Recently, Schwartz,
in Paris, identified a third histamine receptor (H3) in the brain that affects the presynaptic release of histamine. Outside the nervous system, classically, histamine Hx receptors are involved with allergic reactions, and histamine H2 receptors are involved with secretion of gastric acid. In the brain, histamine H1 receptors likely are involved with arousal and appetite. The actions of antidepressants at histamine receptors do not account for their antidepressant effects.
Muscarinic acetylcholine receptors are the predominant type of cholinergic receptors in the brain. In that organ, they may be involved with memory and learning.
Antidepressants have a broad range of affinities for human brain muscarinic receptors (Table 1).
At the α1-adrenoceptor, the most potent compounds, although somewhat weaker than the antihypertensive drug phentolamine, are likely to have clinical effects at this receptor. In general, antidepressants are weak at blocking the o^-adrenoceptor of human brain (Table 1).
Antidepressants are also weak competitive antagonists of dopamine (D2) receptors (Table l).
The most potent compound, amoxapine, is a demethylated derivative of the neuroleptic agent loxapine. Most likely, this in vitro activity of amoxapine explains its extrapyramidal side effects
Because of this dopamine receptor blocking property of amoxapine, some clinicians are prescribing this drug for patients who have psychotic depressions.
Some antidepressants are potent at blocking 5-HT2 receptors relative to methysergide, a drug sometimes used to treat migraine headaches prophylactically (Table 1). Most are weak at blocking other subclasses of the serotonin receptors. Studies in animals have shown that antidepressants have no effects on opiate, benzodiazepine, or γ-aminobutyric acid receptors.
Long-term treatment of laboratory animals with antidepressants causes adaptation of brain neurotransmitter receptors. From this research comes the elegant hypothesis that supersensitivity of catecholamine receptors in the presence of low levels of serotonin is the biochemical basis of depression.
This thesis, however, lacks supportive clinical evidence despite many years of experimentation. Its validation likely will continue to be difficult. Evidence may be derived from imaging studies of brain receptors in depressed patients before and after treatment with medication or electroconvulsive therapy. Other approaches include discovering new chemical entities that cause more rapid down-regulation of β-adreno-ceptors and testing them clinically to determine whether they alleviate depression more rapidly than other drugs.
Nonetheless, the vast amount of data about the immediate pharmacologic effects of antidepressants is useful. As a reasonable first approximation, one can ascribe certain adverse effects of antidepressants and some of their interactions with other drugs to their properties of uptake and receptor blockade. Some examples as they pertain to the properties listed in Table 1 are presented in Table 2.
Table 2Possible Clinical Consequences of Some Pharmacologic Properties of Antidepressants
Property
Possible consequences
Blockade of norepinephrine uptake at nerve endings
Alleviation of depression
Tremors
Tachycardia
Erectile and ejaculatory dysfunction
Blockade of the antihypertensive effects of guanethidine (Ismelin and Esimil) and guanadrel (Hylorel)
Augmentation of pressor effects of sympathomimetic amines
The more potent compounds are more likely than the weaker compounds to cause these problems. The newer antidepressants (for example, bupropion and fluoxetine) are generally weaker at blocking neurotransmitter receptors and much less frequently cause the adverse effects evident with the older compounds, especially the tricyclic antidepressants (for example, amitriptyline and doxepin).
A possible common mechanism of action of antidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.
Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered I-isoproterenol.
A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action of parachlorophenylalanine by 5-hydroxytryptophan.
5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.
Enhancement of responsiveness of the central serotonergic system and serotonin-2 receptor density in rat frontal cortex by electroconvulsive treatment.
Down-regulation of serotonin2 but not of beta-adrenergic receptors during chronic treatment with amitriptyline is independent of stimulation of serotonii2 and beta-adrenergic receptors.
Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.
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