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Antidepressants and Brain Neurochemistry

  • Author Footnotes
    * Mayo Clinic Jacksonville, Jacksonville, Florida.
    ELLIOTT RICHELSON
    Correspondence
    Address reprint requests to Dr. Elliott Richelson, Department of Pharmacology, Mayo Clinic Jacksonville, Jacksonville, FL 32224
    Footnotes
    * Mayo Clinic Jacksonville, Jacksonville, Florida.
    Affiliations
    Departments of Psychiatry and Pharmacology
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  • Author Footnotes
    * Mayo Clinic Jacksonville, Jacksonville, Florida.
      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.
      Figure thumbnail gr1
      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,
      • Kuhn R
      The treatment of depressive states with G 22355 (imipramine hydrochloride).
      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
      • Axelrod J
      Noradrenaline: fate and control of its biosynthesis.
      and others
      • Alpers HS
      • Himwich HE
      An in vitro study of effects of tricyclic antidepressant drugs on the accumulation of C14-serotonin by rabbit brain.
      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.
      • Maas JW
      Biogenic amines and depression: biochemical and pharmacological separation of two types of depression.
      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.
      Figure thumbnail gr2
      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.
      • Axelrod J
      Noradrenaline: fate and control of its biosynthesis.
      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
      • Lee C-M
      • Snyder SH
      Norepinephrine neuronal uptake binding sites in rat brain membranes labeled with [3H]desipramine.
      and [3H]imipramine,
      • Langer SZ
      The imipramine binding site in depression.
      respectively.
      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.
      • Hall H
      • Ögren S-O
      Effects of antidepressant drugs on different receptors in the brain.
      • Richelson E
      • Nelson A
      Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
      • Wander TJ
      • Nelson A
      • Okazaki H
      • Richelson E
      Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro.
      This antagonism can lead to a reduction in transmission for certain neurotransmitter systems.
      In the early 1970s, Prange and co-workers
      • Prange AJ
      • Wilson IC
      • Lynn CW
      • Alltop LB
      • Stikeleather RA
      L-Tryptophan in mania: contribution to a permissive hypothesis of affective disorders.
      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,
      • Prange AJ
      • Wilson IC
      • Lynn CW
      • Alltop LB
      • Stikeleather RA
      L-Tryptophan in mania: contribution to a permissive hypothesis of affective disorders.
      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).
      • Shopsin B
      • Friedman E
      • Gershon S
      Parachlorophe-nylalanine reversal of tranylcypromine effects in depressed patients.
      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.
      In 1976, Vetulani, Sulser, and associates
      • Vetulani J
      • Stawarz RJ
      • Dingell JV
      • Sulser F
      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.
      • Minneman KP
      • Dibner MD
      • Wolfe BB
      • Molinoff PB
      ß1- and ß2-adrenergic receptors in rat cerebral cortex are independently regulated.
      • Ordway GA
      • Gambarana C
      • Frazer A
      Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered I-isoproterenol.
      • Heal DJ
      • Butler SA
      • Hurst EM
      • Buckett WR
      Antidepressant treatments, including sibutramine hydrochloride and electroconvulsive shock, decrease ß1 but not ß2-adrenoceptors in rat cortex.
      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,
      • Wolfe BB
      • Harden TK
      • Sporn JR
      • Molinoff PB
      Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants.
      • Janowsky A
      • Steranka LR
      • Gillespie DD
      • Sulser F
      Role of neuronal signal input in the down-regulation of central noradrenergic receptor function by antidepressant drugs.
      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.
      • Sulser F
      Mode of action of antidepressant drugs.
      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.
      • Heninger GR
      • Charney DS
      • Price LH
      α2-Adrenergic receptor sensitivity in depression: the plasma MHPG, behavioral, and cardiovascular responses to yohimbine.
      In addition, β-adrenoceptor blockers that reduce neurotransmission at these receptors can cause depression in some patients.
      • Pollack MH
      • Rosenbaum JF
      • Cassem NH
      Propranolol and depression revisited: three cases and a review.
      Recently, however, the theory that β-blockers cause depression was challenged.
      • Carney RM
      • Rich MW
      • teVelde A
      • Saini J
      • Clark K
      • Freedland KE
      Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications.

      CURRENT STATUS

      Animal Studies.

      Although first presented by Vetulani, Sulser, and colleagues
      • Vetulani J
      • Stawarz RJ
      • Dingell JV
      • Sulser F
      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,
      • Prange AJ
      • Wilson IC
      • Lynn CW
      • Alltop LB
      • Stikeleather RA
      L-Tryptophan in mania: contribution to a permissive hypothesis of affective disorders.
      investigators have found that the postsynaptic effects of antidepressants require normal levels of brain serotonin. For example, Janowsky and colleagues
      • Janowsky A
      • Okada F
      • Manier DH
      • Applegate CD
      Role of serotonergic input in the regulation of the ß-adrenergic receptor-coupled adenylate cyclase system.
      and Brunello and co-workers
      • Brunello N
      • Barbaccia ML
      • Chuang D-M
      • Costa E
      Down-regulation of ß-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons.
      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
      • Janowsky A
      • Steranka LR
      • Gillespie DD
      • Sulser F
      Role of neuronal signal input in the down-regulation of central noradrenergic receptor function by antidepressant drugs.
      found that such lesions did not prevent the desensitization by desipramine, whereas Brunello and colleagues
      • Brunello N
      • Barbaccia ML
      • Chuang D-M
      • Costa E
      Down-regulation of ß-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons.
      found that they did. A difference in experimental design might explain this discrepancy: Janowsky and co-workers
      • Janowsky A
      • Steranka LR
      • Gillespie DD
      • Sulser F
      Role of neuronal signal input in the down-regulation of central noradrenergic receptor function by antidepressant drugs.
      used tissue slices for their cyclic adenosine monophosphate studies, and Brunello and associates
      • Brunello N
      • Barbaccia ML
      • Chuang D-M
      • Costa E
      Down-regulation of ß-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons.
      used membranal preparations. In a follow-up study, Sulser's group
      • Manier DH
      • Gillespie DD
      • Steranka LR
      • Sulser F
      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.
      • Asakura M
      • Tsukamoto T
      • Kubota H
      • Imafuku J
      • Ino M
      • Nishizaki J
      • Sato A
      • Shinbo K
      • Hasegawa K
      Role of serotonin in the regulation of ß-adrenoceptors by antidepressants.
      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).
      • Snyder SH
      • Peroutka SJ
      A possible role of serotonin receptors in antidepressant drug action.
      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.
      • Kendall DA
      • Nahorski SR
      5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.
      Neuroleptics, however, also cause 5-HT2 receptor down-regulation.
      • Andree TH
      • Mikuni M
      • Tong CY
      • Koenig JI
      • Meltzer HY
      Differential effect of subchronic treatment with various neuroleptic agents on serotonin receptors in rat cerebral cortex.
      The effect of imipramine on serotonin-mediated inositol phospholipid hydrolysis in rat cerebral cortical slices has been inconsistent.
      • Kendall DA
      • Nahorski SR
      5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.
      • Butler PD
      • Barkai AI
      Agonist-stimulation of cerebral phosphoinositide turnover following long-term treatment with antidepressants.
      In addition, electroconvulsive therapy has consistently increased the density of 5-HT2 receptor sites.
      • Kellar KJ
      • Cascio CS
      • Butler JA
      • Kurtzke RN
      Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain.
      • Vetulani J
      • Lebrecht U
      • Pile A
      Enhancement of responsiveness of the central serotonergic system and serotonin-2 receptor density in rat frontal cortex by electroconvulsive treatment.
      Electrophysiologic studies involving long-term treatment with antidepressant agents also show increased sensitivity of serotonin receptors.
      • De Montigny C
      • Aghajanian GK
      Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin.
      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.
      • Dumbrille-Ross A
      • Tang SW
      • Coscina DV
      Lack of effect of raphe lesions on serotonin S2 receptor changes induced by amitriptyline and desmethylimipramine.
      • Scott JA
      • Crews FT
      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.
      • Mann JJ
      • Stanley M
      • McBride A
      • McEwen BS
      Increased serotonin2 and ß-adrenergic receptor binding in the frontal cortices of suicide victims.
      • Biegon A
      • Israeli M
      Regionally selective increases in ß-adrenergic receptor density in the brains of suicide victims.
      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.
      • Cheetham SC
      • Crompton MR
      • Katona CLE
      • Horton RW
      Brain 5-HT2 receptor binding sites in depressed suicide victims.
      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.
      • Richelson E
      • Nelson A
      Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
      • Wander TJ
      • Nelson A
      • Okazaki H
      • Richelson E
      Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro.
      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.
      • Richelson E
      Antidepressants: pharmacology and clinical use.

      Uptake Blockade.

      Early research on uptake blockade by antidepressants was misinterpreted. Most antidepressants are more potent at blocking uptake of norepinephrine than serotonin
      • Richelson E
      • Pfenning M
      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.
      Table 1Potencies
      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
      D2 = dopamine; H1 = histamine; 5-HT and 5-HT2 = 5-hydroxytryptamine (serotonin-1 and serotonin-2); NE = norepinephrine.
      Uptake blockade
      10−7 × 1/Ki, in which Ki = inhibitor constant in molarity. Data from Richelson and Pfenning.39
      Neurotransmitter receptor blocke
      10−7 × 1/KD, in which KD = equilibrium dissociation in molarity. Data from Richelson and Nelson.8
      DrugNE5-HTH1Muscarinic5-HT2D2
      Antidepressants
       Amitriptyline4.21.5915.53.40.10
       Amoxapine230.214.00.11700.62
       Bupropion0.0430.00640.0150.00210.00110.00048
       Desipramine1100.290.910.500.360.030
       Doxepin5.30.364201.24.00.042
       Fluoxetine0.368.30.0160.0500.480.015e
       Imipramin7.72.49.11.11.20.050
       Maprotiline140.030500.180.830.28
       Nortriptyline250.38100.672.30.083
       Protriptyline1000.364.04.01.50.043
       Trazodone0.0200.530.280.00031130.026
       Trimipramine0.200.0403701.73.10.56
      Reference compounds
      d-Amphetamine2.0
       Diphenhydramine7.1
       Atropine42
       Methysergide15
       Haloperidol26
      * 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.
      • Richelson E
      • Pfenning M
      Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.
      § 10−7 × 1/KD, in which KD = equilibrium dissociation in molarity. Data from Richelson and Nelson.
      • Richelson E
      • Nelson A
      Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
      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
      • Hall H
      • Ögren S-O
      Effects of antidepressant drugs on different receptors in the brain.
      and human
      • Richelson E
      • Nelson A
      Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
      • Wander TJ
      • Nelson A
      • Okazaki H
      • Richelson E
      Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro.
      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.
      • Richelson E
      Tricyclic antidepressants: therapy for ulcer and other novel uses.
      • Greene SL
      • Reed CE
      • Schroeter AL
      Double-blind crossover study comparing doxepin with diphenhydramine for treatment of chronic urticaria.
      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,
      • Schwartz J-C
      Histamine receptors in brain.
      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.
      • Bartus RT
      • Dean III, RL
      • Beer B
      • Lippa AS
      The cholinergic hypothesis of geriatric memory dysfunction.
      In addition, evidence suggests that these brain receptors are involved with disorders of mood, such as depression and mania.
      • Janowsky DS
      • El-Yousef MK
      • Davis JM
      • Sekerke HJ
      A cholinergic-adrenergic hypothesis of mania and depression.
      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).
      • Richelson E
      • Nelson A
      Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
      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
      • Steele TE
      Adverse reactions suggesting amoxapine-induced dopamine blockade.
      and its ability to increase prolactin levels in patients.
      • Cooper DS
      • Gelenberg AJ
      • Wojcik JC
      • Saxe VC
      • Ridgway EC
      • Maloof F
      The effect of amoxapine and imipramine on serum prolactin levels.
      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.
      • Hall H
      • Ögren S-O
      Effects of antidepressant drugs on different receptors in the brain.

      FUTURE DIRECTIONS

      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
      PropertyPossible consequences
      Blockade of norepinephrine uptake at nerve endingsAlleviation 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
      Blockade of serotonin uptake at nerve endingsAlleviation of depression
      Gastrointestinal disturbances
      Anxiety
      Blockade of histamine H1 receptorsPotentiation of central depressant drugs
      Sedation drowsiness
      Weight gain
      Hypotension
      Blockade of muscarinic receptorsBlurred vision
      Dry mouth
      Sinus tachycardia
      Constipation
      Urinary retention
      Memory dysfunction
      Blockade of serotonin 5-HT2 receptors
      5-HT2 = 5-hydroxytryptamine (serotonin-2).
      Hypotension
      Prevention of migraine headaches
      Blockade of dopamine D2 receptorsExtrapyramidal movement disorders
      Endocrine changes
      * 5-HT2 = 5-hydroxytryptamine (serotonin-2).
      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).
      • Hayes PE
      • Kristoff CA
      Adverse reactions to five new antidepressants.
      • Cooper GL
      The safety of fluoxetine—an update.
      In practice, this information gives the clinician the best rationale for the choice of antidepressant.

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