Pharmacotherapy of depression: a historical analysis*

T. A. Ban


Summary. Iproniazid and imipramine, the prototypes of monoamine oxidase inhibitor (MAOI) and monoamine (re)uptake inhibitor (MAUI) antidepressants, were introduced in 1957. The relationship between iproniazid’s antidepressant effect and its MAO inhibiting property was tenuous. Because of the potential drug-drug interactions and the need of dietary restrictions, the use of MAOIs became restricted to atypical depression. The confounding of reserpine reversal with antidepressant effect led of the theory that MAU inhibition is responsible for imipramine’s antidepressant effect. Driven by neuropharmacological theory, non-selective reuptake inhibitors were replaced first by selective norepinephrine reuptake inhibitors, then by selective serotonin reuptake inhibitors, and more recently, by a series of new antidepressants to relieve the stimulation of seorotonin-5HT2A receptors and the compensatory decline of dopamine in the brain. Each antidepressant has its own identity, but meta-analyses indicate a widening of the antidepressant response range from 65-70% to 45-79% and a lowering of the antidepressant threshold from 65% to 45%. Although one can no longer expect that two of three depressed patients will respond to treatment, the newer antidepressants are better tolerated because they produce less anticholinergic side effects.

Keywords: Depression, pharmacotherapy, opium, monoamine oxidase inhibitors, monoamine reuptake inhibitors, selective serotonin reuptake inhibitors.



Poppy, “papaver somniforum” as the plant would be referred to today, was given to mankind by the goddess Ceres. It had been used for thousands of years to relieve “pain” and “sorrow” before any attempt to find out what was responsible for its “soothing effect.”

            In early 16th century, Paracelsus prepared an elixir (“Arcanum”), he referred to as “Laudanum,” that contained the active ingredient of the plant. About 200 years later, in the mid-18th century, Albrecht von Haller recognized that opium was responsible for poppy’s analgesic and antidepressant effects (Garrison, 1960).


Opium in the treatment of depression

Opium (tincture) was introduced into the treatment of depression at the end of the 19th century by Emil Kraepelin. Its use was endorsed by Eugen Bleuler. An “Opium cure,” was a three-week procedure during which the dose of the substance was raised by daily increments from 3 to 25 minims, then decreased gradually until discontinued (Nyiro, 1962). There is no documentation about the efficacy of this treatment. It has been estimated that about 50% of the patients were discharged home from the hospital at the time or soon after completion.

            The most frequently employed alternative treatments were dinitrile succinate (Gillis and Salfield, 1953), hematoporphyrin, a photosensitizing substance (Stenberg, 1936; Bruel, 1957). Another less frequently employed alternative was reserpine, a frequently used antihypertensive in those years in low doses (Ban, 1969). It has been noted that it could alleviate anxiety and depression in the treatment of “neurosis” (Davies and Shepherd, 1955) and precipitate depression in the treatment of hypertension (Lewis, 1971). In the mid 1950s chlorpromazine was introduced into the treatment of agitated delusional and involutional depression. For many years, neuroleptics with high central anticholinergic properties, such as thioridazine (Overall, Hollister, Johnson et al., 1966) and levomepromazine (Ban and Schwars, 1963), remained the primary pharmacological treatments of depression with psychotic features.

            With the introduction of Iproniazid (Loomers, Saunders and Kline, 1957), a hydrazine, and imipramine (Khun, 1957) an iminodibenzyl (dibenzazepine), in 1957 the use of opium and its alternatives was promptly abandoned. Ipronazid and imipramine were to become the prototypes of the two major classes of antidepressants, the monoamine oxidase inhibitors (MAOIs) and the monoamine (re)uptake inhibitors (MAUIs).


Monoamine oxidase inhibitors

The origin of hydrazines, the first structurally distinct group of MAOI antidepressants, is in Emil Fischer’s research in the mid-1870s (Garrison, 1960). Isoniazid was derived from hydrazine hydrate, a powerful reducing agent in 1912 (Berger and Barchas, 1977). Iproniazid, the isopropyl derivative of isoniazid, was synthesized Herbet Fox at Roche Laboratories in 1951 (Fox and Givas, 1953). Both drugs were introduced first as tuberculostatic agents found to induce hyperactivity and euphoria in some tubercular patients (Selikoff, Robitzek and Orenstein, 1952; Flashery, 1952).

            Ipronazid’s monoamine oxidase (MAO) inhibiting effect was detected by Zeller and his associates in 1952 (Zeller, Barsky, Fouts et al., 1952). MAO is the enzyme responsible for the oxidative deamination of monoamines implicated in synaptic events. Oxidative deamination was first described in 1929 by Bernheim (Berger and Barchas, 1977). The enzyme, which was to become known as monoamine oxidase – after distinguished from diamine oxidase in 1938 (Zeller, 1938) – was identified in 1937 by Pugh and Quastel (1937) and also by Blaschko, Richter and Scholassman (1937).

Cerebral monoamines are derived by hydroxylation and decarboxylation from essential amino acids. The origin of norepinephrine (NE) is in phenylalanine and of serotonin (5-HT) in tryptophan. NE and 5-HT, stored preferentially in the granules of nerve endings, become activated on release and inactivated by oxidative deamination and neuronal reuptake.

Employment of the spectrophotofluorimeter in the mid 1950s rendered accessible the detection of changes in cerebral monoamine levels for direct investigations. By measuring their turnover rate, it was revealed that administration of reserpine decreased, whereas administration of Iproniazid increased brain 5-HT (Besendorf and Pletscher, 1956) and NE (Carlsson, 1998). Considering the euphoria (elation) encountered in some tubercular patients in the course of treatment with Iproniazid, and the depression in some hypertensive patients in the course of treatment with reserpine (Holister, 1998), the possibility was raised that MAO inhibition, and the resulting increase of 5-HT and NE in the brain, was responsible for Iproniazid’s mood lifting (antidepressant) effect. Supportive of the relationship between MAO inhibition and antidepressant effects are reports on the effectiveness of Iproniazid in the treatment of depression (Loomers, Saunders and Kline, 1957; Crane, 1957). In variance of the relationship are reports on the antidepressant effect of isoniazid, a substance which has no MAO inhibiting property (Delay, Laine and Buisson, 1952; Salzier and Luric, 1953). In view of these and other conflicting findings Burger (1977) maintains that it remains “a matter of speculation whether MAO inhibition, resulting in a rise of catecholamines and 5-HT, is responsible for the antidepressant properties of MAOIs.” According to him, one cannot ignore the possibility “that the inhibition of MAO, which has been the guiding factor in the development of many early antidepressants, may have been no more than a fortuitous ‘lead’ and that actually inhibition of MAO may be a side effect rather than an intrinsic property of MAOI antidepressants.”

Despite the tenuous evidence that MAO inhibition is responsible for iproniazid’s antidepressant effect, a series of MAOI antidepressants were introduced. Included among them were five hydrazine (isocarboxazid, nialamide, mebanazine, phenelzine and pheniprazine) structurally related to Iproniazid, one cyclopropylamine (tranylcypromine), structurally related to the amphetamines, and one indole (entryptamine).

For a short period of time it appeared that MAOIs would become the prevailing treatment modality of depression (Rees, 1960). By the mid-1960s however, the situation changed. Just as rapidly as their ascent, the use of MAOIs fell out of grace. First Iproniazid then pheniprazine had to be withdrawn because of hepatotoxicity, and after the introduction of tranylcypromine the frequent incidence of hypertensive crises, i.e., tyramine cheese reactions, focused attention on potential drug-drug interactions and the need for dietary restrictions in the course of treatment. The use of MAOIs became gradually restricted to atypical depression (Ban, 19811; Sargant, 1961; West and Dally 1959).

The decent of MAOIs could not be reversed by the development of selective and reversible inhibitors of the Type A (Youdim, 1967) and Type B (Knoll, 1988) isoenzymes. Because of a lack of interest in these drugs, from the 18 MAOI antidepressants listed in Poldinger and Wider’s Index Psychopharmacorum in 1990 (Poldinger and Wider, 1990), only three, phenelzine, a nonselective hydrazine, tranylcypromine, a nonselective phenylcyclopropylamine and moclobemide, a selective type A inhibitor with a benzamide structure, are available in Canada for clinical use (CPS, 2000). As of date none of the selective inhibitors have become available on prescription in the USA.


Monoamine reuptake inhibitors

Imipramine, the prototype of MAUI antidepressants, is the chlorpromazine analogue of dibenzazepines (iminodibenzyls), a structure synthesized by Thiele and Holzinger in 1899 (Ban, 199a). It was one of the 42 substances selected in the mid 1950s from Geigys’s chemical library in the search to find promethazine-like antihistaminic or chlorpromazine-like tranquilizing drugs (Healy, 1997)

            Roland Kuhn (1957) was first to report on the therapeutic effect of imipramine in depression. It took approximately eight years from the time of his first report in 1957 that Klerman and Cole (1965) succeeded to demonstrate that imipramine is significantly superior to an inactive placebo in the treatment of depression.

            Their report was based on a pooled analysis of data from 23 published studies with a total of 1,009 patients treated with imipramine (550 patients) or administered placebo (459 patients). The evidence for imipramine’s antidepressant effect was derived from the comparison of the 6% improvement rate with imipramine and the 31% improvement rate with placebo. A 65% response rate with imipramine implies that one can expect that two out of three patients included in a study will improve; and 31% placebo response rate in the imipramine studies indicates that in one of the patients who improve, the improvement can be attributed to treatment with the drug. Similar response rates to Klerman and Cole’s (1965) were reported also by Klein and Davis in 1969 (Klein and Davis, 1969), and Angst in 1970 (Angst, 1970).

            Early research with imipramine brought to attention the multiple pharmacological actions of the drug, i.e., antihistaminic, anticholinergic, noradrenergic and serotonergic (Domenjoz and Theobold, 1959), without offering any clues as to which of the actions are related to its “antidepressant” effect. Searching for a lead it was found that imipramine antagonized and reversed the reserpine-induced sedation, hypothermia, ptosis and diarrhea in the rat. Since reserpine’s pharmacological action is not restricted to the depletion of NE and 5-HT, but also includes cholinomimetic effects, the effect of imipramine on reserpine-induced behavior has not contributed to the disentangling of the action mechanism of the drug. Instead, it provided a means (test) which has been in use for decades in pharmacological screening for imipramine-like drugs (Costa, Garattini and Valzelli,1960).

Employment of the reserpine reversal test triggered research which led to the isolation of desipramine, the demethylated metabolite of imipramine, and the demonstration of its antidepressant effect. The postulation that desipramine’s antidepressant effect is mediated by NE is based on findings that desipramine’s reserpine reversal is suspended in animals selectively depleted of catecholamines by the administration of alphamenthylparatyrosine (AMPT) (Brodie, Biskel and Sulser, 1961; Ban and Lehmann, 1962; Sulser, Watts and Brodie, 1962;  Sulser, Bickel and Brodie 1964), a selective tyrosine hydroxylase blocker. The confounding of reserpine reversal with antidepressant effect was compounded by the confounding of the action mechanism of a drug with the pathomechanism of an illness. The belief that depression is the result of a chemical imbalance in which NE deficiency plays a pivotal role has not been corrected by the demonstration that administration of AMPT did not yield relapse in patients successfully treated with imipramine (Shopsin, Gershon and Goldstein, 1975). It has persisted in spite of any indication that selective NE reuptake blockers would be superior to other antidepressants. Driven by neuropharmacological theory, the non-selective (prevailingly NE) reuptake inhibitors of the late 1950s and early 1960s, such as imipramine and amitriptyline, were replaced first by selective NE reuptake inhibitors (NARI), e.g., desipramine, nortriptyline and subsequently, by selective serotonin (5-HT) reuptake inhibitors (SSRIs), e.g., fluoxetine, fluvoxamine.

The shift from NARI’S to SSRIs began with the recognition that an intact 5-HT system is an essential prerequisite for beta-adrenergic receptor downregulation (Vetulani, Stawarz, Pingell et al., 1975) - the focus of interest in the action mechanism of antidepressants. It culminated in 1980 with the recognition of the correspondence between imipramine binding sites and 5-HT binding sites in the human platelet (Paul, Rehavi, Skolnick et al., 1980) and in the hypothalamus of the rat (Langer, Moret, Raisman et al., 1980). The shift was also supported by clinical pharmacological findings which indicated that administration of parachlorophenylalanine, a 5-HT synthesis inhibitor, produced relapse in depressed patients successfully treated with antidepressants (Shopsin, Friedman and Gershon, 1976).

By the early 1990s the SSRIs dominated the antidepressant scene. But in spite their unprecedented marketing success, clinical expectations from the SSRIs were not fulfilled. Instead of helping patients to eat, relax and sleep, SSRIs interfered with appetite and sex; and induced nausea, vomiting, irritability, anxiety, insomnia and headache. Less frequently, they induced parkinsonism, agitation, spasms and tics; and occasionally precipitated suicidal and homicidal behavior (Klein, 2000).
            To relieve the (side) effects created in part by the stimulation of serotonin 5-HT2a receptors, and in part by the compensatory decline   of dopamine in the brain, a series of new antidepressants emerged during the 1990s. One of the first was venlafaxine and one of the last so far was reboxetine. With the introduction of venlafaxine, a nonselective but prevailingly 5-HT reuptake inhibitor, a full circle of NE and/or 5-HT reuptake inhibitors was completed. With the introduction of reboxetine, a NARI, the circle opened with the introduction of desipramine in the early 1960s was reopened in the late 1990s virtually unchanged. Other drugs of the new series included selective serotonin 5-HT2A receptor blockers, such as nefazodone, a weak 5-HT reuptake inhibitor, structurally and pharmacologically related to trazodone and mirtazapine, an a2-andrenoreceptor blocker, pharmacologically related to both, mianserin and trimepramine (Ban, 1999).


Historical Analysis

During the 40+ years which followed the introduction of Iproniazid and imipramine, a rapidly growing number of antidepressants, first MAOIs and subsequently MAUIs, were rendered accessible for clinical use.  Presently, there are 22 MAOI and MAUI or related drugs available in Canada on prescription: six nonselective reuptake inhibitors, i.e., four prevailingly NE reuptake blockers (amitriptyline, amoxapine, doxepin and imipramine) and two prevailingly 5-HT reuptake blockers (clomipramine and venlafaxine), four selective NE reuptake blockers (desipramine, maprotiline, nortriptyline and protriptyline), four selective 5-HT reuptake blocker (fluoxetine, fluvoxamine, paroxetine and sertraline), two noradrenergic and 5-HT selective agents (trimepramine and mirtazapine), two serotonergic and 5-HT selective agents (nefazodone and trazodone), two nonselective MAOIs (phenelzine and tranylcypromine), one selective type A MAO enzyme inhibitor (moclobemide) and one NE and dopamine reuptake inhibitor (bupropion) (CPS, 2000). Each of these drugs has its own identity with a distinct chemical structure and adverse effect profile. While the overall frequency of adverse effects is about the same with all these antidepressants, anticholinergic side effects are less frequent with the newer drugs.

In table 1, therapeutic response rates for 10 of the 22 antidepressants available in Canada are presented. The figures are based on Davis, Wang and Janicak’s (1993) meta-analyses of about 300 double-blind randomized controlled clinical trials.

Table 1. Response rates


Response rates (%)













































Response (efficancy) rates: measured by a 50% or greater decrease in the total scores of the Hamilton Rating Scale for Depression. SSRI selective serotonin reuptake inhibitor, NRSI non-selective reuptake inhibitor, TA tryciclic antidepressant, MAOI monoamineoxidase inhibitor, MAOI-A selective inhibitor of the Type A isoenzyme of MAOI, NaSSA noradrenaline and serotonin selective agent, atypical no effect on NE or 5-HT reuptake.

As shown on table 1, response rates with six of the 10 drugs, i.e., two MAOIS (phenelzine and moclobemide), two NSRIs (amoxapine and amitriptyline), two SSRIs (fluvoxamine and fluoxetine) were just slightly lower than with imipramine, ranging from 60% to 68% (Davis, Wang and Janicak, 1993; Ban, 1999b). Response rates with sertraline, an SSRI, was about 15% higher than with imipramine, considering, however, the 20% higher placebo response rates between the two drugs. The same does not apply to paroxetine and mirtazapine. Although the effect sizes versus placebo for mirtazapine, an NaSSA, and paroxetine, an SSRI, were comparable to imipramine, response rates with both drugs were markedly lower than with the standard tricyclic antidepressant. Since response rates with both drugs were below placebo response rates in the sertraline studies, the low response rates could not be explained by population differences alone (Fawcett and Barkin, 1997).

Response rates in these meta-analyses indicate a widening of the antidepressant response range from 65%-70% (Klerman and Cole, 1965; Klein and Davis, 1969; Agst, 1970) to 45%-79% (55,57), and a lowering of the antidepressant threshold from 65% to 45%. As a result, from concentrated efforts to replace TAs (and also of MAOIs) by SSRIs an NaSSAs one can no longer respond to treatment. Nevertheless, the newer SSRIs and NaSSAs are better tolerated and more accepted by patients than the older TAs, primarily because they produce less anticholinergic side effects. Would affective states represent a balance between central cholinergic and adrenergic activity with depression being a disease of cholinergic dominance, and central anticholinergic receptor blockade an essential feature in the action mechanism of antidepressant drugs (Selbach,1959; Janowsky, 2000; Janowsky, El-Yousef and Davis 1974), the lower therapeutic response rates encountered in meta-analyses with some of the newer drugs might be explained by their lesser affinity to central muscarinic cholinergic receptors. However, this does not seem to be the case. Adjunctive treatment with the cholinolytic biperiden did not enhance the antidepressant efficacy of mianserin or viloxazine (Fritze, 1993).

Concluding Remarks

The history of pharmacological treatment of depression was reviewed. Attention was focused on the widening gap between neuropharmacological theory and clinical practice and on the lack of progress – or maybe even regress – in the overall treatment efficacy of antidepressant drugs. If new drugs offer any advantage in any form of depression, it is covered up by the available information. 



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* Ban, T. Pharmacotherapy of depression: a historical analysis. J Neural Transm 2001; 108:707–16.