Literature Review

Monoamine Theories of Depression: Historical Impact on Biomedical Research

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DOI: 10.1080/0964704X.2011.623917 · Source: PubMed
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Monoamine theories associate depression with reduced brain monoamine levels. These theories achieved broad popularity in the mid-1960s. The present article reviews the historical development of monoamine theories and their subsequent impact on biomedical research. Alleged divisions between West European and US researchers over competing versions of the theories are investigated using bibliometrics. Subsequently, the application of monoamine theories in the NIMH Collaborative Program on the Psychobiology of Depression is covered. The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas.
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Continental divergences and convergences in citation of four key monoamine articles. Number of research articles in the ISI Web of Knowledge database between 1968–1980 citing AJP, BJP, or both (A), and AJP / Science , BJP / Lancet, or both (B), grouped according to country or region in which authors were based. Numbers below graphs indicate the AJP to BJP ratio and AJP / Science to BJP / Lancet ratio , respectively, for each country / region . A few articles co-authored by researchers based in more than one of the selected countries or regions were removed in the subsequent statistical analysis. Chi-square tests for differences in citation distributions corrected for multiple comparisons (Bonferroni) yield the following results: In (A) United States versus United Kingdom, p < .01; United States versus West Europe, p < .001; United States versus West Europe excluding United Kingdom, p < .001; United Kingdom versus West Europe excluding United Kingdom, p > .05. In (B) United States versus United Kingdom, p < .001; United States versus West Europe p < .001; United States versus West Europe excluding United Kingdom, p < .001; United Kingdom versus West Europe excluding United Kingdom, p > .05. Calculation of standardized residuals demonstrated that differences in citation distributions between US and West European / UK articles confirmed in the chi-square tests are explained by a statistically significant tendency of US articles to cite AJP with increased probability and BJP with reduced probability (in A), and AJP / Science with increased probability and BJP / Lancet with reduced probability (in B), compared with West European / UK articles. By contrast, there was no evidence of divergence in tendencies to cite both AJP and BJP (in A), or both AJP / Science and BJP / Lancet (in B) between US and West European / UK articles.
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Monoamine Theories of Depression:
Historical Impact on Biomedical Research
Shai Mulinari a
a Centre for Gender Studies, Lund University, Lund, Sweden
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DOI: 10.1080/0964704X.2011.623917
Monoamine Theories of Depression: Historical
Impact on Biomedical Research
Centre for Gender Studies, Lund University, Lund, Sweden
Monoamine theories associate depression with reduced brain monoamine levels. These
theories achieved broad popularity in the mid-1960s. The present article reviews the
historical development of monoamine theories and their subsequent impact on biomed-
ical research. Alleged divisions between West European and US researchers over
competing versions of the theories are investigated using bibliometrics. Subsequently,
the application of monoamine theories in the NIMH Collaborative Program on
the Psychobiology of Depression is covered. The article argues that the impact of
monoamine theories is best explained by the ability of researchers, governmental agen-
cies, and pharmaceutical companies to invoke theories that advance various projects
and agendas.
Keywords history, biological psychiatry, depression, monoamine hypothesis,
monoamine theory, Psychobiology of Depression Program, NIMH, bibliometrics
Monoamine theories, perhaps more than any other pathophysiological theories, are
said to have inaugurated the modern psychopharmacological era in psychiatry (Healy,
1997). Briefly, monoamine theories stipulate that depression is related to decreased lev-
els of centrally available monoamines, typically either the catecholamine, noradrenaline
(norepinephrine in the United States), or the indoleamine, serotonin (also known as
The catecholamine version of the monoamine theory gained wide popularity in
academic circles after 1965 following the publication of a review article by American psy-
chiatrist Joseph Schildkraut in The American Journal of Psychiatry (AJP), which suggested
that affective states may be precipitated by altered brain catecholamine levels, particularly
noradrenaline levels (Schildkraut, 1965). Within two years an analogous paper by British
psychiatrist Alec Coppen surfaced in The British Journal of Psychiatry (BJP), this time
implicating serotonin in the pathophysiology of depression (Coppen, 1967). Because both
catecholamines and indoleamines are monoamines, these hypotheses became known as the
monoamine theories of depression.
The formulation of divergent hypotheses by Schildkraut and Coppen initiated a long-
standing debate over the relative importance of serotonin and noradrenaline in the etiology
of depression. Interestingly, several scientists active in these debates in the 1960s and 1970s
Riksbankens Jubileumsfond in Sweden supported this work. The author also wishes to thank
Anna V. Zetterqvist for valuable comments.
Address correspondence to Shai Mulinari, Centre for Gender Studies, Lund University, Box
117, 221 00 Lund, Sweden. E-mail:
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Impact of Monoamine Theories 367
cite a tendency from US researchers to follow the catecholamine hypothesis, while their
West European—and especially UK-based—colleagues pursued the serotonin hypothe-
sis track. One prominent British researcher even claimed that in the 1960s and 1970s,
there was “almost a continental divide” between scientists; while “America was nora-
drenaline ...England, anyway, was 5HT” (Eccleston & Healy, 2000, p. 204). Similarly,
Dutch researcher Herman van Praag, a long-time key figure in the serotonin camp, recalled:
“In the USA, for many years it was only catecholamines; so the few people that remained
true to serotonin, became the ‘serotonin people’ ” (van Praag & Healy, 1996, p. 360).
Schildkraut, however, maintained that the “serotonin versus noradrenaline dichotomy”
was never a major issue for him (Schildkraut & Healy, 2000, p. 126), although Donald
Eccelston, then at the Department of Pharmacology in Edinburgh, has described how he
and Schildkraut “agreed to disagree as to which was more important, noradrenaline or
5-HT” (Eccleston & Healy, 2000, p. 205).
Monoamine theories held sway in biological psychiatry for roughly a decade but
eventually, at least within academia (Lacasse & Leo, 2005; Mulinari, forthcoming), they
morphed into monoamine receptor theories, which associate depression with lesions
at the level of monoamine receptors (Vetulani & Sulser, 1975; Stahl, 1984). More
recently, however, even receptor theories have come under siege following the unfold-
ing of the neurosciences (Krishnan & Nestler, 2008). Rather than stemming from primary
defects in monoamine signaling, contemporary neuroscientists hypothesize that depres-
sion may result from stressful life experiences that cause substantial neuronal damage
and consequent defects in brain processing. The new buzzword is “neuroplasticity”
(Berlucchi & Buchtel, 2009), or the changes in neuronal architecture that arise in response
to environmental contingencies—perspective that is rapidly replacing older notions of
neurotransmitter or receptor defects in scientific circles.
Previous work on the history of monoamine theories has underscored that the the-
ories helped consolidate the biomedical turn in psychiatry during the 1960s and 1970s,
in part because they provided impetus and direction to psycho- and neuropharmacologi-
cal research (Healy, 1997; Baumeister, Hawkins, & Uzelac, 2003; Baumeister & Hawkins,
2004). But how, more precisely, and to what extent monoamine theories actually stimulated
biomedical research in psychiatry and related academic fields needs further clarification.
Moreover, the magnitude of the “continental divide” over competing monoamine hypothe-
ses has remained poorly investigated. This article begins by offering a summary of the
historical development of monoamine theories. Next follows a bibliometric survey of
four classic monoamine theory papers with the aim of evaluating, on the one hand, their
impact on psychiatry and related biomedical fields and, on the other hand, addressing the
alleged split between US and West European researchers in the 1960s and 1970s over
the relative importance of noradrenaline and serotonin in depression. The final section
outlines the history of the Biological Studies Component of the National Institute of
Mental Health’s (NIMH’s) Collaborative Program on the Psychobiology of Depression.
This story illustrates how monoamine theories contributed to the forging of an intellectual
and organizational framework in US psychiatry, which provided an impetus and direction
to biomedical research on depression and antidepressants.
Monoamine Theories of Affective Disorders: Historical Overview
Speculations about the role of monoamines in affective states owe a great deal to the
serendipitous discovery in the late 1950s that members of two structurally unrelated
classes of compounds were effective in treating severe depression. The first class of
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368 Shai Mulinari
compounds comprised the so-called monoamine oxidase inhibitors (MOAIs), represented
by Iproniazid, an antituberculosis drug with apparent psychotropic effects; the second class
comprised the so-called tricyclic antidepressants (TCAs), represented by Imipramine, a
derivative of an antihistamine.
Previous historical research has documented how academic psychiatrists by the late
1950s had come to regard TCAs and MAOIs as specific chemical cures for certain grave
depressive states (Healy, 1997; Moncrieff, 2008; Shorter, 2009). Although this view was
common among academic psychiatrists, at this point no generally accepted scientific the-
ory explained the mechanisms by which TCAs and MAOIs cured depression. An important
clue to this quandary emerged with the observation that both classes of antidepressants,
albeit via distinct biochemical pathways, increase catecholamine levels in the brain, which
suggested a common pharmacological mechanism of action among antidepressant drugs
(Zeller et al., 1952; Udenfriend, Weissbach, & Bogdanski, 1957; Axelrod, Whitby, &
Hertting, 1961; Glowinski & Axelrod, 1964).
Prompted by this line of work, American psychiatrist Joseph Schildkraut authored
an article entitled The Catecholamine Hypothesis of Affective Disorder: A Review of
Supporting Evidence published in AJP in 1965 (Schildkraut, 1965; Schildkraut & Healy,
2000). In this inaugural article, Schildkraut not only reaffirmed the involvement of cat-
echolamines in the mechanism of action of antidepressant drugs but he went one step
further and suggested that depression itself was related to catecholaminergic neuro-
transmission and, in particular, to decreased noradrenergic neurotransmission caused by
noradrenaline deficiency. In parallel, mania was proposed to be associated with elevated
catecholaminergic neurotransmission.1
In brief, the basic argument advanced by Schildkraut rested on reports that drugs that
deplete catecholamines can cause depression, whereas drugs that enhance availability of
catecholamines are effective antidepressants. Specifically, Schildkraut used three lines of
pharmacological and clinical evidence: (a) MOAIs and TCAs were both inferred to exert
their antidepressant effect by elevating levels of brain catecholamines; (b) the antipsy-
chotic reserpine, an alkaloid extracted from the root of the climbing shrub Rauwolfia
serpentine,2had been reported to precipitate depression in some patients. When given to
laboratory animals, reserpine induced sedation—or a “depression” of animal behavior—
that correlated with depletion of brain catecholamines; (c) reserpine-induced sedation
in animals could be prevented by administration of the catecholamine precursor DOPA
(3,4-dihydroxyphenylalanin) or by administration of MAOIs or TCAs. Schildkraut’s con-
cept was not the first to suggest that brain monoamines were in some way connected
to mood (Everett & Toman, 1959; Pare & Sandler, 1959). Rather, the originality of
Schildkraut’s proposal lay, as David Healy (1997) has argued, in the synthesis of a set
of earlier ideas into a compelling format understandable to both clinicians and researchers.
Two years later, in 1967, Alec Coppen reviewed evidence linking depression to
serotonin deficiency rather than to catecholamine deficiency (Coppen, 1967). Previously,
Coppen and coworkers at the Medical Research Council in Carshalton, England, had found
that the serotonin precursor tryptophan potentiated the antidepressive effect of an MAOI
in patients with severe depressive illness (Coppen, Shaw, & Farrell, 1963). To them, this
suggested that elevation of serotonin levels equated to an antidepressant principle. Now, a
central issue for Coppen was the reported failure of the catecholamine precursor DOPA to
1Shortly after this, Bunney and Davis (1965) published a paper expressing the same idea.
2The Rauwolfia root had a history of use in the treatment of hypertension, snakebite, and insanity
in Ayurvedic medicine, which inspired Western scientists to test it on psychiatric patients in the first
place (Kline, 1954).
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Impact of Monoamine Theories 369
potentiate the antidepressive effect of an MAOI. For Coppen, this seemed to “argue very
much against the involvement of catecholamines in the aetiology of depression,” although
he also conceded that the administered DOPA dose might have been too low (Coppen,
1967, p. 1244).
Thus, after 1967, two competing monoamine theories were circulating. Within two
years, in 1969, the serotonin hypothesis gained additional support in yet another influen-
tial review, this time published in The Lancet (Lapin & Oxenkrug, 1969). The authors,
Soviet researchers Lapin and Oxenkrug, pointed out that all recognized antidepres-
sants, and even electroconvulsive therapy, increased brain serotonin levels. For their
part, the catecholamine camp had advanced the counterargument that Imipramine and
Amitriptyline, two TCAs, metabolized in the body to compounds—desipramine and
nortriptyline, respectively—that inhibit reuptake of noradrenaline much more strongly
than reuptake of serotonin (Healy, 1997). This finding was initially taken to suggest that
serotonin-uptake inhibition was of secondary importance in the pharmacological treatment
of depression, although this soon came to be challenged by the work of Arvid Carlsson’s
group on the prominent serotonin-uptake properties of parent TCAs (Carlsson, Fuxe, &
Ungerstedt, 1968; Carlsson et al., 1969a, 1969b). Carlsson connected this work to Paul
Kielholz’ proposal that TCAs such as Imipramine and Amitriptyline restore mood whereas
their breakdown products increase drive. Specifically, based on the divergent pharma-
cologic and clinical profiles of parent TCAs and their respective breakdown products,
Carlsson speculated that boosting serotonin restores mood whereas boosting noradrenalin
increases drive in the depressed patient (Carlsson & Healy, 1996).
On the other hand, that same Carlsson had shown back in 1957 that a catecholamine
precursor, but not a serotonin precursor, reversed the effects of reserpine-induced sedation
in animals (Carlsson, Lindqvist, & Magnusson, 1957). Because reserpine was believed to
precipitate depression in humans through a mechanism that involved depletion of brain
monoamine stores, and because reserpine-induced sedation in animals was believed to
model aspects of human depression, Carlsson’s data on reserpine were interpreted by oth-
ers, including Schildkraut, as giving credence to the idea that catecholamines rather than
serotonin were the crucial monoamines in depression (Carlsson, 2010).
Finally, evidence favoring catecholamines over serotonin came from animal studies on
the role of monoamines in behavior (Baldessarini, 1972). Interference with catecholamine
metabolism in laboratory animals was reported to result in decreases in locomotion,
exploratory behavior, conditioned avoidance, and, perhaps most importantly, reward-
seeking behavior—in short, behaviors that scientists considered akin to human depression.
By contrast, interference with serotonin metabolism caused insomnia, as well as hypersex-
ual and hyperaggressive behaviors, and, in general, irritability and hyperactivity relative to
the environment—a collection of behaviors not resembling human depression, prominent
scientists argued (Baldessarini, 1972; Mendels & Frazer, 1974).
But even if divisions over catecholamines (and especially noradrenaline) and serotonin
persisted, some researchers did subsequently attempt to integrate both lines of thought.
For example, several teams in the mid-1970s suggested subdividing depression into two
classes: one serotonergic metabolic and one noradrenergic metabolic (Åsberg et al., 1973;
Bertilsson, Åsberg, & Thorén, 1974; Maas, 1975; Spiker et al., 1980). Similarly, by the
mid-1980s, researchers were speculating that certain patients suffered from noradrenergic
receptor depressions, while others suffered from serotonergic receptor depressions (Stahl,
1984). However, by the mid-1980s, it would seem that the balance finally tipped in favor
of serotonin, a development most likely reinforced by the advent of the selective serotonin
reuptake inhibitors (SSRIs).
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370 Shai Mulinari
Some Inconsistencies in the Catecholamine and Serotonin Hypotheses
In his original AJP paper, Schildkraut characterized the catecholamine hypothesis as
“undoubtedly, at best, a reductionist oversimplification of a very complex biological state”
(Schildkraut, 1965, p. 517). In a subsequent 1967 Science publication aimed at bringing
the catecholamine hypothesis to the attention of nonclinicians, he and his renowned NIMH
colleague Seymour Kety wrote that “any comprehensive formulation of the physiology of
affective states will have to include many other concomitant biochemical, physiological
and psychological factors” (Schildkraut & Kety, 1967, p. 28). Coppen also underscored
the ambiguous nature of depressive states and stressed that his own selection of material
was not exhaustive and was “inevitably influenced by the reviewer’s own interests and
prejudices” (Coppen, 1967, p. 1238).
Cautionary words were indeed pertinent because there were at that time several obser-
vations that conflicted with a simple link between monoamine concentrations in the brain
and mood. As Schildkraut himself would later explain, one empirical problem was that
the biochemical effects of antidepressants were almost instantaneous; by contrast, clin-
ical effects only occur after chronic treatment for at least three weeks (Schildkraut &
Healy, 2000). Another problem was cocaine, “a drug that blocks uptake of norepinephrine
and dopamine, but it apparently was not an antidepressant” (p. 124) (noradrenaline and
dopamine are both catecholamines). These troubling facts were never mentioned in the AJP
paper, which was—as the title reads—only “a review of supporting evidence” (Schildkraut,
1965, p. 509). However, they were also omitted from the subsequent Science paper that
Schildkraut coauthored with Kety.
Additional data were available at the time that should have led critically minded
researchers to question the validity of these hypotheses (Healy, 1997; Baumeister,
Hawkins, & Uzelac, 2003; Baumeister & Hawkins, 2004), including a double-blind,
placebo-controlled, randomized trial of reserpine, published in 1955, which demonstrated
that reserpine actually had antidepressant effects (Davies & Shepherd, 1955). That study
was simply ignored and based on anecdotal reports reserpine was portrayed as depresso-
genic, perhaps—as suggested by Baumeister, Hawkins, and Uzelac (2003), who chronicled
the historical role of reserpine in the creation of monoamine theories—because psychiatric
researchers at the time badly needed theories to provide direction and an impetus to their
I suggest that the presentation of the reserpine data contains an additional weak point
that is regularly overlooked. To support his contention that noradrenaline was the key
catecholamine in depression, Schildkraut pointed out that reserpine-induced “depression”
of animal behavior correlates with low noradrenaline levels in the brain. But he then
failed to mention that Arvid Carlsson had already shown back in 1958 that this effect
was mediated by depletion of dopamine but not of noradrenaline (Carlsson et al., 1958).
More specifically, Carlsson had found that by administering the catecholamine precursor
L-DOPA to reserpine-treated rabbits he could reverse the behavioral effects of reserpine.
Most importantly, however, Carlsson showed then that while L-DOPA is converted into
dopamine the subsequent anticipated biochemical step—conversion of dopamine into
noradrenaline—was never completed because it is blocked by reserpine.3In short, L-DOPA
3This is because reserpine blocks the transport of dopamine through the vesicle membrane, and
because dopamine beta hydroxylase, the enzyme that converts dopamine to noradrenaline, can act
solely on intravesicular dopamine. By contrast, administration of L-DOPA to nonreserpine-treated
animals results in an increase of brain noradrenaline, albeit to a lower degree than of dopamine (Arvid
Carlsson, personal communication, May 18, 2011).
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Impact of Monoamine Theories 371
was converted into dopamine and this is sufficient to lift rabbit “depression,” thereby
rendering the involvement of noradrenaline in reserpine-induced rabbit “depression”
Today, Carlsson would call Schildkraut’s use of the reserpine data to substantiate a
noradrenaline hypothesis of depression “not good” (Carlsson, 2010), and when queried he
explains: “In the U.S. researchers didn’t consider European publications to be of much
significance. In addition, Joseph Schildkraut was of course a definite clinician—a psychi-
atrist. His knowledge about the preclinical aspects was probably quite superficial, I could
imagine ...and then you have the fact that the tricyclic drugs didn’t work on dopamine
as they did on noradrenaline.” Thus, according to Carlsson, the failure of Schildkraut
(and others) to recognize the link between dopamine depletion and reserpine-induced
behavior stemmed from several factors—including ignorance of non-American literature—
especially in preclinical fields, as well as also from the fact that this particular piece of data
didn’t fit Schildkraut’s version of the hypothesis.
A further critical point pertaining to the shaky theoretical foundation of monoamine
theories was presented by veteran psychiatrist Thomas Ban (1987, 1998). Ban cites three
large reviews published between 1965–1970 on the efficacy of Imipramine, which all
came to the same conclusion: 65–70% of all inpatient depressions respond favorably
to Imipramine, whereas 30–40% respond favorably to placebo (Klerman & Cole 1965;
Klein & Davis, 1969; Angst, 1970). “These figures,” Ban writes,“suggest that only 1 (or at
most 2 by including placebo responders) out of every 3 depressed patients responds favor-
ably to treatment with an antidepressant” (Ban, 1987, p. 549). Now, if this antidepressant
were to be used as a tool to decipher the pathophysiology of depression, Ban argues, any
resultant theory would apply to at most one third of all inpatient depressions, which is still
a significant, albeit not impressive, figure.4
Such empirical and theoretical quandaries notwithstanding, much of the subsequent
debate concerning the problematic nature of monoamine theories has revolved around the
pharmacological style of reasoning underlying the theories that, some have contended,
is deeply flawed (Baumeister, Hawkins, & Uzelac, 2003; Baumeister & Hawkins, 2004;
Lacasse & Leo, 2005; Shorter, 2009). Thus, it has correctly been pointed out that just
because antidepressants increase brain monoamine levels, it does not follow that depres-
sion must be associated with low monoamine levels. While many others may have failed
to grasp the logical problems linked with this style of reasoning, this crucial point did not
escape Schildkraut, who cautioned his readers:
In interpreting studies of drugs effective in treatment of psychiatric disorders,
it can not be assumed without verification that their mode of action involves
correction of an underlying abnormality. Such drugs could, indeed, produce
unrelated changes which compensate for the naturally occurring abnormality,
and there are many examples of such symptomatic treatments in medicine.
Thus, pathophysiological hypotheses, such as the catecholamine hypothesis,
derived from studies of the mechanisms of action of drugs which induce
mood disorders or drugs which are effective in their treatment are primarily
4It is possible to challenge even this modest figure because it conflates the population level
(statistics) with the individual level (psychobiology). In brief, the point is that it could be a mistake
to assume that the pharmacological profile of Imipramine alone explains recovery from depression.
Rather, it may be the biochemical interaction between the drug’s pharmacological effect and placebo
that explains the antidepressive effect. However, the potential substance-placebo interaction was not
taken into consideration when constructing monoamine theories.
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372 Shai Mulinari
of heuristic value in suggesting directions for further research. (Schildkraut,
1965, p. 517, italics added)
Impact of Monoamine Theories: A Bibliometric Analysis
Despite such empirical, theoretical, and logical caveats, the catecholamine and serotonin
hypotheses had a major impact on the psychiatric universe (Healy, 1997; Schildkraut &
Healy, 2000; Baumeister, Hawkins, & Uzelac, 2003). But how influential were monoamine
theories really within academic research? I propose that one way to assess this is by a
citation-count analysis (Moed, 2005) of the four central monoamine theory papers men-
tioned above: Schildkraut’s 1965 AJP, Schildkraut and Kety’s 1967 Science, Coppen’s
1967 BJP, and Lapin and Oxenkrug’s 1969 Lancet papers.
Consistent with the idea that Schildkraut’s AJP paper played a fundamental role in the
psychopharmacology era, it is recognized as one of the most cited papers in the history of
psychiatry (Schildkraut, 1995). By the end of 2010, it had received a staggering 1,893 cita-
tions by research articles, reviews, and letters connected to the ISI Web of Knowledge, a
bibliographic database that covers over 10,000 of the highest impact journals worldwide.
Although the BJP, Science, and Lancet articles are significantly less cited (641, 622, and
428 citations, respectively), they too must be considered citation classics in the field.
To further examine and compare the historical importance of the four papers, a refined
citation-count analysis was performed, which included all research articles in the ISI
Web of Knowledge database, grouped according to year of publication. This revealed that
Schildkraut’s AJP and Schildkraut and Kety’s Science articles became increasingly cited
in the years leading up to 1970 (Figure 1). The latter achieved its highest citation counts
in 1973 (46) and 1974 (47). However, after this plateau, citation counts rapidly plunged.
By contrast, the AJP article continued to be widely cited throughout the 1970s and 1980s,
receiving the highest citation counts in 1985 (61) and 1988 (60)—a good 20 years after
the original publication. It is conceivable that the difference in temporal citation patterns
between the two articles (i.e., that citation counts of the Science article plunged almost
15 years earlier) reflects a trend by nonpsychiatrists, after a few years had passed and
monoamine theories became generally recognized, to cite the original AJP article rather
than the less clinically oriented Science article. Accordingly, as shown below, a higher
Figure 1. Citation of four key monoamine articles over time. Number of research articles in
the ISI Web of Knowledge database citing the AJP,BJP,Science, or Lancet papers between
1966–2010. Dashed lines below the graph indicate the three citation phases (1966–1974; 1974–1988;
1989–2010) discussed in the text (color figure available online).
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Impact of Monoamine Theories 373
proportion of articles citing the AJP paper stem from nonclinical journals in the period after
1974. For Coppen’s BJP paper, the citation pattern looks comparable to that of the AJP
paper. Thus, the maximum citation counts occurred in 1972 (22) and again in 1981 (22).
In 1987, it received 20 citations. The Lancet paper received its maximum citation counts in
1972 (26) and 1976 (27). But after 1981, the citation counts for this paper began to drop.
In the late 1980s, an apparent decline also occurs in the number of research articles
citing the two original papers. Indeed, between 2000–2010, the average number of cita-
tions per year of Schildkraut’s AJP and Coppen’s BJP papers had fallen to 17.5 and
6.6, respectively. While still substantial, these figures are considerably lower than the
top-ranking years in the 1970s and 1980s, indicating either a decline in the direct influ-
ence of monoamine theories since the late 1980s or, alternatively, the general acceptance
of monoamine theories, which precludes the necessity to cite the original publications.
Arguably, the former interpretation is most suitable: monoamine theories, or modifications
thereof in the form of receptor theories, served as the basis for biomedical research on
depression for roughly 25 years, but by the late 1980s their influence faded amid the rise
of neuroplasticity theories (Holden, 1991; Hyman & Nestler, 1996).
In conclusion, this bibliometric overview revealed three citation phases (delineated in
Figure 1). Phase 1, which lasted until the early 1970s, was characterized by an increasing
number of citations; Phase 2, encompassing the mid-1970s to late 1980s, was characterized
by a relatively steady number of citations for the two original articles, but falling citation
counts for the Science article and, past 1981, also for the Lancet article; and Phase 3, which
was distinguished by comparatively few citations of all four target articles. Tentatively, this
temporal citation pattern may reflect the scientific community’s historical relationship to
monoamine theories. First, there was an enthusiastic phase lasting until the early 1970s,
followed by a contemplation and contestation phase lasting until the late 1980s, and finally,
a rebuttal and superseding phase.
A second issue that can be addressed by citation analysis is the kind of journals that
most frequently contain articles citing one or more of the four papers. Because each jour-
nal has a particular aim and scope, such as clinical psychiatry or applied biochemistry, a
citation analysis based on individual journals can serve as a proxy for the kind of research
typically performed in dialog with monoamine theories. Because journals also differ in
status, the significance and novelty of such research as perceived by the scientific commu-
nity can simultaneously be projected. By no means does this approach constitute a perfect
measure of impact, but it may still serve as a helpful estimate. For instance, if all papers
that cite one or more of the four papers had ended up in minor journals targeting special-
ists, there would be little evidence that monoamine theories exerted any direct influence on
mainstream, preclinical, or experimental research. However, if “citing articles” are found in
a wider spectrum of high-impact journals, it may lend support to the idea that monoamine
theories in fact had a substantial impact on scientific activity, even beyond psychiatry.
Because of the results outlined above, I divided my journal citation search into
three intervals: 1967–1974, 1975–1988, and 1989–2010. The top journals for each of
the four articles during each interval are compiled in Tables 1–12. Between 1967–1974,
all four articles were abundantly cited in leading journals targeting clinical and aca-
demic psychiatrists, including AJP,BJP, and Archives of General Psychiatry,aswell
as in lower ranking yet still highly respectable psychiatric journals, such as Acta
Psychiatrica Scandinavica and Journal of Psychiatric Research (Tables 1, 4, 7, and 10).
Moreover, numerous citations from this period stem from articles published in lead-
ing journals devoted to psycho- or neuropharmacology such as Psychopharmacologia
(now Psychopharmacology), Biochemical Pharmacology, European Journal of Clinical
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374 Shai Mulinari
Table 1
Schildkraut’s AJP Paper (1967–1974)
Journal Articles
American Journal of Psychiatry 29
Archives of General Psychiatry 29
Science 18
Journal of Psychiatric Research 16
Psychopharmacologia 14
International Pharmacopsychiatry 10
Diseases of the Nervous System 9
Psychosomatics 7
Nature 6
Biological Psychiatry 5
Lancet 5
Psychosomatic Medicine 5
Biochemical Pharmacology 4
British Journal of Psychiatry 4
Canadian Psychiatric Association Journal 4
Comprehensive Psychiatry 4
Neuropharmacology 4
Psychological Medicine 4
Arzneimittel-Forschung 3
Clinica Chimica Acta 3
Journal of Nervous and Mental Disease 3
Life Science Part 1 Physiology & Pharmacology 3
Nervenarzt 3
New England Journal of Medicine 3
Psychiatria Clinica 3
Pharmacology, and International Pharmacopsychiatry. Also, several articles citing one or
more of the four papers were published in prestigious journals devoted to general medicine
or science, that is, Lancet, New England Journal of Medicine, and Science. As a rule, arti-
cles in journals targeting clinical and academic psychiatrists tended to cite the AJP or BJP
papers, while articles in journals devoted to psycho- or neuropharmacology tended to cite
the Science or Lancet papers (compare Tables 1 and 4 to Tables 7 and 10).
In brief then, the overall impression is that all four articles were abundantly cited
in leading and semi-leading journals devoted to clinical psychiatric research between
1967–1974. There are also a substantial number of citations stemming from preclinical
and/or experimental research journals. The analysis further suggests a tendency for articles
in nonpsychiatric journals to cite the Science and Lancet articles, while articles in psychi-
atric journals tended to cite the AJP and BJP articles. Taken together, this is consistent with
the idea that monoamine theories had a significant impact not only on mainstream clinical
and academic psychiatry but also on neuro- and psychopharmacology and neurochemistry
research during this period.
Interestingly, the data for 1975–1988 differ somewhat from those for 1967–1974
(Tables 2, 5, 8, and 11). Notably, a higher proportion of articles citing the AJP or BJP
papers come from neuro- or psychopharmacology, pharmacology, or neurochemistry
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Impact of Monoamine Theories 375
Table 2
Schildkraut’s AJP Paper (1975–1988)
Journal Articles
Archives of General Psychiatry 26
Acta Psychiatrica Scandinavica 24
Biological Psychiatry 23
Psychopharmacology 23
Psychiatry Research 20
European Journal of Pharmacology 16
Neuropharmacology 16
Journal of Pharmacology and Experimental Therapeutics 13
Journal of Clinical Psychiatry 12
American Journal of Psychiatry 11
Neuropsychobiology 10
Life Sciences 9
Pharmacopsychiatry 9
British Journal of Psychiatry 8
Journal of Psychiatric Research 8
Polish Journal of Pharmacology and Pharmacy 8
Journal of Affective Disorders 7
Acta Pharmacologica et Toxicologica 6
Brain Research 6
Comprehensive Psychiatry 6
Journal of Neural Transmission 6
Pharmacopsychiatria 6
Psychoneuroendocrinology 6
Journal of Chromatography 5
Pharmacology Biochemistry and Behavior 5
Psychopharmacology Bulletin 5
journals. Between 1967–1974, only 2 of the top 10 journals citing Schildkraut’s AJP or
Coppen’s BJP papers were devoted to neuro- or psychopharmacology, pharmacology, or
neurochemistry, namely Psychopharmacologia and International Pharmacopsychiatry.
Jointly, these two journals published 8.5% and 7.0% of research papers citing AJP
and BJP articles, respectively. By 1975–1988, however, the number of neuro- or
psychopharmacology, pharmacology, or neurochemistry journals on the top 10 lists had
increased to four and five, containing 13.6% and 20.3% of all citations, respectively. During
this period, this trend was consistent with a significant, persistent impact of monoamine
theories on neuro- and psychopharmacology, as well as on neurochemistry. Indeed, it was
during this period that SSRIs were developed and tested, which may partially explain the
increased interest in monoamine theories from preclinical and experimental journals.
If we now consider the same data set for 1989–2010, we find, as outlined above, a
substantial decline in overall citation counts compared with the preceding time interval.
Strikingly, between 1989–2010, relatively few citations occurred from research articles in
AJP,Archives of General Psychiatry, and Molecular Psychiatry, the three leading psychi-
atric journals in recent times (see Tables 3, 6, 9, and 12). In addition, almost no citations
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376 Shai Mulinari
Table 3
Schildkraut’s AJP Paper (1989–2010)
Journal Articles
Biological Psychiatry 29
Neuropsychopharmacology 17
Journal of Affective Disorders 16
Archives of General Psychiatry 13
Journal of Neurochemistry 9
Pharmacology Biochemistry and Behavior 9
Brain Research 8
European Journal of Pharmacology 8
Psychiatry Research 8
Acta Psychiatrica Scandinavica 7
Human Psychopharmacology–Clinical and Experimental 7
Journal of Neuroscience 7
Journal of Pharmacology and Experimental Therapeutics 7
Pharmacopsychiatry 7
Psychopharmacology 7
Journal of Psychopharmacology 6
Life Sciences 6
Neurochemistry International 6
Neuropharmacology 6
Neuropsychobiology 6
British Journal of Pharmacology 5
Drug Development Research 5
European Archives of Psychiatry and Clinical Neuroscience 5
Journal of Biological Chemistry 5
Journal of Clinical Psychopharmacology 5
Medical Hypotheses 5
stem from high-impact journals such as Science, Nature, Nature Neuroscience, and Journal
of Neuroscience, which typically publish influential neuroscience work. This supports the
contention that monoamine theories fell out of favor toward the end of the 1980s.
Before closing this bibliometric section, I would like to take the opportunity to
address another issue that has surfaced in conjunction with the history of monoamine theo-
ries, which is the alleged split in the 1960s and 1970s between US and West European
researchers, especially the British, over the relative importance of serotonin and nora-
drenaline in depression. On the assumption that researchers working on the role of
serotonin tended to cite the BJP and/or Lancet papers (from now on BJP/Lancet), while
researchers working on the role of noradrenaline tended to cite the AJP and/or Science
papers (from now on AJP/Science) with comparable frequency, we may apply the distribu-
tion of citations of US and West European articles vis-à-vis those papers to investigate this
suspected divide. Arguably, this is not an unreasonable assumption in light of the consid-
erable impact of the four papers. Moreover, a manual search readily confirmed that articles
citing BJP/Lancet focused more often on serotonin than on noradrenaline, while articles
citing AJP/Science focused more often on noradrenaline than on serotonin. Finally, the
division between BJP/Lancet on the one side and AJP/Science on the other is supported
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Impact of Monoamine Theories 377
Table 4
Schildkraut and Kety’s Science Paper (1967–1974)
Journal Articles
Psychopharmacologia 16
Science 13
Archives of General Psychiatry 12
Journal of Psychiatric Research 12
Diseases of the Nervous System 8
American Journal of Psychiatry 5
Biochemical Pharmacology 5
Biological Psychiatry 5
Brain Research 5
Psychosomatic Medicine 5
European Journal of Clinical Pharmacology 4
International Pharmacopsychiatry 4
Nature 4
New England Journal of Medicine 4
Annals of the New York Academy of Sciences 3
Archives Of Neurology 3
British Journal of Psychiatry 3
International Journal of Neuropharmacology 3
Journal of Comparative and Physiological Psychology 3
Journal of Nervous and Mental Disease 3
Lancet 3
Life Sciences Part 1 Physiology and Pharmacology and Part 2 Biochemistry
General and Molecular Biology
Neuropharmacology 3
Proceedings of The National Academy of Sciences of The United States
of America
by the fact that only 12.4%, or 142, of all papers published between 1968–1980 citing any
of the four papers cited BJP/Lancet and AJP/Science.
To address this alleged divide, a survey was first performed including all research
articles in the ISI Web of Knowledge database that cited Schildkraut and/or Coppen’s
two original papers between 1968–1980. This showed that Schildkraut’s AJP paper had
the highest citation count not only among US articles but also among West European
and even UK articles (Figure 2a), consistent with the primacy of this paper regardless
of country or region. However, the proportion of US articles that cited solely AJP or
BJP were markedly higher and lower, respectively, than among UK and West European
articles (compare AJP to BJP ratios in Figure 2a). A chi-square analysis confirmed a sta-
tistically significant difference in citation distributions between US and UK articles. That
is, although Schildkraut’s article was mostly cited in both countries, its primacy was more
pronounced in the United States. A similar difference was found when comparing US
with West European articles, even after excluding all articles by UK-based researchers.
Notably, no significant difference was seen in citation distributions between articles by
UK researchers and those by researchers based elsewhere in Western Europe. Similar
results were found after merging research articles citing BJP/Lancet into one group and
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378 Shai Mulinari
Table 5
Schildkraut and Kety’s Science Paper (1975–1988)
Journal Articles
Pharmacology Biochemistry and Behavior 12
Psychopharmacology 10
Archives of General Psychiatry 9
Science 9
Neuropharmacology 8
Brain Research 6
American Journal of Psychiatry 5
Biological Psychiatry 5
Life Sciences 5
Acta Psychiatrica Scandinavica 4
Biochemical Pharmacology 4
European Journal of Pharmacology 4
Experientia 4
Journal of Neural Transmission 4
Journal of Pharmacology and Experimental Therapeutics 4
Nature 4
Psychoneuroendocrinology 4
Behavioral and Brain Sciences 3
Journal of Comparative and Physiological Psychology 3
Neuropsychobiology 3
Pharmacopsychiatria 3
Physiology & Behavior 3
Polish Journal of Pharmacology and Pharmacy 3
Postgraduate Medical Journal 3
Progress in Neuro-Psychopharmacology & Biological Psychiatry 3
Psychiatry Research 3
Psychopharmacologia 3
Psychosomatic Medicine 3
AJP/Science into another (Figure 2b). Taken together, this demonstrates differences in the
citation distribution of US and West European articles but not UK and West European
articles in the sample.
Next, a refined statistical analysis, by calculating standardized residuals (Agresti,
2007), was used to identify the source of the observed difference between US and West
European articles. This revealed a tendency of US articles to (a) cite AJP (in Figure 2a)
and AJP/Science (in Figure 2b) with increased probability, and (b) BJP (in Figure 2a) and
BJP/Lancet (in Figure 2b) with reduced probability, compared with West European articles
(and vice versa). Specifically, the AJP to BJP ratio was more than 3.5 times larger among
US articles than among West European articles (9.0/2.5). Similarly, the AJP/Science to
BJP/Lancet ratio was more than six times larger among US articles than among West
European articles (11.3/1.7).
To sum up, judging from citation patterns, evidence suggests that the catecholamine
hypothesis had a considerably larger relative impact on US than West European research.
Conversely, the serotonin hypothesis seems to have had a much larger relative impact on
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Impact of Monoamine Theories 379
Table 6
Schildkraut and Kety’s Science Paper (1989–2010)
Journal Articles
Biological Psychiatry 6
Brain Research 3
Journal of Affective Disorders 2
Journal of Neurochemistry 2
Pharmacology Biochemistry and Behavior 2
Revista de Investigacion Clinica 2
World Journal of Biological Psychiatry 2
American Journal of Human Biology 1
Archives of General Psychiatry 1
Behavioral Neuroscience 1
Biochemical and Biophysical Research Communications 1
Child Psychiatry & Human Development 1
Clinical and Experimental Pharmacology and Physiology 1
Comparative Biochemistry and Physiology
C-Pharmacology Toxicology & Endocrinology
Cranio—The Journal of Craniomandibular Practice 1
Developmental Brain Research 1
Endodontics & Dental Traumatology 1
European Journal of Medicinal Chemistry 1
European Journal of Neuroscience 1
Frontiers in Bioscience 1
West European than US research. However, West European—and even UK—researchers
cited “the noradrenaline papers” more frequently than they did “the serotonin papers.”
Thus, this analysis points to continental divergences as well as convergences in research
on the role of monoamines in depression between 1968–1980.
Explaining the Impact of Monoamine Theories
But how could two hypotheses charged with cautionary language and perme-
ated with inconsistencies have such an impact on academic psychiatry, neuro- and
psychopharmacology, and neurochemistry research? When attempting to answer this ques-
tion it is imperative to recognize that the conviction that depression is a disease of
biological origin permeated medical thought long before monoamine theories. The somatic
symptoms associated with severe depression (including disturbances in sleep, appetite, gas-
trointestinal function, and sensation), the familiar inheritance of affective disorders, their
clinical association with other medical diagnoses, and the lack of apparent external causes
for many depressive episodes were all viewed as lending general support to this notion
(Baldessarini, 1975).
In addition, I propose five interrelated factors that collectively may account for the
impact of monoamine theories on this field. The first is that the theories actually explained
some clinical and biochemical data that research psychiatrists at the time felt demanded
explanation. For example, the theory clarified why both Imipramine and Iproniazid were
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380 Shai Mulinari
Table 7
Coppen’s BJP Paper (1967–1974)
Journal Articles
Archives of General Psychiatry 13
American Journal of Psychiatry 9
Journal of Psychiatric Research 7
British Journal of Psychiatry 5
Journal of Psychosomatic Research 5
Acta Psychiatrica Scandinavica 4
International Pharmacopsychiatry 4
Psychopharmacologia 4
Science 4
Biological Psychiatry 3
Canadian Psychiatric Association Journal 3
Journal of Pharmacology and Experimental Therapeutics 3
Lancet 3
Archives Internationales de Pharmacodynamie et de Therapie 2
Biochemical Pharmacology 2
Diseases of the Nervous System 2
European Journal of Pharmacology 2
Journal of Clinical Pharmacology and New Drugs 2
Journal of Nervous and Mental Disease 2
Journal of Neurochemistry 2
Nature 2
Psychosomatic Medicine 2
antidepressants, while the antipsychotic Chlorpromazine was not.5The second factor was
that the theories merged data, concepts, standardized experimental techniques, and ani-
mal models that had been introduced or had become generally accepted relatively recently
in time and that were perceived (and several are still perceived) as groundbreaking. This
included the antidepressant drugs themselves as well as the revolutionary idea that commu-
nication between neurons in the brain is mediated by neurotransmitters, rather than through
electrical transmission as believed before. Additionally, Schildkraut and Coppen’s propos-
als drew on the recent elucidation of the pharmacology of some drugs, most importantly
on the notion that TCAs block the uptake of monoamines from the intersynaptic space
between neurons, and that MAOIs increase levels of available monoamines by inhibiting
an enzyme that metabolizes monoamines. Additionally, some empirical data discussed in
the papers were derived from biochemical measurements of monoamine precursors and
metabolites in patients. In short, the theories were shaped in the spirit of scientific novelty
and progress.
A third factor was that monoamine hypotheses were skillfully crafted in a biomedi-
cal language of therapeutic and disease specificity that, as noted by historian of medicine
Charles Rosenberg, appears to be a prerequisite for any disease model to gain wide
5Whether or not Chlorpromazine may in fact be beneficial in certain types of depression, as
suggested by some early clinical case reports and trials (Denber & Bird, 1956; Barsa & Kline, 1957;
Klein & Healy, 1996), is irrelevant; what is of importance is that many psychiatrists at the time
believed that it was not, and that the theories explained this widely held belief.
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Impact of Monoamine Theories 381
Table 8
Coppen’s BJP Paper (1975–1988)
Journal Articles
Acta Psychiatrica Scandinavica 18
Psychopharmacology 17
Journal of Neural Transmission 9
Archives of General Psychiatry 8
Neuropharmacology 8
Journal of Affective Disorders 7
Journal of Clinical Psychiatry 7
European Journal of Pharmacology 6
Neuropsychobiology 6
Biological Psychiatry 5
British Journal of Psychiatry 5
Archives Internationales de Pharmacodynamie et de Therapie 4
Biochemical Pharmacology 4
Psychoneuroendocrinology 4
Diseases of the Nervous System 3
International Pharmacopsychiatry 3
Journal of Neurochemistry 3
Life Sciences 3
Pharmacology Biochemistry and Behavior 3
Polish Journal of Pharmacology and Pharmacy 3
Psychiatry Research 3
acceptance in contemporary biomedicine (Rosenberg, 2006). This also explains why
monoamine theories could be invoked to increase the scientific credentials of psychiatry’s
subject matter: Its drugs, diseases, and explanations, in this way, finally allow psychia-
try to place itself at the heart of the biomedical thought collective (Wilson, 1993; Healy,
1997; Shorter, 1997; Baumeister & Hawkins, 2004; Moncrieff, 2008). Similarly, the fourth
factor relates to the ability of the pharmaceutical industry to employ monoamine theo-
ries to market antidepressants (Baumeister, Hawkins, & Uzelac, 2003; Lacasse & Leo,
2005; Mulinari, forthcoming).
These factors, and probably numerous others, all likely contributed to the unprece-
dented impact of the theories. But above all, I contend that the fifth and key factor
explaining success can be found in the ability of the theories to create and reinforce an
intellectual and organizational framework that enabled clinical psychiatry to join forces
with basic science in organized research on patients, thereby creating a productive research
agenda unique to the field.
Historian of science Evelyn Fox Keller has investigated the role of scientific theories
and language in the creation of productive or stagnating research agendas, respectively
(Fox Keller, 1995, 2000). Specifically, she analyzed how the discourse of “gene action”
despite—or even because of—the paucity of early data supporting the nature of such action
nevertheless allowed genetics to become organized into a productive research undertaking
that ultimately led to the deciphering of the structure of DNA and, more recently, to the
sequencing of the human genome. She writes:
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382 Shai Mulinari
What do I mean when I say that the discourse of gene action ...exerted a
critical force on the course of biological research? Can words have force in and
of themselves? Of course not. They acquire force only through their influence
on human actors. Through their influence on scientists, administrators, and
funding agencies, they provide powerful rationales and incentives for mobi-
lizing resources, for identifying particular research agendas, for focusing our
scientific energies and attention in particular directions. The discourse of gene
action has worked in just these ways. And it would be foolhardy to pretend it
has not worked well. (Fox Keller, 1995, p. 21)
Table 9
Coppen’s BJP Paper (1989–2010)
Journal Articles
Journal of Affective Disorders 10
Biological Psychiatry 9
Pharmacopsychiatry 5
Psychopharmacology 5
Archives of General Psychiatry 4
Pharmacology Biochemistry and Behavior 4
International Clinical Psychopharmacology 3
International Journal of Neuropsychopharmacology 3
Journal of Clinical Psychiatry 3
Journal of Neurochemistry 3
Journal of Pharmacology and Experimental Therapeutics 3
Medical Hypotheses 3
Neuropharmacology 3
Acta Neuropsychiatrica 2
Brain Research 2
British Journal of Pharmacology 2
British Journal of Psychiatry 2
Cellular and Molecular Neurobiology 2
Drug Development Research 2
Electrochimica Acta 2
European Journal of Pharmaceutical Sciences 2
European Journal of Pharmacology 2
Experimental Neurology 2
Human Psychopharmacology-Clinical and Experimental 2
Journal of Neural Transmission 2
Journal of Neural Transmission-General Section 2
Journal of Psychiatric Research 2
Journal of Psychopharmacology 2
Life Sciences 2
Neuroimage 2
Neuropsychopharmacology 2
Neuroreport 2
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Impact of Monoamine Theories 383
Table 10
Lapin and Oxenkrug’s Lancet Paper (1967–1974)
Journal Articles
Archives of General Psychiatry 7
Biulleten Eksperimentalnol Biologii I Meditsiny 5
Psychopharmacologia 5
American Journal of Psychiatry 4
Farmakologiya I Toksikologiya 4
Lancet 4
Activitas Nervosa Superior 3
Biochemical Pharmacology 3
European Journal of Pharmacology 3
International Pharmacopsychiatry 3
Acta Psychiatrica Scandinavica 2
Arzneimittel-Forschung 2
Biological Psychiatry 2
European Journal of Clinical Pharmacology 2
Journal of Neural Transmission 2
Journal of Psychiatric Research 2
Life Sciences 2
Science 2
Voprosy Meditsinskoi Khimii 2
Table 11
Lapin and Oxenkrug’s Lancet Paper (1975–1988)
Journal Articles
Psychopharmacology 18
Acta Psychiatrica Scandinavica 11
Pharmacology Biochemistry and Behavior 8
European Journal of Pharmacology 6
Archives of General Psychiatry 5
Neuropharmacology 5
Archives Internationales de Pharmacodynamie et de Therapie 4
Biochemical Pharmacology 4
Farmakologiya I Toksikologiya 4
Journal of Medicinal Chemistry 4
Journal of Neural Transmission 4
Pharmacopsychiatria 4
Zhurnal Nevropatologii I Psikhiatrii Imeni S S Korsakova 4
Acta Pharmacologica et Toxicologica 3
Journal of Affective Disorders 3
Journal of Clinical Psychiatry 3
Postgraduate Medical Journal 3
Psychopharmacologia 3
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384 Shai Mulinari
Table 12
Lapin and Oxenkrug’s Lancet Paper (1989–2010)
Journal Articles
Acta Psychiatrica Scandinavica 3
Biological Psychiatry 3
Pharmacopsychiatry 2
Zhurnal Nevropatologii I Psikhiatrii Imeni S S Korsakova 2
Acta Neuropsychiatrica 1
Aggressive Behavior 1
American Journal of Psychiatry 1
Archives of General Psychiatry 1
Archives of Sexual Behavior 1
Arzneimittel-Forschung-Drug Research 1
Biological Psychology 1
Biophysical Journal 1
British Journal of Nutrition 1
British Journal of Psychiatry 1
Cellular and Molecular Neurobiology 1
European Journal of Pharmacology 1
European Neuropsychopharmacology 1
International Clinical Psychopharmacology 1
International Journal of Clinical Practice 1
International Journal of Neuropsychopharmacology 1
International Review of Psychiatry 1
Journal of Clinical Psychiatry 1
Journal of Neurochemistry 1
Journal of Pharmaceutical Sciences 1
Journal of Pharmacology and Experimental Therapeutics 1
Journal of Pharmacy and Pharmacology 1
Journal of Psychoactive Drugs 1
Journal of the Royal College of General Practitioners 1
Life Sciences 1
Nature Neuroscience 1
Neurochemistry International 1
Neuropharmacology 1
Neurophysiology 1
Neuroscientist 1
Pharmacology Biochemistry and Behavior 1
Psychiatric Annals 1
Psychopharmacology 1
Psychosomatic Medicine 1
Public Health Nutrition 1
Schweizerische Medizinische Wochenschrift 1
Voprosy Meditsinskoi Khimii 1
Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I P Pavlova 1
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Impact of Monoamine Theories 385
Figure 2. Continental divergences and convergences in citation of four key monoamine articles.
Number of research articles in the ISI Web of Knowledge database between 1968–1980 citing AJP,
BJP, or both (A), and AJP/Science,BJP/Lancet, or both (B), grouped according to country or region
in which authors were based. Numbers below graphs indicate the AJP to BJP ratio and AJP/Science
to BJP/Lancet ratio,respectively, for each country/region.A few articles co-authored by researchers
based in more than one of the selected countries or regions were removed in the subsequent statistical
analysis. Chi-square tests for differences in citation distributions corrected for multiple comparisons
(Bonferroni) yield the following results: In (A) United States versus United Kingdom, p<.01;
United States versus West Europe, p<.001; United States versus West Europe excluding United
Kingdom, p<.001; United Kingdom versus West Europe excluding United Kingdom, p>.05. In (B)
United States versus United Kingdom, p<.001; United States versus West Europe p<.001; United
States versus West Europe excluding United Kingdom, p<.001; United Kingdom versus West
Europe excluding United Kingdom, p>.05. Calculation of standardized residuals demonstrated
that differences in citation distributions between US and West European/UK articles confirmed in
the chi-square tests are explained by a statistically significant tendency of US articles to cite AJP
with increased probability and BJP with reduced probability (in A), and AJP/Science with increased
probability and BJP/Lancet with reduced probability (in B), compared with West European/UK
articles. By contrast, there was no evidence of divergence in tendencies to cite both AJP and BJP
(in A), or both AJP/Science and BJP/Lancet (in B) between US and West European/UK articles.
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386 Shai Mulinari
Drawing on Fox Keller’s ideas, I propose that the monoamine theories had a some-
what similar effect on biological psychiatry and neighboring biomedical fields. Thus,
they contributed to catalyzing a productive research agenda by providing financial and
organizational incentives, scientific motivation, and securing funding, as well as by point-
ing academic and corporate scientists in the direction of certain solutions and not others
(Healy, 1997). For example, in terms of scientific research, the theories directed scientists
toward extensive biochemical investigations of monoamine metabolites and precursors in
the blood, cerebrospinal fluid (CSF), and urine of psychiatric patients (Ashcroft et al.,
1966; Dencker et al., 1966; Ashcroft et al., 1972; Coppen et al., 1972; Maas, Fawcett, &
Dekirmenjian, 1972; Åsberg et al., 1973; Maas, 1975; Åsberg, Träskman, & Thorén,
1976). The theories also stimulated research into the pharmacological mechanism of
action of antidepressant drugs in order to further understand the etiology of depression
(Gluckman & Baum, 1969; Vetulani & Sulser, 1975; Rosloff & Davis, 1974; Goodlet,
Mireylees, & Sugrue, 1977; Peet & Behagel, 1978; Zis & Goodwin, 1979; Charney,
Menkes, & Heninger, 1981; Stahl, 1984). Moreover, the idea that a subset of depressed
patients suffered from a serotonin deficiency became important in justifying the search for
more serotonin-specific antidepressant drugs (Wong et al., 1974; Agurell, 1981).
In terms of organizational incentives, monoamine theories played a chief role in trig-
gering the NIMH to set up a large and collaborative program on the “Psychobiology of
Depression,” outlined in detail below. This was a mega-program that eventually enrolled
about 1,400 patients. Compelling to my argument here, the program was unique in its
time in that it brought experts from different fields—including genetics, biochemistry, and
pharmacology—together with clinical and research psychiatrists under a common research
agenda, supervised by the NIMH, with the aim of solving a set of pertinent clinical and
biomedical questions related to depression and antidepressants (Katz, 2000).
NIMH Collaborative Program on the Psychobiology of Depression
The decision to set up the Program on the Psychobiology of Depression grew out of a
national conference that was held in Williamsburg, Virginia, by the NIMH in 1969. In the
preceding years, NIMH staff had become increasingly impressed by the “burgeoning pro-
ductivity of biochemists, biological psychiatrists, and psychophysiologists in this field, and
the potential these results might have on its [depression’s] understanding and treatment”
(Katz & Friedman, 1974, p. x).Thus, they decided to sponsor a conference on the topic, as
program director Marty Katz and some collaborators later explained, to “seek an up-to-date
analysis of current research, identify obstacles to progress, and consider potential solutions
that might accelerate the pace of research in the field” (Katz et al., 1979, p. 765).
At the Williamsburg meeting, which was attended by 43 of the most accomplished
biomedical depression researchers in the United States, the status of monoamine theories
was discussed (Maas et al., 1980; Secunda et al., 1980; Schildkraut & Healy, 2000). The
delegates collectively recommended initiating a multicenter study to test the theories (Katz,
2000). This research effort would concentrate on three major objectives: “(1) nosology—
the development of a sound, reliable system of classification of the depressive disorders;
(2) genetics—the design of studies to permit the definitive test of hypotheses concern-
ing the role of genetics; and (3) pathophysiology—the investigation of the role of specific
biochemical, neurophysiological, and endocrine mechanisms implicated in the etiology of
depression” (Katz et al., 1979, p. 766). Importantly, the multicenter nature of the study
would allow the inclusion of many more patients than ever before. Moreover, it would
enable researchers to assess several different biological systems in the same patient, which
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Impact of Monoamine Theories 387
would make it possible to test the various existing depression hypotheses on the same
patient sample. However, on the downside, a multicenter study design required develop-
ment of highly standardized laboratory methodology, diagnostic methods, and behavioral
rating methodologies that, it was recognized, also required a significant financial and
scientific commitment from all involved parties.
After the conference two multicenter research groups were formed, subsequently
called the biological and clinical subcommittees. They included key researchers such as
James Maas (chairman of the biological branch), Martin Katz (chairman of the clini-
cal branch), Joseph Mendels, Stephen Koslow, Eli Robins, Gerald Klerman, John Davis,
George Winokur, Paula Clayton, and Robert Spitzer, to name a few. In late 1974, the
biological subcommittee launched its program with Stephen Koslow from the NIMH as
Project Director with coordinating responsibility (for the history of the Clinical Studies
Component, see Healy, 1997). The explicit purpose of the program was to test and develop
pathophysiological hypotheses of depression. It was felt that “without such hypotheses to
guide research, new, more effective treatment methods and deeper understanding of the
affective disorders probably would not be realized” (Katz et al., 1979, p. 767). Specifically,
one of the goals set was to test Schildkraut’s hypothesis by determining whether “in fact
there are abnormalities in the urinary excretion of metabolites of norepinephrine (NE) in
a large sample of depressed or manic patients, when compared with individuals exhibiting
other psychiatric disorders or with normal individuals” (Secunda et al., 1980, p. 786).
The biological program was a large, costly program celebrated by its organizers
for being “unique in its complexity” (Secunda et al., 1980, p. 777). It was intended to
last 10–12 years and involved six investigative groups and centers in the United States
and about 345 human subjects (ultimately it extended over 18 years) (Katz, 2000).
An impressive set of variables was to be assessed and subsequently correlated, including
concentration of neurotransmitter metabolites in the CSF, plasma, and urine of patients,
as well as levels of drugs administered during the study’s treatment phase and, when pos-
sible, their metabolites. To this end, an improved gas chromatograph/mass spectrometric
method had to be developed. Various standardized diagnostic and behavioral tests of the
study subjects were also carried out throughout the study. Some diagnostic and behavioral
tests were designed for the study, specifically to permit reliable and uniform measurements
within and across centers. To further guarantee uniformity a 200-page protocol manual was
assembled and a full-time protocol monitor was hired at each center (Maas et al., 1980).
All personnel had to undergo specific training “to ensure that each centre performed in
the same manner and to limit errors due to inattention to detail, unfamiliarity with proto-
col procedures, and inexperience” (Maas et al., 1980, p. 767). Also, a common system for
sending samples, validation, and sharing and filing of data had to be developed (Secunda
et al., 1980).
In sum then, in the wake of monoamine theories, the explicit aim of the Biological
Studies Component was to establish decisive correlations between depression, pharmaco-
logical treatment, and depressive pathophysiology. To this end, researchers embarked on a
project that would raise the level of standardization and automatization in biopsychiatric
research to that typical of other large-scale biomedical research (Keating & Cambrosio,
But despite this extensive research and logistic undertaking aimed at achieving “a
complete biological evaluation of the depressive disorders” (Secunda et al., 1980, p. 778),
it must be concluded that the researchers ultimately failed to find their Rosetta stone.
Schildkraut (who did not collaborate in the project) said: “On the biological side, it was
research largely based on 1967/1968 science. You can’t set up a project in a new field
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388 Shai Mulinari
that’s going to run for 10 years and be relevant at the end of that 10 years” (Schildkraut &
Healy, 2000, p. 128). Indeed, by the time the researchers came to a point where they could
present their results,6many of the methods, questions, and theories (including monoamine
theories) that had guided the study had become somewhat obsolete (Maas et al., 1982;
Koslow et al., 1983; Stokes et al., 1984; Maas et al., 1984). During this time, attention
in the field had shifted away from a focus on neurotransmitters and toward their recep-
tors. But despite the apparent failure of the Biological Studies Component to reach the
explicit goals set up by its proponents, in a sense it was still a successful enterprise since
it provided a major scientific, methodological, financial, and institutional momentum to
biological research in US psychiatry. Thus, as stressed by program director Martin Katz,
the study resulted in hundreds of publications—many of which addressed issues related
to monoamine theories—and helped launch the careers of many distinguished scientists in
psychiatry and neuroscience (Katz, 2000).
Summary and Conclusion
From the onset, monoamine theories were formulated not as realistic accounts of available
data but as selective hypotheses of primarily heuristic value. This article has argued that
monoamine theories, despite some more or less well-recognized flaws, had a major impact
on the course taken by research in psychiatry, neuropharmacology, psychopharmacology,
and neurochemistry. Arguably, this impact owes a great deal to the capacity of research
groups, national institutes such as the NIMH, and pharmaceutical companies to embrace
the theories to advance unique yet sometimes overlapping projects and agendas. In a sense,
the story told here can be said to illuminate the historical productivity of heuristic hypothe-
ses in biomedicine (Baumeister & Hawkins, 2004). Thus, even though monoamine theories
were “born” refuted, they unmistakably contributed to the organization of a highly produc-
tive research undertaking centered on a set of compatible topics relating to depression
and antidepressants, which included nosology, pharmacology, genetics, and pathophysiol-
ogy. In addition, this article has shown that the choice of theory was influenced, albeit not
determined, by nationally divergent and convergent traditions. The origin and propagation
of those traditions are undoubtedly topics for further historical and sociological inquiry.
More recently, biomedical depression research has assumed a more neuroscientific
appearance. Nevertheless, the research still appears to be driven by the same preoccupa-
tions as before. An attendant question is whether today’s neurosciences have inherited
not only the preoccupations of previous generations of brain research but also a set of
embedded assumptions. Among identifiable assumptions, the most debated is perhaps that
psychotropic drugs act directly on the substrates of psychiatric illnesses and, consequently,
that their pharmacology can be used to decipher psychiatric etiology. Following this line of
thought, it may be worth pointing out that contemporary neuroplasticity theories of depres-
sion were originally conceived using exactly this pharmacological style of reasoning. Thus,
only after finding that antidepressants trigger morphological changes in neurons did sci-
entists in the mid-1990s hypothesize that depression may be associated with neuroplastic
maladaptations (Hyman & Nestler, 1996; Post, 1997; Duman, Heninger, & Nestler, 1997).
While this fact does not in any way undermine the validity of contemporary biomedical
6The first results from the Biological Studies Component were presented at a symposium at the
1980 International College of Neuropsychopharmacology (CINP) Congress in Gothenburg (Katz,
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Impact of Monoamine Theories 389
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  • ... The discoveries that we just described were soon accompanied by the proposal of theories to explain them. The action of antidepressants was soon accompanied by a "monoamine theory of depression" (Mulinari, 2012;Schildkraut and Kety, 1967) where emphasis was put on the role of noradrenaline in depression while others betted on serotonin (Coppen, 1967). This could explain the actions of, on one side the monoamine inhibitors and on the other side the tricyclic antidepressants (Domino, 1999) and postulate monoaminergic mechanisms as etiopathological agents in depression. ...
  • ... The pathophysiology of the MDD remains uncertain. The monoamine hypothesis is most common in the explanation of MDD [7]. This hypothesis supposed the deficiency of monoamines, such as serotonin, noradrenaline, and dopamine in the synapse results in depressive status. ...
    Major depressive disorder (MDD) is an important cause of disability in the world. Depression has negative influences on a person’s mental and physical health, quality of life, and functioning. The pathophysiology of depression has not yet been confirmed. The traditional monoamine hypothesis of MDD could not explain the unsatisfactory treatment response of antidepressants. Thus, it is necessary to search other probable pathophysiology of MDD. In recent years, the role of glutamate neurotransmission in depression has drawn much attention. The N-methyl-D-aspartate receptor (NMDAR) is a subclass of glutamate receptors and is implicated in the pathogenesis of MDD and other mental disorders. Furthermore, NMDAR ligands, such as ketamine and D-cycloserine, have shown antidepressive effects in several studies. The diagnosis of MDD depends on physician’s subjective evaluation which is often inconsistent. Therefore, reliable objective laboratory biomarkers are essential for more accurate and consistent diagnosis of MDD. In this review, we firstly described the structure and regulation of the NMDAR. We then searched different genes that involved in the pathway of glutamatergic neurotransmission and NMDAR, including D-amino acids, glycine, and glutamate. Various related enzymes and transporters that play a role in the modulation of NMDAR neurotransmission were also surveyed. This review aims to investigate NMDAR related metabolism, which may serve as feasible indicators for MDD and may contribute to further exploration of reliable biomarkers for MDD and promote new treatment of depression.
  • ... These substances have high biological activity, which means that they influence and regulate metabolic and physiological processes at low concentrations. Some of them are tissue hormones; others are precursors for physiologically essential substances [7]. However, the positive effect of biogenic amines is limited by their amount in the body, the increase of which can lead to undesirable effects on the body. ...
  • ... The online comments, for instance, describe the same drug, Mirtazapine, as both a savior and a personal hell, accentuating the ambivalent nature of the body-mind encounter: both attraction and repulsion characterize antidepressant drug use (Martin, 2007, 171). How antidepressants are put to work, and how the underlying physiological processes triggered by drugs are understood, depend on their historical and organizational contexts (Mulinari, 2012). Sandell (2016, 133) points to a curious paradox: whereas most pharmaceutical companies no longer develop psychoactive drugs such as SSRIs because the hypothesis of biological mechanisms underlining the efficacy of such drugs is not solid enough to justify further development, in primary health clinics, SSRIs are still the treatment of choice for depressionor what is believed to be depression. ...
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    This article is inspired by the social life of methods approach, joining a movement among social scientists engaging with ‘big data’ to contribute to methodological innovation and conceptual development in research and knowledge translation. It explores human-drug associations using a computational tool, Medicine Radar, meanwhile raising questions about the ways a digital device pushes us to rethink how drugs are known in the everyday. Medicine Radar is an apparatus for exploring human-drug associations by means of Suomi24 (Finland24) data, containing 19 million health-related online posts spanning a period of 16 years. Using defined markers, Medicine Radar sorts the medicine talk in health-related discussions, thereby assisting us to ‘see’ the actions of the drug and human responses to them. This kind of approach distances the drug from the illness experience, drawing attention to the private details of the human-drug relationship. The empirical analysis separates three areas of antidepressant use: articulations of reactions, stabilizing the life effects of drugs and coming to terms with antidepressants. Together, the online posts urge us to think of everyday experience where the effects of drugs – intended or unintended – are always lived. The side effects of antidepressants, including drowsiness, ravenous hunger, loss of sexual desire and emotional numbness, become life effects. As will be demonstrated, the move from conceptualizing such fallout as side effects to understanding them as life effects has political ramifications. The computation tool adds collective weight to antidepressant experiences and calls for politicizing their effects on life.
  • ... Similarly, many antidepressant drugs are understood to inhibit the reuptake of serotonin and noradrenaline, both classed as monoamine neurotransmitters, and this has been used to formulate, and as evidence to support, the monoamine hypothesis of depression. In particular, it has been suggested that the experiences associated with a diagnosis of depression are a manifestation of some form of imbalance, and in particular a deficiency, of either serotonin, noradrenaline or a combination of these two neurotransmitters (Hirschfeld, 2000;Mulinari, 2012). ...
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    Purpose: The purpose of this paper is to examine two competing pharmacological models that have been used to understand how psychiatric drugs work: the disease-centred model and the drug-centred model. In addition, it explores the implications of these two models for mental health service users and the degree to which they are meaningfully involved in decisions about the use of psychiatric drugs. Design/methodology/approach: The approach is a conceptual review and critical comparison of two pharmacological models used to understand the mode of action of psychiatric drugs. On the basis of this analysis, the paper also provides a critical examination, supported by the available literature, of the implications of these two models for service user involvement in mental health care. Findings: The disease-centred model is associated with a tendency to view the use of psychiatric drugs as a technical matter that is to be determined by mental health professionals. In contrast, the drug-centred model emphasises the centrality of the individual experience of taking a psychiatric drug and implies a more equitable relationship between practitioners and mental health service users. Originality/value: Although infrequently articulated, assumptions about how psychiatric drugs work have important consequences for service user involvement in mental health care. Critical consideration of these assumptions is an important aspect of seeking to maximise service user involvement in decisions about the use of psychiatric drugs as a response to their experience of mental distress.
  • ... Growing evidences indicate that mitochondrial dysfunction may also be involved in the pathophysiology of schizophrenia, autism and affective spectrum disorders and others [7][8][9][10][11][12]. In spite of domination of the theory that a depletion in the levels of monoamines, including serotonin, is a trigger of depression [13,14], the publications of last years strongly support the negative impact of mitochondrial dysfunction on synaptic plasticity and neurogenesis in depression [11,[15][16][17]. The concepts of mitochondrial dysfunction and monoamines are thought to be interrelated [9] and mitochondrial dysfunction is considered ubiquitous to many psychiatric disorders, including bipolar disorder and depression [18][19][20][21][22][23]. ...
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    Background Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica (, Moscow, Russia). Results Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. Conclusion Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders. Electronic supplementary material The online version of this article (10.1186/s12868-018-0480-6) contains supplementary material, which is available to authorized users.
  • Article
    Full-text available
    The authors conducted the first-ever study into counselor conceptualization of client problems using neuroscience theories. The authors selected an embedded mixed-methods design. Participants (N = 334) provided quantitative demographic information and responded to an open-ended qualitative question regarding a hypothetical situation of a client asking the counselor to explain depression from a neuroscience perspective. The authors coded, tallied, and transformed qualitative responses to quantitative data via frequency counts. Kappa coefficients for the coding team exceeded the threshold for acceptable reliability. Approximately half of the counselors applied neuroscience theories to explain client experiences o f depression (97.7%, n = 194), and some counselors integrated multiple neuroscience theories in their response (23.2%, n = 45). The monoamine and neuroplasticity theories were the two most common neuroscience theories for depression. Implications for research and training are discussed.
  • Article
    Alterations in brain intrinsic activity—as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN), and default-mode network (DMN)—and in neurotransmitters signaling—such as dopamine (DA) and serotonin (5-HT)—have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link, as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, whereas the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, whereas a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitter-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, whereas 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia.
  • Article
    Dopamine is the principal transmitter of several central nervous system pathways originating in the midbrain and critically involved in motor activity, learning and motivation, disruptions of which have been implicated in a number of disorders, including Parkinson disease and schizophrenia. Dopamine played a particularly significant role in the history of neurochemistry. Following a series of investigations between 1957 and 1965, commencing in the laboratory and completed in the clinic, the significance of chemical neurotransmission for normal CNS function was first demonstrated in the case of dopamine.
Literature Review
  • Article
    • The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.
  • Article
    Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3', 5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3', 5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stressvulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stressinduced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
  • Article
    • Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.
  • Article
    Introduction LITTLE IS known about the possible etiological biochemical factors relating to depressive reactions. Clinical evidence suggests that many depressions respond to the following somatic treatment: electric convulsive therapy (ECT), the imipramine type of drugs, and the monoamine oxidase inhibitor group of drugs.2,3 Do these two classes of drugs have common factors in their mechanism of action and can this be related to the fact that one antihypertensive agent, namely, reserpine, produces severe depression in a small but consistent number of hypertensive patients?4-8Rosenblatt et al,9 in 1959, were among the first to specifically suggest that changes in brain norepinephrine (NEP) may be involved in depression. Based in part on the knowledge of the effect of reserpine and monoamine oxidase inhibitors on depressed mood and norepinephrine (NEP), they hypothesized that the depressive state might be associated with a relative decrease of norepinephrine
  • Article
    IN THIS ISSUE of the Archives, the article by Duman and colleagues1 helps clarify the next layer of understanding of the neurobiology of depression and, ultimately, brings to light more powerful and selective treatment interventions. As in the catecholamine and indoleamine hypotheses of the 1960s, Duman et al appropriately rely heavily on a pharmacological bridge to better understand potential alterations in depression based on the effects of antidepressant medications. In addition, microstructural alterations in the brains of patients with depression have begun to be reported, with initial reports of increased expression of corticotropin-releasing hormone in the brains of suicide victims who had depression; increased size of the pituitary and adrenal glands; and a variety of findings concerning receptor, peptide, and structural alterations in the hippocampus, including preliminary findings of decreased hippocampal size as a function of duration of prior depressions.2 It is against this background that tracing the effects
  • Article
    • This is a report on the history and implications of the collaborative effort that evolved from the 1969 National Institute of Mental Health conference on the psychobiology of depression. The major issues identified at that time were the need to (1) assess relative validities of current systems of nosology and (2) retest critical biological hypotheses concerning the etiology and nature of the depressive disorders. Research was required that would be multidisciplinary and involve clinical settings treating diverse types of depression. The objectives and the nature of the biological and clinical collaborative programs that were designed to address these problems are described. These unique programs, initiated In the early 1970s, currently span research on nosology, genetics, neurochemistry, neuroendocrinology, and psychosocial factors. Although these studies are still in the early stages, they have resulted in significant methodologic developments in diagnosis, descriptive psychopathology, and biological measurements.