The Dopamine Hypothesis of Schizophrenia: An Historical and ...

The Dopamine Hypothesis of Schizophrenia: An Historical and 

Philosophical Analysis 

Kenneth S. Kendler 

Kenneth F. Schaffner 

Philosophy, Psychiatry, & Psychology, Volume 18, Number 1, March 

2011, pp. 41-63 (Article) 

Published by The Johns Hopkins University Press 

DOI: 10.1353/ppp.2011.0005 

For additional information about this article 

http://muse.jhu.edu/journals/ppp/summary/v018/18.1.kendler.html 

Access Provided by Purdue University at 03/04/13 6:09PM GMT

The Dopamine 

Hypothesis of 

Schizophrenia: 

An Historical and 


Kenneth S. Kendler and 

Kenneth F. Schaffner 

Abstract: The dopamine (DA) hypothesis of schizophrenia 

(DHS) has, since its inception over 30 years ago, 

been among the most prominent etiologic theories in 

psychiatry. This essay begins by summarizing the history 

of its emergence and efforts to empirically test it 

through the examination of (i) cerebrospinal fluid DA 

metabolites, (ii) neuroendocrine measures, (iii) clinical 

response to psychostimulants, (iv) brain levels of DA 

and its metabolites, (v) brain studies of DA receptors, 

and (vi) genetic association studies. We then examine 

how successful the DHS has been and by what criteria 

its performance should be evaluated. In this process, it 

is critical to distinguish the etiological DHS from the 

pharmacological DA hypothesis of neuroleptic action. 

Although the DHS stimulated much science, most efforts 

to empirically validate it have failed, in contrast with 

the well-supported pharmacological DA hypothesis of 

neuroleptic action. Nonetheless, the DHS has held the 

status of a scientific paradigm defended by some with 

great avidity. Like other temporally extended theories, 

the DHS in its most general form is relatively nonspecific 

and protean in nature. In its evolution through 

successive more specific forms, often embodying ad hoc 

modifications of subsidiary hypotheses, it became very 

difficult to falsify. Although stimulating much research, 

it has not produced a progressive research program 

generating various novel and confirmed predictions 

about schizophrenia. For most of its history, the DHS 

has lacked a viable competing alternative theory against 

which it could be incisively compared. Sociological factors, 

especially the rise to prominence of the biological 

psychiatry movement, and the conflation of the DHS 

and the DA theory of antipsychotic drug action have 

probably played an important role in its persistence. 

Psychiatry needs theories with higher levels of specificity 

and falsifiability. As the science of psychiatry matures, 

the field needs to become more self-critical about the 

validity of its theories. 

Keywords: dopamine, schizophrenia, etiology, philosophy 

of science 

This essay selectively reviews, from an 

historical and philosophical perspective, 

the dopamine (DA) hypothesis of schizophrenia 

(DHS; Table 1 lists the abbreviations 

used in this essay). Our goal is not to adjudicate 

the validity of the theory—although we arrive at 

a generally skeptical conclusion—but to focus on 

the process whereby the DHS has evolved over 

time and been evaluated. Since its inception, the 

DHS has been the most prominent etiologic theory 

in psychiatry and is still referred to widely in current 

textbooks (e.g., Buchanan and Carpenter, Jr. 

2005, 1336; Cohen 2003, 225; Gazzaniga 2004, 

© 2011 by The Johns Hopkins University Press

42 ■ PPP / Vol. 18, No. 1 / March 2011 

1257; Kandel et al. 2000, 1200). Understanding 

its origins and evolution should help to clarify the 

nature of modern psychiatry. 

This essay has two parts. First, we review 

how the DHS emerged, how it was subsequently 

tested, and how well its predictions were verified. 

We are necessarily selective because the DHS has 

generated a huge literature. We concentrate on 

earlier episodes in its history where the results of 

empirical efforts at verification are relatively clear. 

We examine the modern areas of genetics and 

receptor imaging, but given the great flux these 

fields are now in, definitive conclusions about 

their ability to verify predictions of the DHS are 

not possible. Second, we evaluate the DHS from 

the perspective of prominent theories of the nature 

of scientific progress. 

(For most of this essay, we are forced by 

historical circumstance to make the unrealistic 

assumption that schizophrenia is an etiologically 

homogenous entity. This is because, despite huge 

amounts of effort and many proposed typologies, 

no broadly validated or deeply meaningfully method 

for subdividing schizophrenia has yet emerged 

that approaches the wide acceptance of the division 

of diabetes mellitus into types I and II (or 

even the lower standard of the division of affective 

illness into unipolar and bipolar). Although there 

are important exceptions, the large majority of 

the literature on the etiology of schizophrenia that 

we here review assumes etiologic homogeneity.) 

An Historical Sketch of 

the Dopamine Hypothesis of 

Schizophrenia 

Methodology 

For empirical questions in this selective review, 

we relied, whenever possible, on the most recent 

meta-analyses or reviews found through PubMed. 

Rise of the Dopamine Hypothesis of 

Schizophrenia 

To understand the development of the DHS 

requires an appreciation of the scientific context 

in which it arose (Baumeister and Francis 2002; 

Valenstein 1998). It is difficult to now recreate 

the excitement felt by the researchers who, in the 

1950s and 1960s, were clarifying “the chemical 

language of the brain” (Carlsson 2001). Although 

chemical neurotransmission was demonstrated 

in the peripheral nervous system in the 1920s, 

debates about whether nerve cells in the brain 

communicated by chemical or electrical means 

raged well into the 1960s. In 1957, Montagu was 

the first to discover DA in brain tissue. This finding 

was quickly followed by the dramatic results 

from Ehringer and Hornykiewicz (Kopin 1993) of 

the lowered content of DA in post-mortem brains 

of patients dying with Parkinson’s disease. This 

finding led directly to the impressive treatment 

effects obtained by giving Parkinson patients L- 

dopa (Kopin 1993). 

A “paradigm shift” took place between 1960 

and 1965 when the budding field of neuropharmacology 

went from skepticism to belief that the 

monoamines—particularly DA, norepinephrine, 

and serotonin—were chemical mediators between 

nerve cells in brain (Carlsson 2001). In the early 

to mid 1960s, histofluorescence stains were developed 

whereby the cell bodies and the neuronal 

pathways for the monoamine neurotransmitters 

DA, norepinephrine, and serotonin could be traced 

(e.g., Dahlstrom et al. 1962; Dahlstrom and Fuxe 

1964; Falck et al. 1982; Fuxe et al. 1966). 

The first clear articulation of the DHS was made 

by van Rossum in 1967: 

When the hypothesis of the DA blockade by neuroleptic 

agents can be further substantiated it may have fargoing 

consequences for the pathophysiology of schizophrenia. 

Overstimulation of DA receptors could then be part of 

the etiology. (p. 327) 

As this quote indicates, a key early impetus 

for the DHS was the discovery by Carlsson and 

Lindqvist in 1963 that neuroleptic drugs effective 

in the treatment of schizophrenia increased DA 

turnover in rodent brain (that is, augmented the 

amount of DA being produced and degraded). 

However, research on the mechanism of action 

of stimulants also played an important role in 

van Rossum’s thinking (Baumeister and Francis 

2002). (van Rossum’s work was not cited in early 

American papers on the DHS. Two of the early 

theorists [S. Matthysse and S. Snyder, written 

communication, July 2006] were not aware of it 

until years later.) Although hinted at in a lengthy

Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 43 

Table 1. Abbreviations 

Abbreviation 

CSF 

Meaning 

Cerebrospinal fluid 

D1, D2, D3, D4 and D5 Names for five distinct brain DA receptors 

DA 

DHADA 

DHS 

GH 

HVA 

IT 

IRF 

TET 

Dopamine 

Dopamine hypothesis of antipsychotic drug action 

Dopamine hypothesis of schizophrenia 

Growth hormone 

Homovanillic acid (main breakdown product of DA in humans) 

Increased turnover 

Increased receptor function 

Temporally extended theory 

1968 review by Faurbye and briefly discussed in a 

1972 symposium summary by Snyder, Aghajanian, 

and Matthysse, the first detailed and widely cited 

articulation of the DHS was by Matthysse in 1973. 

Matthysse reviews evidence that clinically effective 

neuroleptic drugs are distinguished from other 

similar agents ineffective in treating schizophrenia 

by their effect on DA turnover. He then asks 

Suppose we now assume that the hypothesis of specific 

blockade of DA transmission by neuroleptic drugs is 

true; . . . does the theory give us any clues to the neuropathological 

basis of schizophrenia? (p. 203) 

He reviews what was then known about DA 

tracts in the brain, arguing that, although the 

nigrostriatal, retinal, or tubero-infundibular DA 

systems are unlikely candidates for involvement 

in psychosis, the mesolimbic DA system could 

likely influence the emotional, perceptual, and 

cognitive functions disturbed in schizophrenia. 

He concludes 

From the blocking action of neuroleptics on DA synapses, 

it is a relatively small step to postulate over-activity 

of dopaminergic transmission in schizophrenia, whether 

generalized or confined to one nuclear group. (p. 204) 

In a review paper published in 1975 (Matthysse 

and Lipinski 1975), Matthysse provides a more focused 

definition of the DHS: “too much dopamine 

is released at synapses in the central nervous system” 

(p. 558). He then states that, in fact, “there 

are several dopamine hypotheses of the etiology 

of schizophrenia,” including excessive release of 

DA at synapses, hypersensitive DA receptors, 

underactive antagonistic neurochemical systems 

and/or defective feedback loops. Presciently, 

Matthysse’s comment about “several dopamine 

hypotheses” illustrates his early awareness that 

the “general” DHS fact in fact required elaboration 

or further specification using more precise 

subsidiary hypotheses (e.g., specifying whether 

there is excess release or whether the DA receptors 

are hypersensitive). This is a point to which we 

return in the next section. 

The DHS was also influenced by observations 

that chronic administration of high doses 

of amphetamines could produce a paranoid or


schizophrenia-like psychosis (Connell 1958). Two 

studies in 1968 (Griffiths et al. 1968) and 1974 

(Angrist et al. 1974) showed that these effects 

occurred in non-psychotic individuals and did 

not result from sleep deprivation. This work was 

emphasized in Snyder’s early formulation of the 

DHS (Snyder 1976). 

Shortly after the initial articulations of the 

DHS, new scientific results began to appear of 

relevance to the nascent theory. In 1974, Hökfelt 

et al. demonstrated DA terminals in limbic cortex. 

Shortly thereafter, the first DA receptors were isolated 

and it was demonstrated, in 1976, that the 

clinical potency of neuroleptic drugs correlated 

strongly with their ability to inhibit binding of 

specific ligands at the DA receptor (Creese et al. 

1976; Seeman et al. 1976). 

The early status of the DHS was summarized in 

a detailed 1976 review by Meltzer and Stahl. Their 

definition of the DHS was “schizophrenia may be 

related to a relative excess of DA-dependent neuronal 

activity.” In addition to the mesolimbic DA 

system, Meltzer and Stahl focus extensively on the 

mesocortical DA system about which they write: 

It is tempting to assume that the disturbances of thinking 

and symbolic processes that are an essential feature of 

many . . . [p]atients in the schizophrenia spectrum are 

based on dysfunction of these dopaminergic neurons 

with cerebral cortical terminals. (p. 24) 

As emphasized earlier by Matthysse, Meltzer 

and Stahl’s review makes clear that the “relative 

excess” of DA function could arise in many places 

in complex neuronal and biochemical systems. 

A number of further scientific advances had 

direct impact on the DHS. These include the 

discovery in 1977 that low doses of the DA agonist 

drug apomorphine inhibits DA functioning 

(Aghajanian and Bunney 1977), which led to the 

development of the concept of the autoreceptor—receptors 

that sit on the pre-synaptic neuron 

and typically, when stimulated, inhibit neuronal 

firing. In 1979, two subtypes of DA receptors were 

isolated then termed D1 and D2 (Kebabian and 

Calne 1979). Genes were identified for these and 

other DA subtypes for D2 in 1988 (Bunzow et al. 

1988), D3 in 1990 (Sokoloff et al. 1990), and D4 

and D5 both in 1991 (Sunahara et al. 1991; Van 

Tol et al. 1991). 

Attempts at Empirical Validation 

The dopamine hypothesis of schizophrenia is . . . supported 

by no direct evidence. No one has found anything 

conclusively abnormal about dopamine in body fluids or 

brains or schizophrenics. (Snyder 1976, 197–8) 

Although by the late 1970s, the DHS was the 

leading biological theory for schizophrenia, it was 

widely appreciated that the supporting evidence 

for the hypothesis was entirely indirect. There 

then began a wide-spread effort, continuing up to 

the present day, to test empirical prediction of the 

DHS—that individuals with schizophrenia should 

demonstrate a functional DA excess somewhere 

in their brains. This italicized expression represents 

a high-level-of-abstraction, central hypothesis 

that is common to a range of more specific 

elaborations or subforms of a theory. Usually, the 

specific elaborations arise over time, as different 

investigators provide the details of the theory 

that elaborate on the abstract central hypothesis. 

Those details typically specify the etiology and 

mode of action of the excess DA (e.g., increased 

turnover [IT] or increased post-synaptic receptor 

function), the causal consequences of the excess 

DA (both chemical and symptomatic), as well as 

the location of action of the DA in the brain (is 

action global or regional and if the latter which 

region?). The abstract central hypothesis of the 

DHS and one possible manner of its elaboration 

is shown graphically in Figure 1. This way of 

understanding the nature of theory in psychiatry 

parallels the accounts developed both in Schaffner 

(1993, Chapters 3 and 5) and in Thagard (2000, 

Chapter 2, especially pages 34–5). 

From this immense literature, we review six 

research areas, in part because of the availability of 

good quality reviews: (i) Cerebrospinal fluid (CSF) 

DA metabolites, (ii) neuroendocrine measures, (iii) 

clinical response to psychostimulants, (iv) brain 

levels of DA and its metabolites, (v) brain studies 

of DA receptors, and (vi) genetic association studies. 

These areas, outlined in Table 2, are chosen 

to be representative of efforts to validate the DHS 

and do not reflect all relevant information about 

the DHS. Furthermore, the first four areas are no 

longer actively under investigation and so may 

be viewed with some historical detachment and


Figure 1. Schematic view of alternative versions of the dopamine hypothesis of schizophrenia (DHS) as articulated early in its history. This figure is meant 

to be illustrative rather than exhaustive. 

DHS-functional excess DA in brain 

 

 

Regional excess DA 

Global excess DA 

 

 

 

 

Mesolimbic 

DASystem 

Mesocortical 

DA System 

Due to 

increased 

postsynaptic 

receptor 

function 

Due to 

increased 

turnover 

 

 

 

 

Due to 

increased 

postsynaptic 

receptor 

function 

Due to 

increased 

turnover 

Due to 

increased 

postsynaptic 

receptor 

function 

Due to 

increased 

turnover


perspective. The last two areas are, by contrast, 

quite active foci of on-going research and therefore 

cannot be definitively summarized at this time. 

CSF Studies 

The first empirical method widely used to test 

the DHS was an examination of the key DA metabolite 

in humans—homovanillic acid (HVA)—in 

the CSF of schizophrenic versus control patients. 

If, as predicted by the DHS, DA systems in the 

brains of schizophrenic individuals are overactive, 

this overactivity should be reflected in increased 

levels of HVA in CSF. This expectation of an effect 

on the CSF is a subsidiary hypothesis of this 

variant of the general DHS. By 1976, Meltzer 

and Stahl reviewed a number of studies inconsistent 

with this prediction. Indeed, they showed, 

if anything, a tendency toward reduced DA metabolites 

in the CSF of schizophrenic patients. A 

later meta-analysis reached the same conclusion 

as the earlier Meltzer and Stahl review (Tuckwell 

and Kosiol 1993). 

These negative results raise two important 

points about the DHS. First, it could be understood 

as predicting global changes in brain DA 

function or only changes in specific DA systems. In 

this article, we refer to these two subforms of the 

DHS as global and regional, respectively. Second, 

functional excess of DA function could arise in two 

broad ways: IT or increased post-synaptic receptor 

function (IRF for increased receptor function) that 

could in turn result from changes in the number or 

sensitivity of receptors. Only the IT subform of the 

DHS predicts that individuals with schizophrenia 

would have excess CSF levels of HVA. (Indeed, 

some version of the IRF form of the DHS would 

predict decreased levels of CSF HVA.) 

The non-confirmation of the predictions of 

the DHS by the CSF findings had little impact 

on enthusiasm for the DHS. As noted by Meltzer 

and Stahl: 

this result should not be used to reject the hypothesis 

of increased DA turnover in schizophrenia since the 

functional activity of DA relevant to schizophrenia may 

not be measured by the method. (1976, 52) 

In humans, much of the HVA in CSF comes 

from the caudate nucleus (Sourkes 1973), the 

endpoint of the nigrostriatal DA system. We interpret 

Meltzer and Stahl’s comment as suggesting 

that these results argue against a global DHS—in 

which excess DA activity is seen in all brain DA 

systems—but does not disprove a more restricted 

DHS in which excess DA activity is limited to 

certain regional DA systems not reflected in CSF, 

particularly those outside the striatum. 

This point was elaborated upon by Carlsson in 

a 1978 review, which enumerated a total of five 

possible subforms of the DHS including IT, IRF, 

and other possibilities we do not examine in detail 

in this review, including “deficient inactivation of 

DA” and alterations in presynaptic DA systems. 

Hormonal Systems 

Because two pituitary hormones—growth 

hormone (GH) and prolactin—are significantly 

influenced by brain DA systems, early attempts 

were made to validate the DHS by determining 

whether expected abnormalities in these hormonal 

systems were seen in patients with schizophrenia. 

GH is phasically stimulated by DA in the arcuate 

nucleus of the hypothalamus. If schizophrenia 

were due to widespread IT in DA neurons or to 

IRF of the relevant DA receptors, then excess GH 

stimulation should be seen in schizophrenia. As 

reviewed by Marx and Lieberman (1998), studies 

of basal GH secretion in schizophrenic and control 

subjects have been inconsistent with a few finding 

increased levels of GH in schizophrenic subjects, 

but with most finding no difference. The IRF form 

of the DHS could be specifically tested by examining 

whether schizophrenia is associated with 

greater GH stimulation in response to DA agonist 

drugs. A modest number of studies have examined 

this question and results were quite variable. In 

aggregate, Marx and Lieberman conclude that 

“schizophrenic and control subjects do not appear 

to differ significantly in GH response to dopamine 

agonists” (1998, 415). The sensitivity of the GH 

system can also be tested by the administration of 

GH-releasing hormone. In a review of three such 

studies, compared with controls, schizophrenic patients 

had a similar GH response to GH releasing 

hormone in two studies and a diminished response 

in a third (Skare et al. 1994). 

Prolactin is inhibited by DA secreted into the 

portal vein of the pituitary. Increased DA turnover


Table 2. Selected Tests of the Dopamine Hypothesis of Schizophrenia 

Test Prediction of DHS Main Subform Result 

of DHS Tested 

CSF levels of HVA Increased* Reg, IT -- 

Basal levels of growth hormone Increased Reg, IT, or IRF -- 

Growth hormone stimulation to DA agonists Increased Reg, IRF - 

Basal levels of prolactin Decreased Reg, IT, or IRF -- 

Prolactin suppression by DA agonists Increased Reg, IRF -- 

Levels of DA or HVA in post-mortem brain Increased* Glob or Reg, IT - 

Psychotic symptoms in response to Increased Glob, IRF + 

amphetamine administration 

Increase in vivo levels of brain DA receptors Increased Glob or Reg, IRF -+ 

Association studies of DA-related genes 

D1 Altered Glob - 

D2 Altered Glob -- 

D4 Altered Glob -+ 

D5 Altered Glob ? 

COMT Altered Glob - 

DA transporter Altered Glob -- 

DA decarboxylase Altered Glob - 

Abbreviations: --, results strongly against prediction of DHS; - results moderately against prediction of DHS, +- results equivocal 

regarding DHS; +, genetic changes in DA receptors would most likely produce IRF but other changes could produce IT; ++ 

results strongly support prediction of DHS; Glob, global, reflecting DA function in general in the brain (or in unknown more 

specific areas); IRF, increased receptor function (due to increased number or sensitivity of DA receptors); IT, increased turnover; 

Reg, regional, reflecting DA function in specific brain areas. 

*Note that CSF levels of HVA and brain levels of DA or HVA primarily test for the IT version of the DHS. However, if the 

IRF version of the DHS were true, then you might expect the reverse result. That is, due to increased feedback due to increased 

receptor function, the levels of HVA or DA could be reduced.


or IRF in this system should produce reduced 

prolactin levels in schizophrenic subjects. Marx 

and Lieberman (1998) conclude that the available 

literature suggests no systematic differences between 

medication-free schizophrenic subjects and 

control subjects in their basal level of prolactin. 

Several studies have also looked at the suppression 

of prolactin by DA agonist drugs—which would 

test the IRF version of the DHS—and found no 

systematic differences between schizophrenic patients 

and controls. 

The neuroendocrine hypotheses derived from 

DHS have not been empirically validated. How 

strong were these tests? Although we could find 

no published discussion of the broad relevance of 

these findings for the DHS (as there were for the 

CSF results), the conclusions seem similar. These 

results would argue against a global DHS but not 

more restricted hypotheses that postulated that 

IT or IRF versions of the DHS were still, true but 

resided elsewhere in the brain. 

Psychotic Symptoms in Response to 

Psychostimulant Administration 

As noted, an early key finding that helped lead 

to the original formulation of the DHS was the 

clinical observation of schizophrenia-like states 

resulting from administration of amphetaminelike 

drugs. A derivative empirical test for the DHS 

was developed that involved the administration, 

under controlled conditions, of modest doses of 

amphetamine to individuals with schizophrenia 

and matched controls. The prediction of the 

DHS was that schizophrenic individuals but not 

controls would develop psychotic symptoms upon 

amphetamine administration. This test would 

apply specifically to the IRF form of the DHS, 

which hypothesizes excess or supersensitive DA 

receptors. 

In a detailed review published in 1987, 

Lieberman et al. identified eleven controlled 

studies that compared the clinical response to 

psychostimulants in schizophrenic and nonschizophrenic 

comparison subjects. We were unable to 

locate any more recent controlled trials. Of these 

eleven studies (which administered amphetamine, 

methylphenidate or ephedrine), seven found the 

schizophrenics subjects to “worsen in substantially 

greater proportion” than non-schizophrenic controls, 

whereas four did not. This review paper also 

pooled the results across all studies and reports a 

highly significant difference in the rate of clinical 

worsening after psychostimulants in schizophrenic 

versus non-schizophrenic subjects (Lieberman et 

al. 1987). 

These results seem broadly consistent with the 

IRF subform of the DHS. However, the quality 

of this test of the DHS is a function of the degree 

to which the effects of these psychostimulants 

are specific to the DA system. To take one wellcharacterized 

psychostimulant as an example, 

amphetamine is a “dirty drug” and has greater 

potency at causing release of norepinephrine 

than of DA and is about equipotent in blocking 

the reuptake of the two neurotransmitters (Koob 

and Le Moal 2006). If stimulation of DA receptors 

were the sole means by which amphetamine 

increased psychotic symptoms, then the purer DA 

agonist drugs ought to have greater psychogenic 

potential. This has not generally been observed 

(Depatie and Lal 2001). In summary, evidence 

from psychostimulant challenge studies provides 

some support for the DHS. 

Brain DA Metabolites 

Although beset with a range of methodological 

difficulties, a direct test of the IT subform of the 

DHS would be to compare levels of DA or HVA 

in the brains of individuals with schizophrenia and 

controls. In their 1991 review, Davis et al. summarized 

five such studies in postmortem samples. 

In total, these studies examined four subcortical 

regions (amygdala, putamen, caudate, and accumbens) 

and the temporal, cingulate, and frontal 

cortex. Because several studies examined multiple 

brain regions, thirteen comparisons were summarized. 

Focusing where possible on schizophrenics 

who were neuroleptic-free at the time of death, no 

differences were found in ten comparisons and in 

three results were as predicted by the DHS. The 

positive findings were from three different regions: 

amygdala, accumbens, and caudate. We are aware 

of an additional study not included in this review 

(Farley et al. 1977), which found no significant 

elevation in levels of DA or HVA in the brains of 

schizophrenic individuals.


The results from post-mortem studies of DA 

or HVA levels have not, in general, confirmed 

predictions of the DHS. The positive findings 

that have emerged are inconsistent with respect to 

anatomical location. These studies provide a more 

direct test of the IT subform of the DHS than was 

possible using CSF or neuroendocrine approaches. 

In particular, post-mortem studies can examine 

abnormalities in DA function that are anatomically 

restricted in their effect. A complexity in the 

interpretation of these findings is that some of the 

IRF forms of the DHS would predict decreased 

brain levels of DA or HVA, the opposite of that 

predicted by the IT version. 

Brain DA Receptors 

As pointed out in 1975 by Matthysse and 

Lipinski, perhaps the excess DA transmission is 

due to IRF in turn the result of greater numbers or 

increased sensitivity of brain DA receptors. When 

the original DHS was articulated, it could not 

have been foreseen that the DA receptor—which 

was then postulated but not yet isolated—would 

first become two and then five different receptor 

subtypes. 

The literature on post-mortem and in vivo 

measurement of DA receptors in schizophrenia 

is both large and technically complex. We rely 

here largely on results from the most recent metaanalysis 

of the literature published in 2001 (Kestler 

et al. 2001) and a 2005 review by Abi-Dargham 

(Gunderson et al. 1995). Sufficient studies were 

available only to examine D1 and D2 receptors. 

Examining both post-mortem and in vivo studies, 

a moderate to large effect was observed for 

schizophrenic versus control subjects for the D2 

but not the D1 receptor. Interestingly, both receptor 

density and affinity were elevated in patients 

with schizophrenia. The effects on the D2 receptor 

were substantially greater in patients currently or 

recently on neuroleptic medication. Controlling 

for this effect diminished but did not eliminate the 

observed difference. The results differed neither in 

post-mortem versus in vivo studies or across brain 

regions. A number of studies examined multiple 

regions. Of the thirty-six studies, thirty-four examined 

all or parts of the striatum (the terminal of 

the Nigrostriatal pathway). Only four examined 

the nucleus accumbens (a terminal region for the 

mesolimbic DA pathways) and two the frontal 

cortex (the terminal region for the mesocortical 

DA pathway). 

Although it is clear that schizophrenic subjects 

have elevated D2 receptor density in their brains, 

the more crucial question of whether this is due to 

schizophrenia or neuroleptic exposure is less clear 

than this review (Kestler et al. 2001) indicates for 

at least four reasons (J. Kleinman MD, personal 

communication, October 2005). First, the number 

of drug-naïve schizophrenic subjects studied 

post-mortem was probably too small to provide 

definitive data. Second, despite evidence that the 

men and women might differ systematically in the 

number of D2 receptors, several studies included 

in this review were poorly matched for sex in 

a way that could produce artifactually positive 

findings. Third, two of the studies that present 

the strongest evidence for elevated D2 receptor 

numbers in drug-free subjects have a large overlap 

in their schizophrenic subjects (Tune et al. 1993; 

Wong et al. 1997). Fourth, one study showing no 

schizophrenia control difference in baseline D2 

receptor binding potential was not included in the 

review (Abi-Dargham et al. 2000). Abi-Dargham 

concludes that the findings on D2 receptors in 

schizophrenia post-mortem brain tissue “are 

related to prior neuroleptic exposure rather than 

to the disease process per se” (Gunderson et al. 

1995). 

Abi-Dargham reviews seventeen imaging studies 

of striatal D2 receptors in drug-naïve or drug-free 

schizophrenic patients versus controls (Gunderson 

et al. 1995) and finds across studies a significant 

but modest 12% increase. Of concern however, 

is a strong temporal trend in these results. These 

studies can be divided into those published before 

1991 (n = 5), between 1991 and 1995 (n = 6), and 

after 1995 (n = 7). The mean effect size for schizophrenia–control 

differences declines substantially 

across time: before 1991, +0.91; 1991 to 1995, 

+0.53; and after 1995, +0.16. These results, along 

with concerns about this literature raised above, 

at least casts some uncertainty about the correct 

interpretation of the D2 in vivo studies in schizophrenia. 

Abi-Dargham goes on to conclude that 

in vivo imaging studies have consistently failed to


find evidence of altered striatal D1 receptor availability 

in schizophrenic patients and notes that the 

modest number of studies of prefrontal D1 receptors 

in schizophrenia have produced no consistent 

evidence of alterations (Gunderson et al. 1995). 

Even after recognition of these problems, D2 

receptor studies provide some of the strongest 

direct empirical verification of the DHS obtained 

to date, of particular relevance to the IRF subform 

of the general theory. However, contrary to 

prior suggestions that a regional DHS was most 

plausible, these results are supportive of a global 

DHS, because excess DA receptors have been seen 

across three of the major brain DA systems. In fact, 

most of the positive evidence coming from a DA 

system—the nigrostriatal—that earlier advocates 

of the theory had argued was not likely to be 

primarily involved in schizophrenia. As may be 

recalled, the nigrostriatal DA system contributes 

most strongly to CSF HVA concentration. The 

negative results from the CSF HVA studies were 

discounted largely because the nigrostriatal system 

was thought to have little to do with the etiology 

of schizophrenia. 

Genetics 

At the inception of the DHS, it would have 

been impossible to foresee that tools would develop 

to test whether variants in genes involved 

in the brain DA system influence susceptibility to 

schizophrenia. Given that genetic factors impact 

strongly on liability to schizophrenia (Sullivan et 

al. 2003), if the DHS were true, some of this genetic 

risk would likely be expressed in variants that 

directly or indirectly resulted in increased brain 

DA function. This approach might be considered 

a further subdivision of the DHS, with specific genetic 

variants contributing to either the IT or IRF 

mechanisms, in either a global or specific regional 

manner (Figure 1). We do not pursue these specific 

issues further here. 

Association studies are the method of choice 

to determine whether specific genes are etiologically 

involved in a disorder. Therefore, we review 

the large literature for those genes known to be 

directly involved in DA function: DA receptors, 

synthetic and degradative enzymes, and the DA 

transporter. (For a more detailed recent review of 

this literature, see Talkowski et al. 2007). 

We begin with genes for which meta-analyses 

are available. The D2 receptor gene has been 

widely studied with most interest focusing on the 

Cys311Ser polymorphism. A recent meta-analysis 

of 27 case-control studies reported a significant 

but modest association between the Cys allele and 

schizophrenia with estimated odds ratios (ORs) of 

1.4 (Glatt and Jonsson 2006). A meta-analysis of 

10 studies of a different variant in the same gene 

(-141C insertion/deletion) found no evidence for 

association with schizophrenia (Glatt et al. 2004). 

The literature on the Ser9Gly variant in the 

D3 receptor gene and schizophrenia is vast, with 

seven published meta-analyses. The most recent of 

these included more than 11,000 total subjects and 

showed a very small and nonsignificant association 

with schizophrenia (Jonsson et al. 2004). In the D4 

receptor, most interest has focused on the 48-basepair 

repeat in exon 3. A recent meta-analysis of 

19 studies showed no significant association with 

schizophrenia (Jonsson et al. 2003). Seven studies 

had examined a twelve base-pair repeat in exon 1 

and no significant association was found (Jonsson 

et al. 2003). However, three studies examined a 

promoter variant (-521C/T) and a meta-analyses 

of these studied indicated a modest and significant 

association with schizophrenia (OR = 1.22). 

The literature on the association between variants 

in the catechol-O-methyl transferase (COMT) 

gene and schizophrenia is immense and inconsistent. 

Two recent meta-analyses have reached 

negative conclusions for the widely studied Val/ 

Met polymorphism (Fan et al. 2005; Munafo et 

al. 2005) although other variants in the gene have 

been studied and found to be associated (e.g., 

Shifman et al. 2002). A study with more than 

2,800 individuals looking at both the Val/Met 

polymorphism and a previously identified highrisk 

haplotype be was negative (Williams et al. 

2005). (A haplotype is a DNA segment so short 

that it tends to pass through populations intact). 

A recent meta-analysis of six case-control studies 

of the VNTR polymorphism in the 3´ untranslated 

region of the DA transporter showed no evidence 

for association with schizophrenia [Gamma et 

al. 2005]). 

The most studied variant in the DA transporter 

gene is a variable number tandem repeat in the 

3´ untranslated region of the gene. Gamma et


al. (2005) performed a meta-analysis of six casecontrol 

studies that produced no evidence for association. 

They reviewed the known family-based 

association studies of this polymorphism, which 

were also all negative. 

We now turn to those genes for which no 

meta-analyses were available. For the D1 receptor, 

the most recent locatable report, which contains 

both new results and a literature review of several 

polymorphisms, finds no consistent evidence for 

association with schizophrenia (Kojima et al. 

1999). For DOPA decarboxylase, we located two 

negative reports (Borglum et al. 2001; Zhang et 

al. 2004). For tyrosine hydroxylase, we found 

a recent negative report with a short literature 

review that indicated mixed prior results (Pae et 

al. 2003). Also noteworthy is a recent study that 

examined eighteen variants in twelve different 

key DA-related genes in 496 schizophrenic and 

matched control subjects (Hoogendoorn et al. 

2005). None of these were associated. 

Although this review is not exhaustive, a 

general picture emerges. The large majority of 

genetic studies that have attempted to validate 

the DHS have produced negative results. Two 

positive findings emerge, the best validated of 

which is the Cys311Ser polymorphism in the D2 

receptor. Less well studied is a promoter variant 

in the D4 gene. The effect sizes of these variants 

are, however, modest with ORs in the range of 

1.2 to 1.4. A monozygotic twin of an individual 

with schizophrenia has a risk for schizophrenia 

that is increased 50- to 100-fold (Sullivan et al. 

2003). If these gene effects are real, they account 

for very small proportions of the total genetic risk 

for schizophrenia. 

What do the findings from genetic association 

studies tell us about the DHS? The large majority 

of the data is inconsistent with the theory. But how 

strong are these tests? As pointed out by Talkowski 

et al. (2007), many of the association studies of 

DA-related genes in schizophrenia have been 

underpowered to detect modest effect sizes that 

are being seen in complex diseases. Furthermore, 

genomic coverage has also been far from ideal for 

most studies. The number of genetic variants that 

impact on DA function in the human brain may 

be very large. The field has focused to date on the 

obvious suspects, which together may constitute a 

small proportion of all genes influencing brain DA 

systems. Individual negative findings may therefore 

be of limited overall significance. In the next 

several years, multiple genome-wide association 

studies of schizophrenia will be published, further 

clarifying the relationship between DA-related 

genes and risk for schizophrenia. 

How are we to interpret the positive findings, 

especially given that variants at the D2 Cys311Ser 

polymorphism may make a small contribution 

to the genetic risk for schizophrenia? Do these 

results confirm the DHS? Is it significant that the 

leading susceptibility genes for schizophrenia do 

not seem to have a major impact on brain DA, but 

rather may alter glutamate functioning (Owen et 

al. 2004)? 

Reformulations of the DHS 

In its earliest phases, the DHS focused on the 

full syndrome of schizophrenia. However, on 

closer examination, the two major indirect supports 

for the DHS were not equally compelling 

for all aspects of schizophrenia. Neuroleptic drugs 

were more effective at treating positive symptoms 

of schizophrenia than the negative symptoms. 

Amphetamine-induced psychosis reflected much 

more the positive than the negative symptoms of 

schizophrenia (Connell 1958). 

In the 1980s, negative symptoms became more 

central to the conceptualization of schizophrenia 

(Andreasen 1981; Crow 1980). This led to a reevaluation 

of the DHS, which was also prompted 

by studies in Japan (reviewed in Meltzer and Stahl 

1976) and later in the United States (e.g., Cutler 

et al. 1984; Tamminga et al. 1986), showing that 

DA agonist drugs improved the clinical picture in 

schizophrenia, particularly the negative features. 

Although this effect could result from DA autoreceptor 

stimulation, they raised the question of 

whether negative symptoms might actually be due 

to functional DA deficits. 

These and other results lead to an effort by 

Davis et al. to propose, in 1991, a major revision 

of the theory. Their formulation was that 

“schizophrenia can be characterized by hypodopaminergia 

in mesocortical and hyperdopaminergia 

in mesolimbic dopamine neurons” (Davis et al. 

1991). Their proposal represents a modification


of the original DHS in two major ways. First, this 

proposal increased the anatomic specificity of the 

original hypothesis proposing specific pathways or 

regions for the action of DA. Second, and more 

radically, it reversed the direction of the original 

hypothesis with respect to one of these major DA 

tracts. 

Figure 2 outlines the changes in the DHS as 

articulated by Davis et al. Note that the apex of 

the figure is yet more abstract and reads “DHS = 

dysregulation of DA in brain.” The boxes under 

the mesocortical DA system now read “decreased 

turnover” or “decreased post-synaptic receptor 

function.” 

Attempts at Empirical Evaluation of 

the DHS—Summary 

We could not summarize herein all studies relevant 

to the DHS, reviews of which continue to 

appear regularly in the psychiatric literature (e.g., 

Abi-Dargham 2004; Hietala and Syvalahti 1996; 

Willner 1997). For example, we have not examined 

studies of plasma levels of HVA, which may 

help to evaluate a “global” DHS. Surprisingly, no 

meta-analyses or detailed reviews of this literature 

were found. Several (Garcia et al. 1989; Maas et 

al. 1993; Zhang et al. 2001) but not all studies 

(Steinberg et al. 1993) report elevated levels of 

plasma HVA in schizophrenic versus control subjects. 

However, a minority of plasma HVA comes 

from central DA neurons (Amin et al. 1995). Furthermore, 

plasma HVA levels can be substantially 

influenced by state variables (Csernansky and 

Newcomer 1994), such as diet (Donnelly et al. 

1996; Kendler et al. 1983), exercise (Kendler et al. 

1983), and mental stress (Sumiyoshi et al. 1999). 

Studies of plasma HVA are unlikely to provide 

definitive evidence about the validity of the DHS. 

We also have not reviewed the empirical literature 

favoring the role of DA in neuroleptic action. 

We do not dispute the strength of this evidence, 

but argue (see below) that it is of limited relevance 

to an evaluation of the DHS. 

Table 2 summarizes the empirical tests of the 

DHS that we have evaluated. Two summary points 

are noteworthy. First, overall, the DHS has performed 

poorly. Few of its predictions have been 

empirically validated (although we do not claim 

that the quality of these tests has been uniformly 

high or that we have reviewed all the relevant 

information). Second, many of these tests were 

not evaluating the same scientific hypothesis. 

Some were testing the IT version of the DHS and 

others the IRF version. Some were testing regional 

versions of the DHS and other global versions. 

In seeking a perspective on the current status 

of the DHS, we could find no more appropriate 

view than this recent quote from in a text edited by 

Carlsson and Lecrubier (2004, 99) from original 

comments by Stahl: 

In spite of much research effort over more than 30 

years, direct evidence for changes in brain dopamine 

concentrations or in dopamine receptor densities 

remained frustratingly intangible. However, in recent 

years a new lease of life has been given to this hypothesis. 

. . . Rather than seeing dopamine hyperactivity as a 

primary source of pathology in schizophrenia, we now 

see this rather as a vector of a more complex primary 

etiology, which allows the expression of psychotic 

symptomatology. In this model, the primary deficit 

would lie in inappropriate information processing in the 

prefrontal cortex, perhaps through structural anomalies 

in synaptic organization during development, perhaps 

due to plastic changes in connectivity involving 

anomalies in glutamatergic transmission. In addition, 

the abnormalities in dopaminergic neurotransmission 

may be better considered as dysregulation rather than 

hyperactivity, with certain symptoms, particularly cognitive 

ones being related to insufficient dopaminergic 

activity in the cortex. 

The simpler form(s) of the DHS—as originally 

postulated—are difficult to recognize in this formulation. 

Consistent with Davis’s modification, 

the emphasis is on DA “dysregulation” rather 

than hyperactivity. DA abnormalities are no longer 

given etiologic primacy, which in this account 

seems to have been shifted to glutamate. If this 

reflects a “new lease on life” for the DHS, it is 

in the form of a substantially altered theory, and 

even more likely, as a virtual replacement of the 

original DHS. This is an issue we return to toward 

the end of the next section. 


How successful has the DHS been and, by 

what criteria should we evaluate its performance? 

Trying to answer this question leads us through 

several major theories of scientific progress and to 

two further questions: (i) Would a more produc-


Figure 2. Schematic of the revised DHS proposed by Davis et al (1991). 

DHS – dysregulation of DA in brain 

Down regulated 

Mesocortical 

DA System 

 

Up regulated 

Mesolimbic 

DA System 

Due to 

increased 

turnover 

Due to 

increased 

postsynaptic 

receptor 

function 

Due to 

increased 

turnover 

Due to 

increased 

postsynaptic 

receptor 

function 

 

 

tive theoretical approach toward the etiology of 

schizophrenia have been possible? and (ii) Why 

has the DHS persisted despite its relatively poor 

empirical track record? 

Evaluation of the DHS in the 

Light of Four Theories About 

the Nature of the Scientific 

Progress 

Karl Popper 

In their influential review, Meltzer and Stahl 

(1976) wrote 

If, as Karl Popper says, the value of a hypothesis lies 

not so much in whether it is right or wrong but in its 

capacity to stimulate attempts to refute it, then the DA 

hypothesis of schizophrenia has been extraordinarily 

successful. 

A PubMed search for “schizophrenia” or “psychosis” 

and “dopamine” yielded 5,880 articles 

from 1963 to March 2008. If the criterion for success 

of a theory is its ability to generate research, 

then Meltzer and Stahl are correct and DHS has 

been strikingly successful. However, Popper’s work 

on the evaluation of scientific theory repeatedly 

stressed not the generativity of a theory but its 

falsifiability (Magee 1982). Only by examining 

how a theory could be disproven was it possible, 

according to Popper, to discriminate a truly scientific 

from and a pseudo-scientific theory (Popper 

1959, 1962). Furthermore, according to Popper, 

theories could vary in their degree of falsifiability. 

Theories of greater falsifiability are, Popper argued, 

of greater scientific value because they make 

bolder and more informative claims. Scientific 

progress would consist of a series of conjectures


and refutations, as newer and yet more falsifiable 

theories were advanced. 

How would the DHS fare on these Popperean 

grounds? At its inception, the DHS was highly abstract 

and nonspecific, postulating that the etiology 

of a complex neuropsychiatric syndrome was due 

to hyperactivity in one neurotransmitter system. 

Even at the time of the articulation of the DHS, 

neurotransmitter systems were known to be complex 

and diverse, with the same neurotransmitter 

being used in different pathways with distinct 

functional roles. Control mechanisms existed at 

many levels, both within and between cells. Overactivity 

of the system could arise in many ways. 

As scientific understanding of brain functioning 

advanced, this problem became worse, making 

it more and more difficult to articulate a single, 

clear test of the DHS. Because of the complexity 

of the systems involved, the DHS was elastic in 

absorbing a wide range of results. The IT version 

of the DHS predicted that levels of DA and HVA 

should be increased in the brains of individuals 

with schizophrenia. However, the IRF version of 

the DHS could produce a decrease in DA and HVA 

levels. If abnormalities were not found in global 

measures of DA function, then it was because the 

abnormalities in schizophrenia were found only 

in specific brain regions or pathways. 

In Popper’s terms, the DHS had a low degree 

of falsifiability. As Popper might have predicted, 

given its abstract formulation, if one prediction of 

the DHS was not confirmed, another easily took 

its place. This nonspecificity allowed the DHS to 

take on the protean features that we described. In 

this process, the DHS has become nearly immune 

from falsification. Indeed, in its latest incarnation 

(see quote above), it seems to be more of a general 

framework than a specific theory. 

There is a deep irony in the observation that the 

DHS has fared poorly at the Popperean criterion 

of falsifiability. The DHS emerged at a time when 

the nascent field of biological psychiatry argued 

strongly that psychoanalysis had to be abandoned. 

One key argument was that psychoanalysis was 

not a science that was illustrated by the protean 

and non-falsifiable nature of key psychoanalytic 

theories. Such theories, they argued, could explain 

anything. At its inception, early biological psychiatrists 

would have insisted that the DHS was the 

antithesis of psychoanalytic theory. However, over 

time, the nature of DHS as a scientific hypothesis 

has come to resemble the psychodynamic theories 

that it was meant to displace. 

Scientists have frequently embraced the Popperean 

philosophy and, on deeper reflection, later 

became more critical of this approach (Katz 1994), 

in part because the actual flexibility and practice 

of science go beyond the Popperean model. It is to 

such alternative approaches we now turn. 

Thomas Kuhn 

The work of Kuhn in his classic “The Structure 

of Scientific Revolutions” (Kuhn 1996) can help 

us to understand the endurance of the DHS. For 

Kuhn, Popperean falsification did not accord with 

scientific practice. Rather, Kuhn suggested that 

scientists work within broad conceptual frameworks 

or “paradigms.” Like most human beings, 

working scientists find it difficult to think outside 

the framework in which they “grew up.” Indeed, 

Kuhn suggested that scientists typically strongly 

resist purported falsifications of their paradigms, 

and irrationally retain belief in them in the face 

of increasing anomalies. However, at some critical 

point, two things can occur together, which unleashes 

what he termed a “scientific revolution.” 

First, the accumulation of anomalies in a particular 

research paradigm becomes unsustainable. Second, 

another paradigm becomes available that 

does a superior job at explaining these anomalies. 

Then the scientific field undergoes a crisis, and experiences 

a “conversion” as individual researchers 

(more often the young than the old) switch to the 

new paradigm. 

The DHS probably does not rise to the level of 

a Kuhnian paradigm, which might, for example, 

be an appropriate description for the “biomedical 

model” for psychiatric disorders. Nonetheless, 

some of the insights of Kuhn on the historical process 

of science can be usefully applied to the DHS. 

In particular, no revolution has occurred in 

theories about the etiology of schizophrenia that 

has resulted in the wholesale abandonment of the 

DHS. Why? Certainly, many empirical findings, 

some outlined above, are poorly explained by 

the DHS. However, one key ingredient has been


lacking—a viable alternative theory against which 

the DHS has had to compete. Thus, one potential 

lesson from Kuhn for the DHS is a negative one: 

it persisted because no sufficiently prominent and 

more successful alternative theory ever developed, 

in tandem with which the burgeoning empirical 

anomalies of the DHS could generate a true crisis 

leading to a subsequent revolution. At present, 

there is still no consensus on an alternative theory 

to the DHS, although most speculation seems to 

focus on multi-neurotransmitter neurocircuitry, 

in which glutamate may play a prominent role 

(Harrison and Weinberger 2005). 

Imre Lakatos 

In an attempt to synergize Popper’s falsifiability 

approach with Kuhnian insights, Lakatos 

(1970) developed what he termed “a methodology 

of research programs.” Research programs, 

he suggested, typically responded to problems of 

falsifying experiments, not with wholesale rejection 

of their theory, but rather with modifications 

of its peripheral elements, leaving intact what he 

called its “hard core.” Furthermore, in contrast 

with Kuhn, Lakatos suggested that proponents of 

different programs could communicate with each 

other and assess the relative strengths of different 

“programs.” 

Lakatos was particularly interested in distinguishing 

two kinds of programs. Progressive 

research programs confronted difficult empirical 

facts, explained them using their theories, and generated 

novel predictions that were subsequently 

empirically confirmed. Einstein’s theory of general 

relativity is an exemplar of a progressive research 

program. It predicted the unexpected “bending” 

of light around the sun observed by Eddington in 

1919 and continues to be verified by increasingly 

accurate physical measures of our universe (Bennett 

2005). 

By contrast, degenerating research programs 

confront empirical difficulties with ad hoc alterations 

to their hypotheses that explain the individual 

anomaly, but do not account for new facts. 

A classical example of a degenerating research 

program is the Ptolemaic astronomic system 

that, when confronted with increasingly accurate 

measures of planetary motion, simply added more 

epicycles. 

Which of these systems does the DHS most 

closely resemble? The DHS did generate a few 

novel findings such as the association between 

schizophrenia and the Cys311Ser polymorphism 

in the D2 gene. However, this result must be set 

against the many failed predictions of the theory, 

many of which were accompanied by post hoc 

rationalizations about the source of the failure. 

Although the picture is mixed, in general, the DHS 

has more closely resembled a degenerating than a 

progressive research program. 

Bayesian Approaches 

One difficulty with Lakatos’s vision of scientific 

progress is the lack of both a general measure to 

assess how well a program is faring and a system 

by which to determine how experimental successes 

or failures incrementally impact on the validity 

of an underlying theory. Several philosophers 

of science have developed an approach to these 

problems utilizing a Bayesian model of scientific 

reasoning (Dorling 1979; Howson and Urbach 

2005; Schaffner 1993). 

From a Bayesian perspective, the DHS began 

as a theory with a reasonable prior probability of 

being true. The relationship between DA blockade 

and antipsychotic drug action had been well 

supported and consistent evidence indicated that 

DA agonist drugs could produce psychotic-like 

pictures. A Bayesian model allows each new experiment 

to impact on the posterior probability 

that a theory is true. A verification of the predictions 

of the theory makes it more likely to be true. 

A failure of verification makes it less likely to be 

true. The size of the change in this probability 

relates to the quality of the test. The better the 

test, the bigger is the change in either direction. 

So, when Eddington showed that light from a 

distant star was really bent when it passed by the 

sun, this had a big impact on the probability that 

Einstein’s theory of general relatively was true. 

It was a powerful test and the prediction of the 

theory was validated. 

How has the DHS fared from a Bayesian viewpoint? 

It has had many tests, most of them of only 

modest quality. However, a high proportion of 

them were disconfirming—the prediction of the 

DHS was not verified. Therefore, in aggregate, 

although the DHS started with a reasonable prior


probability of being true, this probability has 

declined over the years as non-verifications have 

substantially outnumbered verifications. However, 

it is possible that further advances in genetics or 

imaging that confirm predictions of the DHS could 

reverse this trend. 

The Bayesian viewpoint—one strength of 

which is its ability to be consistently updated as 

new information becomes available—can also 

incorporate evolution of the theory itself. That 

is, we could see the “revised” DHS articulated by 

Davis et al. (Figure 2) as a new theory that might 

have stronger support from a Bayesian viewpoint. 

Other Accounts of Scientific Progress 

and the Issues of Theory Identity and 

Theory Substructure 

Other philosophers of science have grappled 

with the issues of scientific progress, including 

Laudan (1977), Shapere and Dordrecht (1984), 

and Kitcher (1993). These philosophers have additional 

suggestions that, although possibly useful 

for the DHS, cannot be reviewed in the space 

available. It might be of interest, however, to note 

yet another problem for the DHS that would be 

raised by Laudan’s analysis. 

In his Progress and Its Problems, Laudan set 

out a problem-solving model of progress in which 

quite disparate “research traditions” could compete 

with each other by attempting to solve their 

own key problems more efficiently and completely. 

Applying this commonsensical approach to the 

evaluation of scientific progress, we can simply 

ask—Did the DHS achieve its main aim of solving 

the problem of the etiology of schizophrenia? The 

answer, we would suggest, is no. However, we are 

aware that this is a high standard especially for 

the young field of psychiatry. 

The history of DHS’s attempted verifications 

and apparent falsifications reviewed above highlights 

the changing character of the assumptions 

of the DHS over time. This is a feature of what 

Kuhn termed paradigms and Lakatos referred 

to as research programs, and an adaptation and 

elaboration of Lakatos’ distinction between the 

hard core and the peripheral hypotheses of a 

theory might shed some additional light on this 

history. One of us (KFS) has developed a relevant 

philosophical account of scientific progress that 

incorporates these themes from both Kuhn and 

Lakatos (Schaffner 1993), the elements of which 

were introduced above and represented graphically 

in an atemporal manner in Figures 1 and 2 

(that is, we are not showing temporal progression 

of the changing theories over time, but only the 

alternatives at a given time). 

That analysis, extensively applied to a research 

program in immunology in (Schaffner 1992), suggests 

that a research program is best analyzed as 

a temporally extended theory (TET), which is in 

turn partitioned into high-level central hypotheses 

and a temporal series of more specific mechanisms 

that embody the central hypothesis. If the specific 

mechanisms, which instantiate the central high 

level hypothesis and are empirically testable, fail 

tests of verification, and these mechanisms become 

patched up in ad hoc ways, then any competing 

account with a distinctly different central 

high-level hypothesis becomes significantly more 

attractive. On the other hand, if a TET is successful, 

investigators working with it will develop a 

series of rigorous experimental tests that cannot 

be accounted for by other competing mechanisms. 

When that situation occurs, the TET account suggests 

that we have attained “direct evidence” for 

the high-level central hypothesis. Viewed from 

this perspective, the DHS would have the central 

high-level hypothesis of excess DA activity contributing 

to the etiology of schizophrenia. The 

specific mechanisms (and their related tests of 

CSF, endocrine measures, post-mortem DA levels) 

have generally faired poorly in empirical tests and 

thereby reflected poorly on the attractiveness of 

the central hypothesis. The search for such “direct 

evidence” was a “holy grail” of DHS research, 

and, alas, like the grail, it has not yet been found. 

This TET analysis also suggests that only by 

stretching the original central or core abstract 

hypothesis was the theory significantly modified 

as in Davis et al.’s 1991 revised DHS. It is possible 

that the central or core hypothesis could be 

still further abstracted from the original DHS 

formulation, namely to the even more unspecific 

claim that “dopamine must have something to do 

with schizophrenia” or the problem is with DA 

“dysregulation.” However, such an additional


abstraction makes the hypothesis more vague 

and harder to test empirically. Similarly, the very 

broad extension of the theory summarized in the 

quote from Stahl suggests a violation of a core 

hypothesis of the original DHS, and in point of 

fact, a replacement by a more complex theory 

that is actually a competitor of the original DHS. 

In addition, and somewhat similar to the 

Kuhnian point about the need for a competing 

paradigm as a condition for a scientific revolution, 

from the TET perspective, a scientific field would 

not be ready to abandon a central hypothesis in 

the absence of an alternative. In the Stahl quote, 

and much of the recent literature on the DHS, 

this emerging multi-transmitter hypothesis may 

be paving the way for an ultimate rejection of 

any simple DHS. 

How Might We Have Done Better? 

Although we can be justly criticized as passing 

judgment from a position of hindsight, it is nonetheless 

worthwhile to ask how the DHS might 

have done better and been made more falsifiable 

and progressive. Psychiatric researchers might 

have emulated the molecular biology that was a 

model for them during the period that the DHS 

was developed, and attempted to follow a Popperlike 

methodology of “strong inference.” Such an 

approach was articulated by Platt, who in 1964 

attempted to summarize the methods then used 

by the stunningly successful discipline of molecular 

genetics. Platt suggested that rapid scientific 

progress could be made only if well-formulated 

alternative hypotheses were subjected to crucial 

experiments designed to eliminate most of the 

alternatives. He characterized this approach as 

involving the following steps: 

1. Devise alternative hypotheses. 

2. Devise one or more crucial experiments with alternative 

possible outcomes, each of which will, as nearly 

as possible, exclude one or more of the hypotheses. 

3. Carrying out the experiment so as to get a clean 

result. 

1’.Recycle the procedure, making subhypotheses or 

sequential hypotheses to refine the possibilities that 

remain; and so on. 

Closely integrated with this attempt at strong 

tests whose goal was disproof was the need to 

simultaneously entertain multiple hypotheses. It 

was critical, he argued, for the working scientist 

to avoid being wedded to one favorite, and thus 

look for ad hoc excuses to save the preferred hypothesis. 

In this line of argument, Platt drew on 

Chamberlin’s 1897 methodological caution which 

we quote in extenso: 

The moment one has offered an original explanation 

for a phenomenon which seems satisfactory, that 

moment affection for his intellectual child springs 

into existence, and as the explanation grows into a 

definite theory his parental affections cluster about his 

offspring and it grows more and more dear to him. . 

. . There springs up also unwittingly a pressing of the 

theory to make it fit the facts and a pressing of the facts 

to make them fit the theory. . . . To avoid this grave 

danger, the method of multiple working hypotheses is 

urged. It differs from the simple working hypothesis 

in that it distributes the effort and divides the affections. 

. . . Each hypothesis suggests its own criteria, its 

own method of proof, its own method of developing 

the truth, and if a group of hypotheses encompass the 

subject on all sides, the total outcome of means and 

of methods is full and rich. 

The lack of a genuine alternative to the DHS 

facilitated Kuhnian resistance prevented a robust 

competition between alternative research programs, 

and militated against strong tests from both 

a Popperean and Bayesian perspective. 

This paper is not the place to speculate on 

what genuine alternatives might have emerged 

or what types of alternatives might best be now 

developed. The currently fashionable glutamate/ 

NMDA hypothesis may have similar defects to the 

DHS. We suspect that successful candidates will be 

multi-systems models incorporating both multiple 

explanatory levels as well as incorporating aspects 

of neurodevelopment (Kendler and Parnas 2008). 

Future research might also succeed in efforts begun 

in the days of Kraepelin and Bleuler to subdivide 

the syndrome of schizophrenia into more discrete 

etiologic subtypes. 

The Persistence of the DHS 

When viewed from the perspective of these four 

major theories of scientific progress, the DHS has 

performed relatively poorly. Yet it has remained a


major theory in psychiatry for over four decades 

and still has a prominent place in many textbooks 

(e.g., Buchanan and Carpenter, Jr. 2005; Cohen 

2003 Gazzaniga 2004; Kandel et al. 2000;). How 

can we account for its tenacity? Addressing this 

question requires us to segue from philosophical 

analyses of science to a sketch of the sociological 

factors that have impacted on the development 

and persistence of the DHS. Of these, the most 

important was surely the rise of the biological 

psychiatry movement. 

Psychiatry has long sought for simple etiologic 

explanations of the complex clinical syndromes 

that it describes and treats. The dramatic successes 

with General Paresis of the Insane and Pellagra 

held out the promise that similar advances would 

be possible for other syndromes. Beginning in the 

early twentieth century, an etiological approach 

based on increased understanding of physiology 

and biochemistry began to have success in general 

medicine (Schaffner 2002). Psychoanalysis, 

which held a dominant position in mid-twentieth 

century American psychiatry, had, however, little 

interest in these developments, believing that the 

causes of psychiatric disorder lay in the mental 

realm. Led by a few key individuals, especially 

Kety, the nascent biological psychiatry movement 

began in the 1950s to seek physiological explanations 

for major psychiatric disorders, especially 

schizophrenia. However, a number of their early 

efforts (e.g., ceruloplasman, taraxein, the “pink 

spot” and transmethylation theories [Kety 1959, 

1966; Predescu et al. 1968]) went nowhere—an 

embarrassing situation for a young field seeking 

to legitimize itself. Snyder et al. summed up this 

situation: 

Innumerable “discoveries” of the biochemical abnormality 

in one or another body fluid of schizophrenics 

have relentlessly been followed by failures of confirmation 

in other laboratories. (1974, 1243). 

We suggest that the DHS was grasped with 

avidity by the nascent biological psychiatry 

movement for three reasons. First, the DHS was 

grounded in two inter-related “new” basic sciences—neurochemistry 

and psychopharmacology. 

By linking etiologic theories to these high-prestige, 

“hard-science” disciplines, biological psychiatry 

could obtain legitimization and be seen as applying 

to psychiatry the biological etiologic approach 

that had proved increasingly successful in the 

rest of medicine. This fulfilled one central goal 

of the movement—to bring psychiatry back into 

the medical mainstream. The history of medicine 

provides other examples of groups of physicians 

attempting to ground their theories in new scientific 

advances, in part to bolster their professional 

status (e.g., Brown 1970). Second, the stunning 

success with Parkinson’s disease, where all the 

features of the illness could be apparently traced 

to a single neurotransmitter deficit, suggested the 

viability of the tempting “one transmitter, one 

disease” model for neuropsychiatric disorders 

(Shorter 1997). This model fit very well with the 

reductive zeitgeist of the biological psychiatry 

movement that sought to continue in the tradition 

of the stories of GPI and pellagra. Third, the 

DHS tied the etiologic theory of schizophrenia 

to the increasingly unassailable evidence of the 

efficacy of antipsychotic drugs for the treatment 

of schizophrenia. Thus, the DHS could, at least in 

this indirect manner, be anchored in the practical 

world of psychiatric therapy. Relatedly, Shorter 

has suggested that a “one transmitter one-disease 

hypothesis” was “a perfect marketing concept for 

the drug companies” (1997, 267). 

The DHS has also been sustained over time by 

increasing evidence that the therapeutic effect of 

antipsychotic drugs correlates robustly with their 

capacity to block DA receptors. Such results are 

still commonly used as support for the DHS. In 

our view, this argument is logically flawed and 

results from a conflation of two distinct theories: 

The DHS, a theory of disease etiology, and the 

“dopamine hypothesis of antipsychotic drug 

action” (DHADA), a theory about pharmacologic 

mechanism. Information in support of the 

DHADA was clearly useful in supporting the 

plausibility of DHS at the time of its proposal. 

However, medicine has many examples in which 

the mechanism of action of a therapeutic drug is 

far removed from disease etiology, albeit perhaps 

not from its downstream pathophysiology. Diuretics 

are common treatments for congestive heart 

failure, yet the mode of action of these drugs in 

the kidney tell us little about the etiology of heart 

failure. Anti-inflammatory drugs reduce symptoms 

in a wide variety of conditions, but typically act on


physiological processes remote from those which 

cause the disorder. For this reason, we suggest 

that further evidence supporting the DHADA is 

of minimal relevance to the validity of the DHS. 

Although one can justly claim from the DHADA 

that “dopamine must have something to do with 

schizophrenia,” this is a weak argument because 

the mode of action of drugs can be so far removed 

from basic disease etiology as to be largely uninformative 

about etiologic processes. 

We suggest that, in their enthusiasm for this 

theory, the biological psychiatry movement was, 

initially and for many subsequent years, willing 

to overlook the substantial limitations of the DHS 

that we have reviewed above and conflate the DHS 

and DHADA. Although a further explication of 

this part of the story lies outside the bounds of this 

review, a full historical understanding of the DHS 

would require consideration both of scientific and 

extra-scientific forces. 

Concluding Thoughts 

In conclusion, we want to be clear about what 

we are and are not saying. We do not claim that 

DA is unrelated to the etiology of schizophrenia 

or that DA does not explain a lot about the action 

of antipsychotic drugs. Furthermore, we 

recognize that theories can be useful in guiding 

treatment even if they are etiologically incomplete 

or wrong (Schaffner 2002). Many hypotheses in 

medicine that were not based on deep etiological 

understanding have produced practical therapeutic 

benefits. This is likely the case for the DHS. 

By contrast, we do conclude that, as a scientific 

theory, the DHS has to date performed relatively 

poorly and has, from the perspective of leading 

models of science, important deficiencies. Furthermore, 

we suggest that the story of the DHS 

has at least four important lessons for our field. 

First, psychiatry needs theories with higher levels 

of specificity and falsifiability. Global, nonspecific 

theories like the DHS have heuristic value and can 

play an important role in stimulating research 

in the short run. However, such theories are less 

effective at guiding research in the long run in 

fruitful and progressive directions. Several of the 

etiologic theories for schizophrenia that compete 

with the DA hypothesis, including those focusing 

on glutamate or NMDA receptors, probably also 

suffer from lows levels of specificity and falsifiability. 

Other leading “neurochemical” theories in 

psychiatry, such as the serotonin hypothesis of depression, 

may be similar (Lacasse and Leo 2005). 

Second, science works best when diverse theories 

with distinct predictions compete with one 

another. This has been hard to implement in the 

field of mental health research for many reasons. 

Third, it has been common in the history of science 

in general and the medical and social sciences in 

particular for theories to be defended with a fervor 

that cannot be justified by the available evidence. 

More than we may wish to admit, this has been 

the case with the DHS. As our science and field 

matures beyond ideologically driven controversy, 

it would be wise and mature for all of us, regardless 

of whether we see ourselves as biological, 

social or psychodynamic, to be more self-critical 

about the theories we adopt and as more tolerant 

of diversity in theory articulation. Finally, psychiatry 

is probably not ready for “big” unitary 

theories like the DHS. Although very tempting, 

it will likely be more realistic and productive for 

us to focus on smaller questions, and to settle for 

“bit-by-bit” progress as we clarify, in a piecemeal 

manner, the immensely complex web of causes that 

contribute to disorders like schizophrenia (Kendler 

2005; Schaffner 1994). 

Acknowledgments 

This work is supported in part by the Rachael 

Banks Endowment Fund (KSK) and the National 

Science Foundation under Grant Nos. 0324367 

and 0628825 (KFS). Any opinions, findings, 

conclusions, or recommendations expressed in 

this material are those of the author(s) and do 

not necessarily reflect the views of the National 

Science Foundation. Helpful comments on earlier 

versions of this essay were kindly provided by Joel 

Kleinman, MD, Steven Matthysse, PhD, Solomon 

Snyder, MD, Carl Craver, PhD, Robert Malenka, 

MD, PhD, Karoly Mirnics, MD, John Bickle, 

PhD, James Bogen, PhD, Peter Machamer, PhD, 

Edouard Machery, PhD, Robert C. Olby, PhD, 

and Carol Tamminga, MD.


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