DOI 10.1515/revneuro-2013-0011 Rev. Neurosci.
2013; 24(4): 389–400
Chi-Ieong Lau, Han-Cheng Wang*, Jung-Lung Hsu and Mu-En Liu
Does the dopamine hypothesis explain
schizophrenia?
Abstract: The dopamine hypothesis has been the corner-
stone in the research and clinical practice of schizophre-
nia. With the initial emphasis on the role of excessive
dopamine, the hypothesis has evolved to a concept of
combining prefrontal hypodopaminergia and striatal
hyperdopaminergia, and subsequently to the present
aberrant salience hypothesis. This article provides a
brief overview of the development and evidence of the
dopamine hypothesis. It will argue that the current
model of aberrant salience explains psychosis in schizo-
phrenia and provides a plausible linkage between the
pharmacological and cognitive aspects of the disease.
Despite the privileged role of dopamine hypothesis in
psychosis, its pathophysiological rather than etiological
basis, its limitations in defining symptoms other than
psychosis, as well as the evidence of other neurotrans-
mitters such as glutamate and adenosine, prompt us to
a wider perspective of the disease. Finally, dopamine
does explain the pathophysiology of schizophrenia,
but not necessarily the cause per se. Rather, dopamine
acts as the common final pathway of a wide variety of
predisposing factors, either environmental, genetic, or
both, that lead to the disease. Other neurotransmitters,
such as glutamate and adenosine, may also collabo-
rate with dopamine to give rise to the entire picture of
schizophrenia.
Keywords: aberrant salience; dopamine; dopamine
hypothesis; psychosis; schizophrenia.
*Corresponding author: Han-Cheng Wang, Department of
Neurology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang
Road, Shih-Lin District, Taipei, Taiwan; College of Medicine, National
Taiwan University, Taipei, Taiwan; and College of Medicine, Taipei
Medical University, Taipei, Taiwan, e-mail: drhan@ms1.hinet.net
Chi-Ieong Lau: Department of Neurology, Shin Kong Wu
Ho-Su Memorial Hospital, Taipei, Taiwan; and Division of Clinical
Neurology, Nuffield Department of Clinical Neurosciences,
University of Oxford, UK
Jung-Lung Hsu: Department of Neurology, Shin Kong Wu
Ho-Su Memorial Hospital, Taipei, Taiwan; Institute of Biomedical
Engineering, National Taiwan University, Taipei, Taiwan; and
Graduate Institute of Medical Informatics, College of Medical
Science and Technology, Taipei Medical University, Taipei, Taiwan
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Mu-En Liu: Department of Psychiatry, Kaohsiung Veterans General
Hospital, Kaohsiung, Taiwan
Introduction: a brief history of the
dopamine hypothesis
The birth of the dopamine hypothesis came from the dis-
covery, in animal experiments, that antipsychotic agents
(neuroleptics) blocked dopamine receptors (Carlsson
and Lindqvist, 1963). This was followed by further evi-
dence showing that amphetamine produced psychotic
symptoms. The hypothesis finally became influential in
the 1970s, when studies found the correlation between
clinical effectiveness and the affinity of antipsychotics for
dopamine receptors (Seeman and Lee, 1975). The role of
excessive dopaminergic transmission as a possible cause
of schizophrenia thus emerged. By contrast, a consider-
able body of evidence seemed to refute the hypothesis.
For example, clozapine, which has a low affinity for dopa-
mine D2 receptors, showed superior clinical responses in
some patients (Meltzer, 1989). The dopamine metabolites
in cerebrospinal fluid or serum in some patients were
also found to be normal. Taken together, these contra-
dictions, as well as the new evidence from PET studies,
led to a hallmark revision of the hypothesis. Davis et al.
proposed that schizophrenia is characterized by reduced
frontal dopamine and excessive striatal dopamine (Davis
et al., 1991). They further hypothesized that the positive
symptoms of schizophrenia are the results of striatal D2
receptor hyperstimulation due to hyperactive mesolimbic
dopamine projections, whereas the negative symptoms
and cognitive impairments are due to prefrontal cortex D1
receptor hypostimulation caused by reduced mesocortical
dopamine projections (Davis et al., 1991).
Since the revised dopamine hypothesis proposed by
Davis et al., an extensive and growing body of literature
on dopamine in schizophrenia has emerged. Whilst a
comprehensive review of all lines of evidence is impos-
sible, the current article will focus on the most compel-
ling evidence, including recent neuroimaging studies and
cognitive neuroscience, with an aim to provide a critical
review of the current version of dopamine hypothesis.
390 C.I. Lau et al.: Dopamine hypothesis of schizophrenia
Evidence of the current version of
dopamine hypothesis
Neurochemical imaging evidence for
subcortical dopamine hyperfunction
A wealth of in vivo studies using positron emission tomog-
raphy (PET) and single-photon emission computed tomog-
raphy (SPECT) has contributed to the understanding of the
first arm of the dopamine hypothesis, namely the striatal
hyperdopaminergia of schizophrenia. First, the presyn-
aptic striatal dopaminergic capacity and synthesis rate
can be measured by means of radiolabeled L-dopa. The
majority of studies using this method showed an eleva-
tion of striatal presynaptic dopaminergic synthesis rate in
patients with schizophrenia (Nikolaus et al., 2009; Howes
et al., 2009a). For example, a PET study showed increased
[18F] fluorodopa uptake in the ventral striatum in 16 medi-
cated patients compared to 12 controls (McGowan et al.,
2004). Increased striatal [18F]fluorodopa uptake was also
found in patients with prodromal symptoms of schizo-
phrenia and a correlation existed between the severity
of symptoms and the elevation of uptake (Howes et al.,
2009b), suggesting that the striatal presynaptic hyperdo-
paminergia exists in both schizophrenia patients as well
as subjects prone to the disease.
Second, early studies compared dopamine D2
receptor densities in patients with controls, under the
speculation that patients would have increased striatal
D2 receptors. Unlike the studies of presynaptic striatal
dopaminergic synthesis rate, these studies revealed
inconsistent results, with some showing increased D2
receptor binding (Crawley et al., 1986; Wong et al., 1986;
Pearlson et al., 1993; Tune et al., 1996) and others no dif-
ference compared to controls (Martinot et al., 1991, 1994).
These discrepancies were believed to be the results of
methodological factors, including the different sensitivi-
ties of ligands as well as the relatively small sample sizes
(Kestler et al., 2001). This prompted the conduction of
several meta-analyses showing a tendency of increased
D2 receptor density, regardless of the effects of antip-
sychotic treatment (Zakzanis and Hansen, 1998; Kestler
et al., 2001).
Third, the release of dopamine in the striatum can be
evaluated indirectly by measuring the reduction of radio-
tracer binding after pharmacological challenge (e.g.,
amphetamine). Animal and human studies on stimulant-
induced sensitization of the dopamine system indicate
that schizophrenia is associated with increased ampheta-
mine-induced dopamine release (Laruelle, 2000). Among
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the three SPECT studies in humans and one meta-analysis,
a greater reduction of dopamine receptor availability was
found in schizophrenic patients after challenge (Laruelle
et al., 1996; Breier et al., 1997; Abi-Dargham et al., 1998;
Laruelle et al., 1999). For example, using the radiolabeled
ligand [123I]IBZM, Laruelle et al. showed a greater reduc-
tion in amphetamine-induced binding potential (BP) in
patients (n = 15) compared to controls (n = 15) (Laruelle
et al., 1996). This was confirmed in subsequent studies
using [123I]IBZM (Abi-Dargham et al., 1998; Laruelle et al.,
1999) and [11C]raclopride (Breier et al., 1997), suggest-
ing an increase of amphetamine-induced striatal dopa-
mine release in schizophrenia. However, two of the three
studies (Laruelle et al., 1996; Abi-Dargham et al., 1998)
demonstrated a correlation between decreased BP and
increased positive symptoms, whereas the other did not
(Breier et al., 1997).
Fourth, controversies also seem to rage over the con-
flicting results in imaging the human dopamine trans-
porter (DAT), a specific marker of the structural integrity
of presynaptic dopamine neuron in the striatum (Fusar-
Poli and Meyer-Lindenberg, 2013). A recent meta-anal-
ysis, including 13 SPECT or PET studies, concluded that
there was no overall significant difference in striatal DAT
density between patients and controls, and no effects
of age, antipsychotics or duration of illness on striatal
DAT density (Fusar-Poli and Meyer-Lindenberg, 2013).
This conclusion is in line with the findings of unaltered
DAT density in several postmortem studies (Pearce et al.,
1990; Knable et al., 1994) as well as the unaffected struc-
tural striatal presynaptic index, the striatal vesicular
monoamine transporter type 2 (VMAT2), in schizophrenia
(Taylor et al., 2000).
Taken together, the existing evidence suggests that
the established increases in presynaptic striatal dopamine
release in schizophrenia are likely the consequence of
functional changes, rather than a change in the integrity
of presynaptic dopamine terminals or treatment-related
changes.
Neurochemical imaging evidence for
cortical dopamine hypofunction
By contrast, hypostimulation of dopamine D1 receptors
(D1R) in the prefrontal cortex is believed to be related to
the negative symptoms and cognitive deficits in schizo-
phrenia (Davis et al., 1991; Abi-Dargham and Moore,
2003). Although a positive correlation was found between
cerebrospinal fluid homovanillic acid, a metabolite of
dopamine, and performance in prefrontal tasks including

working memory (Kahn et al., 1994), postmortem studies
were inconclusive with either no change of D1R density
(Knable et al., 1996) or decreased dopaminergic inner-
vation in the dorsolateral prefrontal cortex (DLPFC) of
schizophrenia patients (Davis et al., 1991; Akil et al.,
1999). Again, recent attempts to explore this prefrontal
D1 dopaminergic dysregulation in schizophrenia using
neurochemical imaging (PET and SPECT) revealed incon-
sistent results. While PET studies showed reduced acti-
vation of D1R in the prefrontal cortex of patients (Okubo
et al., 1997; Kosaka et al., 2010), other studies showed
increased (Abi-Dargham et al., 2002; Abi-Dargham, 2003)
or no change of D1R availability in patients compared to
controls (Karlsson et al., 2002). For example, using [11C]
SCH23390 as a radioligand, Okubo found a reduction of
binding of the ligand to D1R in the prefrontal cortex of
patients, which was related to the severity of negative
symptoms as well as to the poor cognitive performance
(Okubo et al., 1997). By contrast, elevated [11C]NNC112 BP
at the DLPFC was found in patients with schizophrenia,
which was also correlated with the poor performance in
working memory (Abi-Dargham et al., 2002). These dis-
crepancies could be interpreted as the differential effects
of dopamine on various D1R radioligands, the interaction
of D1R with serotonin receptors, the stage of disease, as
well as the effect of prior antipsychotic exposure (Guo
et al., 2003). More recently, the same research group
attempted to explore the controversy and revealed higher
prefrontal cortical D1R [11C]NNC112 BP in drug-naive, but
not in previously treated drug-free patients compared
to healthy individuals. Furthermore, they found a posi-
tive correlation between drug-free duration and cortical
BP, suggesting the presence of an upregulation of D1R in
schizophrenia that may be normalized by antipsychotics
(Abi-Dargham et al., 2012).
Functional magnetic resonance imaging
studies
Unlike PET and SPECT studies that visualize the direct
changes of the dopaminergic system in schizophrenia,
functional magnetic resonance imaging (fMRI) measures
the hemodynamic changes induced by local neuronal
activities and provides a platform for investigating the
effects of antipsychotics on brain activities (Ogawa and
Lee, 1990). In support of the notion of prefrontal hypoac-
tivity in schizophrenia (Davis et al., 1991), fMRI studies
demonstrated reduced activation in the DLPFC, ventro-
lateral prefrontal cortex (VLPFC) and anterior cingulate
region during cognitive tasks in patients compared to
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C.I. Lau et al.: Dopamine hypothesis of schizophrenia 391
controls (Barch and Ceaser, 2012). For example, first-
episode, medication-naive patients with schizophrenia
showed deficits in DLPFC activation when performing
a working memory task involving context processing
(Barch et al., 2001). Reduced activation of the DLPFC and
anterior cingulate region can also be found in unmedi-
cated patients during a modified Stroop task (Weiss et al.,
2007). Presumably, if prefrontal hypodopaminergia holds
true in the dopamine hypothesis of schizophrenia, the
benefits of antipsychotics in improving cognitive impair-
ment and negative symptoms would appear to be related
to the normalization of prefrontal function via dopamin-
ergic input. Attempts to evaluate the effects of antipsy-
chotic treatment on cognitive functions, such as working
memory or verbal fluency, generally revealed enhanced
prefrontal activations in patients with schizophrenia
following treatment (da Silva Alves et al., 2008; Abbott
et al., 2013). At baseline, patients with schizophrenia
showed hypoactivation at the DLPFC and VLPFC during
a working-memory task compared to controls (Meisen-
zahl et al., 2006). After 12 weeks of treatment with que-
tiapine, activation at the VLPFC increased along with
clinical improvement. Likewise, using various prefrontal
cognitive tasks, the majority of fMRI studies were able to
demonstrate increases (normalization) of the blood oxy-
genation level dependent (BOLD) signal at the anterior
cingulate cortex (Snitz et al., 2005), frontotemporal area
(Wolf et al., 2007), left inferior frontal cortex (Jones et al.,
2004), frontal cortex (Honey et al., 1999; Lund et al.,
2002) and VLPFC (Meisenzahl et al., 2006) following
treatment with atypical antipsychotics. A meta-analysis
of eight fMRI longitudinal studies that investigated antip-
sychotic-naive or antipsychotic-free patients demon-
strated a trend of normalization of BOLD signals over the
course of antipsychotic treatment (Abbott et al., 2013).
Arguably, the increase of prefrontal BOLD signal by
dopaminergic antagonists is sometimes difficult to inter-
pret, as it reflects a net result of a complex cascade of
neurovascular coupling and may therefore be the result
of direct modification of prefrontal neurons or cerebral
blood flow (Abbott et al., 2013). Besides, in addition to
D2 antagonism, antipsychotics have multiple receptor
affinities, including dopamine, serotonin, norepineph-
rine, acetylcholine (Kebabian and Calne, 1979) as well as
interactions with these and other neurotransmitter path-
ways (Goldman-Rakic and Selemon, 1997). Thus the role
of dopamine-modulation in the normalization of prefron-
tal hypoactivity seems to be less clear and more future
studies will be needed to clarify these issues.
Over the past 20 years, a considerable number of in
vivo studies have quantified various neurometabolites in
392 C.I. Lau et al.: Dopamine hypothesis of schizophrenia
schizophrenia using magnetic resonance spectroscopy
(MRS) (Port and Agarwal, 2011; Kraguljac et al., 2012;
Rowland et al., 2012). Due to the nature of the technique,
these MRS studies did not directly unravel the dopaminer-
gic dysregulation in schizophrenia, but focused mainly on
the assessment of the neurometabolites of phospholipid,
N-acetyl aspartate (NAA), choline (Cho), creatine (Cr),
GABA and glutamine that reflect neuronal integrity, energy
metabolism, and neuroexcitability (Kraguljac et al., 2012).
Genetic evidence
Genetic studies also provide clues to the dopamine
hypothesis. Until recently, an online update (SzGene) of
the massive genetic data associated with schizophrenia
was created and a meta-analysis of these findings was
published (Allen et al., 2008). Overall, the results showed
no single gene which codes for schizophrenia. However,
genes that are related to the dopaminergic system, such
as the dopamine transporter 1, dopamine receptor 1–5,
and catechol-O-methyltransferase (COMT), are consid-
ered to be potential candidates. Four of the 10 gene vari-
ants that correlated mostly with schizophrenia involve the
dopaminergic system. For example, the gene affecting the
monoamine transporter protein (rs2270641) that works
to accumulate dopamine into vesicles is believed to be
associated with schizophrenia. Although far from being
mature, this preliminary evidence does provide some
support for the role of dopamine in schizophrenia (Nier-
atschker et al., 2010).
Evidence from environmental risk factors
A large number of notable environmental factors have
been reported as risk factors for schizophrenia. Many
obstetric complications, such as hypoxia (Butwell et al.,
2000; Taylor and Duncan-McConnell, 2000), prematurity
(Monchi et al., 2000) and low birth weight (Taylor et al.,
2002; Walsh et al., 2002) are known to predispose to the
disorder. Animal studies showed that obstetric complica-
tions damaging the hippocampus might trigger dopamine
sensitization (Boksa and El-Khodor, 2003). There is also
evidence that prenatal exposure to infection may alter the
normal development of the mesocorticolimbic dopamine
system, resulting in structural and functional disruption
of the system that would contribute to the development
of behavioral and cognitive disturbances in adulthood
(Meyer and Feldon, 2009).
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Other environmental factors, such as social isola-
tion and submissive social position, also increase striatal
dopamine D2 receptors. Isolation-reared rats, with symp-
toms similar to schizophrenia, such as hyperactivity to
novel stimuli, were found to have dopamine overactivity,
as illustrated by an elevated proportion of striatal dopa-
mine receptors in the functional high affinity state (Berton
et al., 2006; King et al., 2009).
Finally, a number of stimulant drugs also seem to
increase the risk of schizophrenia. For example, as men-
tioned above, amphetamine may sensitize striatal dopa-
mine release and give rise to schizophrenia-like psychotic
behavior (Yamasue et al., 2002; Rzanny et al., 2003). The
active component of cannabis, delta 9-tetrahydrocannabi-
nol, binds to cannabinoid receptors and has been shown
in animal studies to increase striatal dopamine release
(Waddington et al., 1992; Stanley et al., 1994; Thomas
et al., 1998). A recent PET study in humans also confirmed
that the inhalation of cannabis induced the striatal release
of dopamine (Bossong et al., 2009).
Together, these findings suggest that there is a rela-
tion between the established environmental risk factors
of schizophrenia and dopaminergic overactivity, thus pro-
viding evidence for the dopamine hypothesis.
Evidence from gene-environmental
interaction in schizophrenia
Until recently, there has been considerable interest in
how variation in specific genes moderates the sensitiv-
ity of specific environmental risk factors in developing
psychosis. This gene-environment interaction gives rise
to synergism of effects and either factor alone may not
result in schizophrenia (van Os et al., 2008). A famous
study investigated the interaction between a functional
polymorphism of the COMT gene and cannabis use (Caspi
et al., 2005). The study showed that carriers of the func-
tional polymorphism of the COMT gene were more likely
to develop psychosis after cannabis use. This synergic
effect of individual risk factors, with each modulating the
dopamine pathway, is yet more evidence of the dopamine
hypothesis (Stefanis et al., 2007).
Evidence from population with high risk of psychosis
If the dopamine hypothesis does explain schizophrenia,
we would expect to see traces of dopaminergic dysfunc-
tion in people prone to psychosis. Indeed, there is evi-
dence showing the dysregulation of the dopamine system

in relatives of schizophrenic patients. A recent PET study
measured the striatal dopamine synthesis capacity and
found that the asymptomatic first-degree relatives of
patients had a higher fluorodopa (FDOPA) uptake in
the caudate-putamen (Huttunen et al., 2008). Similarly,
patients with prodromal symptoms of schizophrenia also
showed excessive dopamine activities in the striatum and
that this altered dopaminergic transmission was corre-
lated with the severity of prodromal psychiatric symptoms
(Fusar-Poli et al., 2010).
Aberrant salience as the basis of
the revised version of dopamine
hypothesis
Dopamine, reward learning, and
motivational salience
The role of dopamine in human reward behavior is
well established. Pioneer work in animal studies sug-
gested that dopamine is crucial in reward learning and
that the blockade of dopamine receptors leads to blunt-
ing of hedonic stimuli (Wise et al., 1978; Barch et al.,
2001). Administrating the D2 dopamine receptor blocker
pimozide to hungry rats alleviated reward (food)-seeking
behavior of lever-pressing and running (Wise et al., 1978).
However, the fact that dopamine is also involved in aver-
sive stimuli and the release of dopamine often precedes
hedonic stimuli led to the consequential modification of
the idea (Meltzer, 1979; da Silva Alves et al., 2008; Mat-
sumoto and Hikosaka, 2009). In rodents, a subgroup of
dopamine neurons in the ventral tegmental area (VTA),
were excited by aversive footshocks (da Silva Alves,
2008). Similarly, dorsolateral dopamine neurons at the
substantia nigra pars compacta of nonhuman primates
were excited by aversive face air-puff stimuli (Kebabian
and Calne, 1979). Kosobud et al. showed that VTA activ-
ity increased in rats prior to the presentation of sucrose
and failed to discharge when the animals were experi-
encing the sucrose in their mouth (Meltzer, 1979). One
contemporary theory is the incentive salience hypothesis
(Berridge and Robinson, 1998). It suggested that the mes-
olimbic dopamine system is critical in the attribution of
salience that modulates attention and influences actions.
According to this hypothesis, rather than the reactions of
pleasure (liking) towards hedonic stimuli, the dopamine
system plays a role in the motivation of action (wanting)
– ‘incentive salience’. This idea of dopamine as a central
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C.I. Lau et al.: Dopamine hypothesis of schizophrenia 393
component in motivational salience gave rise to an excit-
ing breakthrough of the dopamine hypothesis in explain-
ing schizophrenia (Kapur, 2003).
Aberrant salience in psychosis
How does the dopamine-regulated incentive salience
hypothesis lead us to a better understanding of psycho-
sis in schizophrenia? Under normal circumstances, dopa-
mine mediates contextually relevant saliences. However,
according to the aberrant salience hypothesis, this normal
attribution of salience is disrupted by the increased dopa-
mine firing in psychosis (Kapur, 2003). Rather than being
a regulator of relevant saliences, the excessive dopamine
in psychosis becomes a creator of aberrant saliences. In
other words, the persistence of aberrant salience in the
absence of external stimuli leads to psychosis.
This revised version of the dopamine hypothesis
appears to explain some of the clinical and pharmaco-
logical phenomena of schizophrenia. First, patients with
schizophrenia often undergo a period of time before the
full-blown presentation of psychosis. According to Kapur,
2003, it is this period of time when, owing to excessive
striatal dopamine, the aberrant attributions of salience
to external and internal stimuli gradually develop. In
order to rectify their false percepts, personal experience
and cultures of the patients are involved, to provide an
‘insight relief ’ of the disturbing saliences. It is when the
aberrant salience becomes too prominent, or when the
patients share their beliefs with people, that their psycho-
sis begins to surface.
Second, the aberrant salience hypothesis seems to
shed light on the question of why antipsychotics take
weeks to achieve clinical responses, even with their
rapid onset of constant level (Leucht et al., 2005; Agid
et al., 2006). Emerging evidence showed that D2 recep-
tor occupancy by risperidone at 48 h correlated with
clinical improvement after 2 weeks of treatment onset
(Catafau et al., 2006). A meta-analysis of 1708 patients
with schizophrenia taking the D2 receptor antagonist
amisulpride revealed that a large proportion of improve-
ment of positive symptoms was achieved as early as week
2 (Leucht et al., 2005). It is proposed that by blocking stri-
atal dopamine D2 receptors, classical antipsychotics are
able to alleviate hyperdopaminergia instantaneously and
thus dampen aberrant salience. Nevertheless, despite the
dampening of aberrant salience, a period of time predates
the abandoning of preoccupied delusions by the patients.
Thus, antipsychotics do not relieve psychotic symptoms
per se, but rather they alleviate the degree to which these
394 C.I. Lau et al.: Dopamine hypothesis of schizophrenia
aberrant internal percepts occupy the mind. Eventually,
the symptoms resolve, along with the patient’s own psy-
chological process.
Third, the current framework provides a plausible
explanation to the adverse effect of reduced motivation
in antipsychotic-medicated patients (Kirsch et al., 2007).
As postulated by Kapur, 2003, the dopamine blocking
effect of antipsychotics also alleviates normal pleasurable
drives. Arguably, this side effect may contribute to the evi-
dence of dampened salience of antipsychotics and hence
supports the aberrant salience hypothesis.
Fourth, the inevitability of relapse of psychosis after
antipsychotic withdrawal provides more evidence. Antip-
sychotics only dampen aberrant salience and yet the dys-
regulated dopaminergic system still exists. Accordingly,
the recurrence of symptoms after the withdrawal of medi-
cations is inevitable.
Evidence for the salience hypothesis
Preliminary studies did provide evidence for the aberrant
salience hypothesis. To test the hypothesis, Rosier et al.
employed the Salience Attribution Test (SAT), to quan-
tify and compare the adaptive and aberrant saliences in
schizophrenic patients and controls (Roiser et al., 2009).
In the 20 medicated patients and 17 controls, they found a
reduction of adaptive salience in patients compared with
controls, where adaptive salience was defined as faster
responding to, or higher subjective probability rating
for high-probability-reinforcement trials relative to low-
probability reinforcement trials. Second, there was no dif-
ference in aberrant salience between medicated patients
and controls, suggesting that antipsychotics alleviated
aberrant salience to a normal level. Third, if the aberrant
salience hypothesis holds true, medicated patients with
persistent positive symptoms should present more aber-
rant salience than those without. Consistent with the
hypothesis, the results showed significantly greater aber-
rant salience in the former. Moreover, aberrant salience
also correlated positively with negative symptoms. Fourth,
they showed that the aberrant salience in controls corre-
lated positively with their personality traits of schizotypy.
These findings support the aberrant salience hypothesis.
By contrast, fMRI studies also provide important evidence
to support the revised dopamine hypothesis. In a reward
task, Walter et al. found that the mesolimbic dopamine
system was normal to hyperactive, and the anterior cingu-
late gyrus or the right VLPFC were hypoactive, in partially
remitted patients medicated with olanzapine (Walter
et al., 2009). The research team replicated their study and
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consistently found that the right VLPFC of patients with
schizophrenia was associated with a significant decrease
in salience coding, i.e., the receipt or omission of high
reward in a monetary incentive task (Walter et al., 2010). In
addition, the salience attribution was correlated inversely
with negative symptoms. Again, these data provide evi-
dence to support the aberrant salience as the basis of the
revised dopamine hypothesis, suggesting that there is a
hyperactivity of the mesolimbic dopaminergic system,
as well as a reduced prefrontal activation in schizophre-
nia. Nevertheless, the limitation of the studies is that all
patients were treated with antipsychotics. Future studies
with medication-naive patients would be invaluable in
evaluating the role of salience in the pathophysiology of
schizophrenia.
Limitations of the aberrant salience
hypothesis
The above hypothesis with dopamine dysregulation as the
main cause of aberrant salience attribution provides an
important linkage between the neurobiological and cogni-
tive bases of schizophrenia. Conceivably, this hypothesis
enables us to have a better understanding of schizophrenia
and yet it is not without criticism. First, it speculates only
on the pathophysiology, but not the etiology of schizophre-
nia. Opposing the current hypothesis, Moncrieff argued
that the concept of salience is similar to cognitive function-
ing that involves attention, motivation, arousal, and affect
which may involve a number of other neurotransmitters in
addition to dopamine (Moncrieff, 2009). Second, not all
symptoms of schizophrenia can be eliminated by dopa-
mine blocking agents. Notably, neuroleptics appear to be
less effective in alleviating cognitive dysfunction and nega-
tive symptoms (Meltzer et al., 1986; Heinrichs, 2007). Thus,
the aberrant salience hypothesis alone may be insufficient
to explain the complete picture of schizophrenia. Third, the
current framework mainly elucidates psychosis in schizo-
phrenia. It provides no plausible explanation for other axes
of the disease, such as negative symptoms and cognitive
deficits (Andreasen, 1982). Fourth, the hypothesis may not
be disease specific. It is possible that the aberrant salience
may also participate in the pathophysiology of psychosis
in other disease entities, such as Alzheimer’s disease, Par-
kinson’s disease, and bipolar disorder. As van Os proposed,
analogous to the idea of ‘metabolic syndrome’, schizophre-
nia may be considered as a combination of categorical and
dimensional representations in the spectrum of ‘salience
dysregulation syndrome’ (van Os, 2009).
 C.I. Lau et al.: Dopamine hypothesis of schizophrenia 395

Further criticisms of the dopamine Beyond the dopamine

hypothesis hypothesis – other collaborating
First, the core evidence of the dopamine hypothesis
neurotransmitters in schizophrenia
comes from the fact that most effective antipsychotics
Even if aberrant salience or the dopamine hypothesis
have at least some degree of antagonism of dopamine
remains to be the cornerstone in schizophrenia, the afore-
D2 receptors. Nonetheless, some patients taking high
mentioned criticisms remind us of the limitations of the
dosages of typical antipsychotics failed to achieve a clini-
framework. New evidence from research of other neuro-
cal response, even though there were high levels of central
transmitters, including glutamate (Farber, 2003; Coyle and
dopamine D2 receptor occupancy (Pilowsky et al., 1993).
Tsai, 2004), serotonin, GABA, and adenosine, provided
Furthermore, clozapine, an antipsychotic drug with supe-
a multifactorial perspective of schizophrenia. Among
rior therapeutic efficacy, was found to block D2 receptors
these, the ‘glutamate hypothesis’ appears to be attractive,
(Meltzer, 1989; Pilowsky et al., 1992), suggesting that other
because of its ability to integrate disparate evidence as
binding sites may also mediate the effects of antipsychot-
well as various neurotransmitters into a unified theory of
ics. For example, many atypical antipsychotics share the
the pathophysiology of schizophrenia. It proposes that the
property of high binding affinity to 5-hydroxytryptamine
glutamatergic control of the N-methyl-D-aspartate (NMDA)
type 2 receptors (Kapur et al., 1999; Lewis et al., 1999;
receptor, which normally balances GABA release, is com-
Remington and Kapur, 1999).
promised in schizophrenia (Gordon, 2010). The notion
Nonetheless, rather than reversing the assumed
came from NMDA receptor antagonists, namely ketamine
hyperdopaminergic state of schizophrenia, an alternative
and phencyclidine, that cause symptoms analogous to
explanation is that the beneficial effect of typical antipsy-
schizophrenia, such as psychosis, negative symptoms and
chotics in alleviating hallucinations, might be the sedation
cognitive symptoms (Coyle, 2006). A SPECT study pro-
and cognitive impairments that the drugs produce (McClel-
vided the first in vivo evidence, by showing a reduction
land et al., 1990; Moncrieff, 2009). A Cochrane review of
of NMDA receptor binding in the hippocampus of medi-
34 studies proposing benzodiazepines as having compara-
cation-free patients (Pilowsky et al., 2006). Another PET
tive effects to antipsychotics in schizophrenia appears to
study revealed an increase in striatal dopamine concen-
support this notion, but the results remain inconclusive
tration with the NDMA antagonist S-ketamine, supporting
due to the low quality of evidence (Dold et al., 2012).
the notion that the glutamatergic NMDA receptor may con-
Second, another line of evidence for the dopamine
tribute to psychotic symptoms via the modulation of the
hypothesis maintains that stimulant drugs, such as
dopaminergic pathway (Vollenweider et al., 2000). Prelim-
amphetamine, cause psychosis, which is assumed to
inary data also showed that LY404039, a selective mGlu2/3
underlie the same mechanism in schizophrenia. However,
receptor agonist, improves both positive and negative
it remains a question of debate whether schizophrenia
symptoms without the adverse effects of extrapyramidal
and stimulant-induced psychosis produce the same clini-
symptoms or weight gain (Patil et al., 2007). More recently,
cal picture, let alone the underlying mechanism (Ujike,
a more complex theory, the ‘adenosine hypothesis’, has
2002). Furthermore, it is argued that amphetamine acti-
been put forward, which represents another promising
vates noradrenalin and serotonin, in addition to the dopa-
candidate to integrate the dopamine and glutamate theo-
mine system (Rothman et al., 2001). Therefore, it raises
ries, by reversing the imbalances of the neurotransmitters
the question of the validity of stimulant drugs as evidence
at a molecular level (Boison et al., 2013). Taken together,
of the dopamine hypothesis. Third, studies showed that
these preliminary data suggest that, while dopaminergic
stress (Pruessner et al., 2004), smoking (Brody et al.,
dysregulation still plays the key role in the pathophysiol-
2004) and arousal (Isaac and Berridge, 2003) also alter the
ogy of schizophrenia, glutamate hypofunction is likely to
release of dopamine. It is possible that psychotic patients
be a complementary component of the entire model.
are under a higher level of stress, which may provoke
an elevated level of dopamine. Yet, there has been little
attempt to control these confounding factors in most
studies. Fourth, many imaging studies of L-dopa uptake Conclusion
and amphetamine-challenge studies involve patients with
prior exposure to neuroleptics, which might have altered With several lines of evidence supporting the dopa-
the patients’ dopamine systems. mine hypothesis, the critical role of dopamine in

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396 C.I. Lau et al.: Dopamine hypothesis of schizophrenia
schizophrenia is beyond doubt. The current aberrant
salience model explains the cognitive and neurobio-
logical pathophysiology of psychosis in schizophrenia.
Yet, with evidence pointing to the involvement of gluta-
mate and adenosine, a more complex mechanism, with
dopamine as the core player in the pathophysiology, has
emerged.
In conclusion, the dopamine hypothesis explains
schizophrenia by proposing dopamine as the final
common pathway for various predisposing environmental
and genetic factors to go through. Other neurotransmitters
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400 C.I. Lau et al.: Dopamine hypothesis of schizophrenia

human movements and movement disorders. He is interested in

linking clinical features with functional connectivity of the brain,
reflected in his recent works correlating regional cerebral blood
flow (CBF) changes and tract-specific abnormalities with severity of
Parkinsonism.

Chi-Ieong David Lau is a Consultant Neurologist whose research

interests focus on the cognitive neuroscience underpinning neuro-
logical diseases. His recent work includes the investigation of the
visual system in migraine, as well as the modulation of slow-wave-
sleep-related memory consolidation using a variety of methods,
including EEG, neuroimaging, brain stimulation, and genetics. He
completed his medical degree and neurology training in Taiwan Jung-Lung Hsu is a Clinical Neurologist. He is interested in behav-
and postgraduate studies at the University College London and ioral/cognitive neuroscience. His main study is focused on brain
the University of Oxford, supported by the British Chevening structural change and human behavior. He is also participating in
Scholarship. the event-related potential (ERP) study (P50 and MMN) of schizo-
phrenia patients.

Han-Cheng Wang is a Consultant Neurologist at Shin Kong Wu

Ho-Su Memorial Hospital, with specialist clinics for Parkinson’s
disease and movement disorders. He is Assistant Professor of
Neurology at the College of Medicine, National Taiwan University.
He is the former President and present Standing Member of the
Executive Board of Taiwan Movement Disorder Society. His research
interests include understanding basic neurophysiology underlying
Mu-En Liu’s research interests include biological psychiatry and
geriatric psychiatry. Some of the study topics are novel in the
genetic study of cognitive ageing. Recently, he examined genetic
effects on age-related morphologic changes in the brain. His
researches may clarify the underlying molecular mechanisms of
brain aging.

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