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For more than 30 years much of the focus of neurochemical research in schizophrenia has been on the dopamine hypothesis, although serotonin systems may also be dysfunctional. Certainly, the primary action of antipsychotic drugs is to diminish dopamine D2 receptor-mediated neurotransmission. Although there is little indication of primary disturbances in dopamine (or serotonin) neurotransmission in the schizophrenia, recent functional neuro-imaging studies have demonstrated an increase in stimulated release of dopamine in the brain of patients with schizophrenia. It seems likely that this neurochemical correlate of positive symptoms might be secondary to disturbances in other neurotransmitter systems. Evidence from in vivo imaging and post-mortem studies of the brain in schizophrenia, as well as from experimental models, points to deficits of γ-aminobutyric acid (GABA)-containing neurons, and dysfunction of glutamate-containing neurons, in the cortex and elsewhere. Such regionally specific neuronal abnormalities probably underlie negative features and cognitive deficits, as well as contributing to a disinhibition of subcortical dopamine. Experimental models suggest that GABAergic deficits, perhaps of developmental origin, could result in progressive damage to other neuronal systems. Several of the recently identified genetic risk factors for schizophrenia also influence neurotransmitter and synaptic function, with some convergence on glutamate. This is providing new targets for antipsychotic drug treatment.
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The neurochemistry of
Gavin P Reynolds
For more than 30 years much of the focus of neurochemical research in
schizophrenia has been on the dopamine hypothesis, although serotonin
systems may also be dysfunctional. Certainly, the primary action of an-
tipsychotic drugs is to diminish dopamine D2 receptor-mediated neuro-
transmission. Although there is little indication of primary disturbances
in dopamine (or serotonin) neurotransmission in the schizophrenia, re-
cent functional neuro-imaging studies have demonstrated an increase
in stimulated release of dopamine in the brain of patients with schizo-
phrenia. It seems likely that this neurochemical correlate of positive
symptoms might be secondary to disturbances in other neurotransmitter
systems. Evidence from in vivo imaging and post-mortem studies of the
brain in schizophrenia, as well as from experimental models, points to
deficits of γ-aminobutyric acid (GABA)-containing neurons, and dysfunc-
tion of glutamate-containing neurons, in the cortex and elsewhere. Such
regionally specific neuronal abnormalities probably underlie negative
features and cognitive deficits, as well as contributing to a disinhibition
of subcortical dopamine. Experimental models suggest that GABAergic
deficits, perhaps of developmental origin, could result in progressive
damage to other neuronal systems. Several of the recently identified
genetic risk factors for schizophrenia also influence neurotransmitter and
synaptic function, with some convergence on glutamate. This is provid-
ing new targets for antipsychotic drug treatment.
Keywords antipsychotic drugs; dopamine; dopamine receptors; GABA;
glutamate; N-acetylaspartate; neuro-imaging; neurotransmitter
Methods and models
The first approaches to understanding the pathophysiology of
psychiatric disorders were chemical investigations of body fluids
and, occasionally, brain tissue. These were under way long before
the emergence of modern psychiatry, and for over 200 years have
reflected methodological development, starting with the applica-
tion of quantitative chemical analysis. The neurochemical study
of the brain in schizophrenia depends on technological advance
as much now as it did two centuries ago. Recently, exciting
Gavin P Reynolds PhD is Professor of Neuroscience in the Division
of Psychiatry and Neuroscience at Queen’s University, Belfast,
Northern Ireland, UK, and President of the British Association for
Psychopharmacology. His main research interests are the pathology of
neurotransmitter systems in schizophrenia and the mechanisms and
pharmacogenetics of antipsychotic drug action. Conflicts of interest:
none declared.
observations of neurochemical disturbances in living brains have
been obtained using magnetic resonance spectroscopy (MRS),
and positron and single-photon emission (computed) tomog-
raphy (PET and SPET/SPECT respectively). The application of
molecular genetics has also provided clues as to the underlying
aetiologies and pathological processes in schizophrenia.
Despite these technological developments, there are never-
theless inconsistencies in neurochemical findings in the disease.
These problems may be due in part to the effects of drug treat-
ment, as well as differences between patient cohorts (diagnosis
in schizophrenia has not always been reliable, and symptom pro-
file can vary enormously between individuals). The absence of a
single core syndrome, and the multiplicity of proposed aetiologi-
cal factors, indicates that schizophrenia is likely to be a complex
disorder in which brain pathology may well differ between indi-
viduals owing to differences in pathogenic mechanisms.
Early hypotheses
Initial neurochemical hypotheses of brain dysfunction in schizo-
phrenia assumed a disturbance of brain biochemistry. This
approach originated in the observation that psychosis in humans,
and equivalent bizarre behaviours in animals, could be induced
by certain ‘psychotogenic’ drugs. It was assumed that the meta-
bolic and pharmacological effects of these drugs might reflect the
underlying biochemical abnormality in schizophrenia.
Two hypotheses of the early 1950s involved excessive trans-
methylation and serotonin deficiency. It was suggested that
neuro-active drugs with similarities to neurotransmitters, such as
mescaline and dimethyltryptamine, were proposed to be formed
by an overactive methylation process. Structurally similar psy-
chotogenic compounds, such as lysergic acid diethylamide (LSD),
were found to have effects via serotonin (5-hydroxytryptamine;
5-HT) receptors, and hence a deficiency of 5-HT neurotransmis-
sion was proposed. In retrospect, it is easy to identify limitations of
these hypotheses, one being the inadequacy of the drug-induced
‘model psychosis’ in which distortions of reality and visual hallu-
cinations are a major feature, rather than the auditory hallucina-
tions and delusions more commonly seen in schizophrenia.
5-HT neurotransmission
Nevertheless there remains an interest in the role of 5-HT in
schizophrenia. Circumstantial support is provided by the atypical
The genes implicated as risk factors in schizophrenia are
increasingly found to influence neuronal and synaptic
Research has focused particularly on glutamatergic systems,
and drugs are now in development that directly act on
glutamate neurotransmission. If they prove successful in
the clinic, this integration of genetics, neurochemistry, and
pharmacology may have brought about a move away from
dopamine antagonism in antipsychotic treatment
What’s new?
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PSYCHIATRY 7:10 426 © 2008 Elsevier Ltd. All rights reserved.
antipsychotic drugs, which all exhibit antagonism for the 5-HT2A
receptor subtype; this provides a putative mechanism, not only
for their low propensity to cause extrapyramidal side effects,
but also for some efficacy in ameliorating the negative features
of schizophrenia.1 More direct involvement is demonstrated by
post-mortem and some neuro-imaging studies that have shown
decrements in 5-HT2A receptors, and increases in 5-HT1A recep-
tors, in the brain in schizophrenia. This is likely to reflect distur-
bances in 5-HT neurotransmission, although it is far from clear
how these neurochemical abnormalities might originate in, or
be secondary to, other neuronal pathologies such as those of γ-
aminobutyric acid (GABA) and glutamate systems (see below).
Nevertheless, changes in 5-HT function are perhaps unsurpris-
ing, given its central role in depression, a frequent symptom in
schizophrenia, and the sensitivity of 5-HT systems to stress, an
inevitable experience for many patients.
Other neurochemical hypotheses have been proposed, based
on aberrant neurotransmitter function (e.g. implicating nor-
adrenaline or enkephalin), or metabolism, such as diminished
monoamine oxidase activity. However, none of these has sur-
vived careful scrutiny and testing.
The dopamine hypothesis
Dopamine receptors
What has survived the test of time, albeit with some elabora-
tion, is the dopamine hypothesis of schizophrenia. This was first
based on the ability of amphetamine, which stimulates dopamine
release, to induce a psychosis with schizophreniform features.
Further support came from the finding that almost all antipsy-
chotic drugs are effective antagonists of the D2 subtype(s) of
dopamine receptor, this antagonism correlating closely with
clinical dosage. Subsequently, the finding of more D2 recep-
tors in post-mortem brain from schizophrenic patients led to
the hypothesis that the increase in D2 receptors resulted in the
positive symptoms of schizophrenia. However, as an up-regula-
tion of D2 receptors is seen in animals after chronic administra-
tion of antipsychotic drugs, it seemed likely that the increase in
schizophrenia is a consequence of drug treatment and unrelated
to the disease process. Most post-mortem and imaging studies
now conclude that D2 receptors are not increased in drug-free
schizophrenic patients.
Nevertheless, dopamine receptors have remained of interest
for schizophrenia research (Table 1). Advances in molecular
biology permitted the identification of new subtypes of dopa-
mine receptor. Two further ‘D2-like’ dopamine receptors, D3
and D4, attracted interest as potential drug targets, and the D3
site remains under-researched as a potentially important site of
antipsychotic action. Initial excitement over the selectivity of
clozapine for D4 receptors and their possible over-expression in
schizophrenia was short-lived, however, and specific D4 antago-
nists are not antipsychotic.
Understanding drug mechanisms
In addition to permitting the measurement of brain receptor den-
sities in vivo, neurochemical imaging using PET and SPECT has
contributed enormously to our understanding of antipsychotic
drug mechanisms. These techniques can measure the binding
of radioactive ligands to a variety of sites, including dopamine
D2 receptors; antipsychotic drugs compete with, and thereby
decrease, ligand binding to these receptors. Thus it is possible to
obtain an in vivo measure of receptor occupancy by drugs. This
methodology has demonstrated that, at effective clinical doses,
the classical antipsychotics occupy at least 70% of D2 receptors.
Drug doses that induce extrapyramidal side effects are associated
with higher (>80%) occupancy. However, the partial D2 agonist
aripiprazole has very high occupancy without inducing extrapy-
ramidal side effects, whereas clozapine, and now some newer
antipsychotics, are found to be clinically effective at far lower
levels of receptor occupancy. These findings imply differences in
receptor mechanisms between classical and some atypical drugs.
Such an interpretation has been reinforced by further PET and
SPECT findings indicating regional differences in receptor occu-
pancy of atypical antipsychotic drugs.2 These approaches are
also being used to study occupancy at other receptors, including
the 5-HT receptor subtypes, involved in atypical antipsychotic
Synaptic dopamine function
There is some evidence for changes in pre-synaptic dopamine,
although these are likely to be secondary to changes in other
neuronal systems, rather than a primary feature of the disease
pathology. The greatest impetus in support of the dopamine
hypothesis in the past few years has been the work emerging
from in vivo neuro-imaging studies of dopamine release.
PET imaging techniques can employ certain radioactive D2
antagonist drugs to provide an indirect indicator of synaptic
dopamine levels. The extent by which such radioligands bind to
the receptor will diminish with increasing amounts of compet-
ing dopamine, thus providing a relative measure of dopamine
release in the synapse. Using this technique, a greater release
of dopamine in the striatum is seen in schizophrenic subjects,
relative to controls, following amphetamine administration
(Figure 1).3 This process can be modelled by administration of
Dopamine pathways in the brain
Pathway Physiological effects
Nigrostriatal Involved in motor control; blockade of
striatal dopamine D2 receptors produces
extrapyramidal side effects; also
involved in some cognitive circuits
Mesolimbic Blockade of limbic D2 receptors
may alleviate positive symptoms of
schizophrenia; limbic dopamine is also
involved in reward and addiction
Mesocortical Dopaminergic mechanisms in the frontal
cortex modulate cognitive function,
primarily via D1 receptors; COMT activity
influences cortical synaptic dopamine
Tubero-infundibular Projection from hypothalamus controls
pituitary hormonal secretion; blockade
of D2 receptors disinhibits secretion of
Table 1
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the psychotogenic anaesthetic ketamine, which also increases
the release of dopamine; in both cases dopamine release appears
to be proportional to the severity of psychosis. As ketamine is an
antagonist at glutamate receptors, this might indicate that dis-
turbed glutamate neurotransmission could underlie the findings
in schizophrenia.
However, these findings do not inevitably reflect disease
pathology. In addition to psychosis, stress and nicotine can
increase dopamine release and may both be experienced to a
greater extent by schizophrenic patients. It is also far from clear
whether these changes in dopamine function occur in the other
brain regions that are more strongly implicated in the pathophys-
iology and pathology of the disease (Table 1). Nevertheless, one
interpretation is that the control of dopamine release is disinhib-
ited in schizophrenia, and that this effect may reflect a distur-
bance of glutamatergic neurotransmitter function.
A further potential involvement of dopamine in schizophre-
nia is in the negative and cognitive symptoms. Dysfunction in
the frontal cortex is likely to contribute to these symptoms and,
on the basis of observations of an inverse relationship between
the activities of cortical and striatal dopamine systems, it has
been proposed that there is a hypofunction of dopamine in
the frontal cortex in schizophrenia. Some supporting evidence
has emerged from studies of catechol-O-methyltransferase
(COMT),4 an enzyme involved in the metabolism of dopamine
and noradrenaline. COMT can influence synaptic dopamine in
the cortex, where increased dopamine concentrations – through
effects at D1 receptors – may be associated with improved cog-
nitive function. COMT has a common genetic polymorphism,
whereby one allele codes for a less stable form of the enzyme,
resulting in greater cortical dopamine concentrations. An
association, albeit weak, between the COMT polymorphism
and schizophrenia has been reported, where a relative over-
representation of the higher-activity COMT form implicates
cortical dopamine hypofunction as a disease risk factor. This
focus on neuronal activity in the cortex also emphasizes the
possible importance of disturbances in the intrinsic cortical
neurons, containing GABA or glutamate, in the pathology of
GABA and glutamate – correlates of neuronal pathology
GABA and glutamate are, respectively, the most common inhibi-
tory and excitatory neurotransmitters in the brain. It is thus
hardly surprising that they have both been substantially impli-
cated in the widely investigated, yet subtle and poorly defined,
neuronal pathology of schizophrenia.6
Glutamate dysfunction – models and consequences
The evidence for disturbances in glutamate systems in the brain
in schizophrenia is substantial. It includes the psychosis associ-
ated with administration of drugs such as phencyclidine (PCP)
and ketamine, brought about by their blockade of the N-methyl-
d-aspartate (NMDA) subtype of glutamate receptor. PCP’s psy-
chotogenic effects include the development of negative as well
as positive symptoms, providing a better model of schizophre-
nia than the primarily positive psychotic syndrome induced by
(dopamine-releasing) amphetamine.
The blockade of NMDA receptors by PCP or ketamine can
have longer-term neurotoxic effects, a process that has led to an
important hypothesis relating to a postulated neurodegeneration
underlying progressive cognitive dysfunction in schizophrenia.7
Interestingly, this pathology is thought to be mediated by a hypo-
function of GABAergic neurons, on which NMDA receptors can
be found, resulting in disinhibition, and hence (toxic) overactiv-
ity of downstream neurons.
GABAergic neuronal deficits
There is much evidence for cortical and hippocampal losses of
GABA-containing neurons. Along with morphological studies,
a variety of different immunochemical markers of these inter-
neurons, including co-existing neuropeptides, calcium-binding
proteins, and the GABA-synthesizing enzyme glutamate decar-
boxylase (GAD), have all indicated selective deficits of subtypes
of GABAergic neurons in the cortex and hippocampus.8 A recent
analysis of 100 neurochemical investigations on a series of post-
mortem brain tissues demonstrated that the strongest findings in
schizophrenia (and also, interestingly, in bipolar disorder) were
frontal cortical or hippocampal deficits in parvalbumin, reelin,
The effect of amphetamine administration on dopamine release
Increased dopamine in synapse results in
greater dopamine occupancy of D2 receptors
Normal Schizophrenia
dopamine release
D2 receptor
Figure 1
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PSYCHIATRY 7:10 428 © 2008 Elsevier Ltd. All rights reserved.
and GAD, all associated with subtypes of GABAergic neurons.9
A loss of these neurons may well have consequences equivalent
to the long-term effects of NMDA receptor blockade described
above, in which a further neuronal degeneration might result.
Thus, the cortical GABAergic deficit in schizophrenia could well
be an initial deficit, perhaps of neurodevelopmental origin, that
subsequently results in a further, progressive, glutamatergic neu-
ronal loss (Figure 2).
Glutamatergic abnormalities
Changes have been observed in markers of glutamatergic neuro-
transmission in post-mortem studies. In general, these have indi-
cated deficits of glutamate systems in the temporal cortex, medial
temporal lobe, and striatal regions in schizophrenia, with losses
of markers of glutamatergic terminals and increases, presumably
compensatory, in NMDA receptors.6 These abnormalities point
to deficits of cortico-subcortical innervation that may underlie
cognitive dysfunction and negative features, as well as neuronal
deficits (e.g. in the hippocampus) involved in other cognitive
disturbances. The findings in frontal cortex are less clear; there
are indications of an increase in glutamatergic synaptic density
which is corroborated by some MRS measurements of glutamate
in vivo. The observation that a polymorphism in a gene for a glu-
tamate receptor (mGlu3) is a risk factor for schizophrenia, and
that at least three other risk genes (DAAO, G72, and NRG1) can
influence NMDA receptor function, further underlines the impor-
tance of glutamate neurotransmitter function in the disease.10
N-acetylaspartate – monitoring neuronal dysfunction in vivo
N-acetylaspartate (NAA) is found in relatively high concentration
in the brain and is one of the few substances that can reliably be
identified there in vivo using proton MRS. The function of brain
NAA is unclear, although it is considered to be a marker of neu-
ronal integrity. It is a metabolite of N-acetyl-aspartylglutamate,
which is found in neurons and is active at glutamate receptors.
There have been many MRS investigations identifying NAA defi-
cits in vivo in schizophrenia; these include cortical losses that
correlate with PET measures of the increased dopamine release
in the striatum, supporting the interpretation that dopaminergic
hyperfunction might reflect disturbed corticostriatal innervation.
There are also indications that cortical NAA losses correlate with
disease duration, indicative of a degenerative process.11 As mag-
netic resonance imaging (MRI) technology has developed in sen-
sitivity and resolution, MRS is being applied to determining other
important molecules in the living brain, among them the individ-
ual components of the Glx complex: glutamate, glutamine, and
GABA, as well as myo-inositol, considered a glial marker.
Neuronal deficits may be responsible for other reported
changes in schizophrenia. Decreases in some transmitter recep-
tor proteins, such as 5-HT2A and the α7 nicotinic subunit, may
reflect deficits of GABAergic cells on which these receptors are
found, whereas other abnormalities may relate to compensatory
up- or down-regulation of receptors, or differences in synaptic
density. In addition, the artefactual influence of drug treatment
on such findings cannot always be ruled out.
Neurochemical abnormalities of synaptic and membrane
Given the complexity and variety of chemical and physiological
processes associated with neuronal function, the opportunities
to investigate these processes in schizophrenia are legion and
impossible to review comprehensively. Nevertheless, reports
relating to some neurochemical mediators of neuronal func-
tion have attracted particular interest. Abnormal amounts and
functioning of certain subtypes of the G-proteins that mediate
the effects of many receptors have been found in schizophre-
nia12; the schizophrenia risk gene RGS4 codes for a protein that
regulates G-protein signalling. Interaction between G-proteins
and their receptors may be disrupted by disturbances in the cell
membranes in which the receptors are found; there is substantial
evidence for imbalances in membrane phospholipids, as demon-
strated by phosphorus-31 MRS of the brain in vivo.13 However,
although it is tempting to implicate primary disturbances of lipid
metabolism in schizophrenia that may respond to dietary supple-
mentation, a variety of other factors including inadequate diet
and substance abuse may contribute to artefactual findings.
Recent findings in the molecular genetics of schizophrenia have
implicated, as risk factors, genes involved in synaptic structure
and function. This particularly includes, but is not restricted to,
the genes influencing glutamate neurotransmission mentioned
above.10,14 It is now emerging that some of these genetic risk factors
have identifiable consequences in brain neurochemistry,14 as does
COMT. The ‘risk allele’ can result in a neurochemical pathology,
often with dysfunction of the gene product that may contribute to
schizophrenia; NRG115 and mGluR316 provide two examples.
A speculative view of the role of neurotransmitter
pathology in the natural history of schizophrenia
2 years
6 years
20 years
60 years
Genetic risk
risk factors
risk factors
neuronal damage
Disinhibition of
of delayed
or disturbed
Onset of
Figure 2
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PSYCHIATRY 7:10 429 © 2008 Elsevier Ltd. All rights reserved.
Neurochemistry: linking pathology and drug treatment
Neurochemistry is at the interface between genetics, brain pathol-
ogy, and pharmacology. The one mechanism shared by current anti-
psychotic drugs is their action at dopamine D2 receptors, although
how this ameliorates (some of) the symptoms of schizophrenia
remains elusive. Current understanding of the regional specificity of
neurochemical abnormalities, most notably those associated with
GABAergic and glutamatergic neurotransmission, provides strong
indications of the neuronal pathology underlying these symptoms.
As there are correlates between these pathologies and abnormal
dopamine release, which are attenuated by D2 antagonists, neuro-
chemistry is beginning to bridge the gap between neuronal pathol-
ogy and pharmacotherapeutic mechanisms. The current challenge
is to ensure that our developing understanding of the neurochemi-
cal pathology underlying negative and cognitive symptoms, in
which dopamine may not have a central role, translates into more
effective treatments for these features of schizophrenia. The recent
development of a potential antipsychotic targeting mGlu2/3 recep-
tors may be a first step in this direction.17
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effect? An in vivo quantitative [123I]epidepride SPET study of
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3 Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic
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4 Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT
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... 19 The prefrontal dopamine hypofunction (mainly in the PFC and anterior cingulate) 1 is known to result in negative and cognitive symptoms of the disorder such as flat affect, lack of volition and thought disorder. 19,20 The sub- cortical dopamine hyperactivity (mainly in Broca's area, STG, cingulate gyrus and hippocampus) 1 is thought to result in positive symptoms such as hallucinations and delusions. Evi- dence supporting this theory comes from the observation of higher dopamine levels correlating to greater positive symp- toms and the response of patients to antipsychotic drugs. ...
... The 5-HT sys- tems are involved in mood balance and emotional process- ing, they are sensible to stress and therefore 5-HT dysfunc- tion results in depression (a common symptom in schizophrenia). 20 Post-mortem and in vivo molecular imaging studies of the serotonergic system show abnormal serotonin receptor function in patients diagnosed with schizophrenia. 24 These studies reported reduction in 5HT 2A receptors density (20 to 50%) and increase in 5-HT 1A receptors density (20 to 90%). ...
... 24 These studies reported reduction in 5HT 2A receptors density (20 to 50%) and increase in 5-HT 1A receptors density (20 to 90%). 20,24 The 5-HT 2A receptors are of interest in schizophre- nia as many of the newly developed (second-generation) anti- psychotic drugs display potent antagonism activity for this particular receptor subtype, 1,20 but they also bind to other 5-HT receptors such as 5-HT 1A , 5-HT 2C and 5-HT 7 receptors. 24 Glutamatergic systems also take part in the neuronal pathol- ogy of schizophrenia and it is believed that schizophrenia re- sults from dysfunctional glutamate and glutamine neurotrans- mission which further damages other neuronal systems. ...
Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.
... Of the neuronal signalling pathways predominantly investigated within the mIA model, neurotransmitter pathways have received particular attention because of their important role in the pathophysiology of neurodevelopmental and neuropsychiatric disorders (Marotta et al., 2020;Reynolds, 2008). ...
... Further, pro-inflammatory cytokines, particularly IL-1β, IL-6 and TNFα, affect normal GABAergic synapse formation and reduce GABAergic interneuron density and GABAA-signalling currents (Crowley et al., 2016;El-Ansary and Al-Ayadhi, 2014). Imbalances in GABAergic function have been noted in a range of NDDs, including schizophrenia and ASD (Manetta et al., 2020, Reynolds, 2008 with delayed GABAergic maturation hypothesised to be akin to schizophrenia (Hyde et al., 2011). Overall, the disturbances we observed for GABAergic candidate genes in this review were primarily tissue-specific ( Figure 10). ...
Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.
... Obsessive-compulsive symptoms among patients with schizophrenia may manifest during the prodromal phase, as part of active psychotic illness, as obsessive ruminations during recovery or the remission phase, as concurrent independent OCD or as de novo obsessive-compulsive symptoms associated with secondgeneration antipsychotic treatment (34,35). Current neurobiological evidence of obsessive-compulsive symptoms in schizophrenia suggests greater prefrontal cortex dysfunction as well as glutaminergic and serotonergic dysregulations (36 ...
Full-text available
Schizophrenia is a complex psychiatric disorder that affects cognitive, perceptual, and emotional functioning. The currently available evidence suggests heterogenous intertwining of biological and psychosocial etio-pathogeneses. Clinical and research interests in the comorbidity issues of schizophrenia were borne out of the real-world clinical challenges that patients often present with multiple coexisting psychopathologies as well as comorbid medical conditions. The recent DSM-5 shift toward a symptom dimensional-based perspective, the NIMH Research Domain Criteria (RDoC) initiative to examine biopsychosocial pathogeneses in mental illness, and the FDA's emphasis on real world-based clinical trial criterion all have promoted a shift in clinical research that has facilitated understanding and treatment of comorbidity in schizophrenia. This emerging conceptual shift as well as pharmacological developments that address the multidimensional pathogeneses in schizophrenia may pave the way for a better understanding and treatment.
... First, our findings confirm that the presence of DS in clinical samples of patients with schizophrenia is not an uncommon condition, and therefore, stress the importance of properly identifying this subset of subjects with primary and enduring negative symptoms in future research. Second, our results lend further evidence against the neurodegenerative hypothesis of schizophrenia in which DS would merely be a result of clinical deterioration [48,65]. Lastly, the study demonstrates the reliability of the two-factor structure of the deficit symptoms of schizophrenia. ...
Background: Cumulative evidence has demonstrated important differences between deficit (DS) and non-deficit (NDS) schizophrenia, suggesting that DS may be a separate disease. However, most data come from the same research groups and more replication is needed to validate this hypothesis. Aims: Our study aimed to examine the distribution of DS, to compare their characteristics with NDS patients and to analyze the reliability of the two-factor structure of its negative symptomatology in a Spanish clinical sample. Methods: Sixty clinically stabilized patients with schizophrenia were evaluated. The Schedule for the Deficit Syndrome was used for DS/NDS categorization. Patient characteristics included age, gender, education, age at onset of psychosis, duration of illness, family history of psychosis, type of antipsychotic regimen, schizophrenia subtype and severity of the disease. Results: DS prevalence was 28.3%. Bivariate analysis revealed statistical differences between DS and NDS in terms of years of education and schizophrenia subtype. Factor analysis replicated the two-factor solution consisting of the ‘Expressive deficit’ and ‘Avolition–apathy’ domains reported in previous studies. Conclusions: Our results were consistent with the published data and indicated that the DS profile in the Spanish population is similar to that in other populations, which would corroborate the homogeneity of DS within the schizophrenia spectrum and contribute to the hypothesis that DS constitutes a separate disease.
... The dopamine hypothesis of schizophrenia was initially postulated based on the observation that the dopamine agonist amphetamine could induce a schizophrenia-like psychosis in healthy individuals (Reynolds, 2005;Howes et al., 2015). The hypothesis was supported by the fact that all APDs are dopamine D2 receptor antagonists and that the clinical dose of a drug closely correlates to the antagonistic actions. ...
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Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, in animal models of negative symptoms and cognitive dysfunctions associated with schizophrenia Inaugural-Dissertation zur Erlangung des akademischen Doktorgrades philosophiae doctor (Ph.D.) in 'Biomedical Science' an der Freien
... These findings could suggest that selective blockade of the α2C-AR may mediate disinhibited GABA release in brain regions with dense dopaminergic innervation and low noradrenergic innervation (3). Considering the presence of α2C-ARs in the striatum (particularly the reward centers), and the role of GABAergic transmission in mania and the action of mood stabilizers (75), selective α2C-AR antagonism could be of value in disorders like schizophrenia in which deficient GABAergic transmission may play a pathophysiological role (76). ...
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2A-and α2C-adrenoceptors (ARs) are the primary α2-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward anti-depressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α2C-and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A-and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer's disease. This review will emphasize the importance and relevance of the α2C-AR as a neu-ropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation.
... Additionally, neurodevelopmental disturbances occurring during birth or genetic defects play critical role in schizophrenia development. (28)(29)(30)(31)(32) ...
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Histamine H3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D2, D3 and serotonin 5-HT1A receptors, antagonism at D2, 5-HT2A, 5-HT2B and 5-HT7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H3 compounds via H3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain.
... Schizophrenia is a severe neuropsychiatric disorder involving environmental, neurodevelopmental and genetic factors (Sigurdsson, 2015), presenting with positive symptoms (disordered thoughts, delusions, hallucinations, psychosis), negative symptoms (affective flattening, social withdrawal) and cognitive impairments (deficits in executive functioning, working, declarative and recognition memory and attention) (Kahn and Keefe, 2013;Tsapakis et al., 2015). Monoaminergic, glutamatergic and GABAergic mechanisms are implicated in its pathology (Reynolds, 2008;Tsapakis et al., 2015), as is impaired neurotrophin function e.g. brain-derived neurotrophic factor (BDNF) (Favalli et al., 2012;Nieto et al., 2013). ...
Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10,921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10,921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10,921 (0.01 mg/kg), clozapine (5 mg/kg), haloperidol (0.2 mg/kg), haloperidol (0.2 mg/kg) + ORM-10,921 (0.01 mg/kg) or vehicle once daily for 14 days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10,921 and haloperidol + ORM-10,921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10,921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol + ORM-10,921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.
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Schizophrenia is a chronic neuropsychiatric disorder characterized by a shortened lifespan and significant impaired social and vocational functioning. Schizophrenic patients can present hypothalamus-pituitary-adrenal (HPA) axis dysfunctions and cortisol dysregulation, which play an important role on the etiology onset, exacerbation, and relapsing of symptoms. Based on its intrinsic neuroprotective properties, taurine is considered a promising substance with beneficial role on various brain disorders, including schizophrenia. Here we evaluated the effects of taurine on shoaling behavior and whole-body cortisol levels in zebrafish treated with dizocilpine (MK-801), which elicits schizophrenia-like phenotypes in animal models. Briefly, zebrafish shoals (4 fish per shoal) were exposed to dechlorinated water or taurine (42, 150, or 400 mg/L) for 60 min. Then, saline (PBS, pH 7.4 or 2.0 mg/kg MK-801) were intraperitoneally injected and zebrafish behavior was recorded 15 min later. In general, MK-801 disrupted shoaling behavior and reduced whole-body cortisol levels in zebrafish. All taurine pretreatments prevented MK-801-induced increase in shoal area, while 400 mg/L taurine prevented the MK-801-induced alterations in neuroendocrine responses. Moreover, all taurine-pretreated groups showed increased geotaxis, supporting a modulatory role on the overall dispersion pattern of the shoal. Collectively, our novel findings show a potential protective effect of taurine against MK-801-induced shoal dispersion and altered neuroendocrine responses, fostering the use of zebrafish models to assess schizophrenia-like phenotypes.
Animal models provide a good starting point for identifying a compound's safety and efficacy, but do not always mirror results in humans. Early indicators of efficacy in humans are needed to minimize costs and time required for clinical trials, by providing reliable information on whether a novel compound warrants further development. Biomarkers provide early data in humans on whether a compound is reaching its intended target or modifying its intended disease pathway. Unfortunately, biomarkers represent a “wild-west” in drug development; few are fully validated, and research on their utility and what they truly represent is often conflicting. In addition, new biomarkers with unknown parameters are constantly being developed and added to the fray. This chapter reviews the most utilized biomarkers of efficacy, and the most promising new biomarkers being developed, in four major CNS indications: Alzheimer's disease, anxiety disorder, depression, and schizophrenia.
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Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val108/158 Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11–16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Several decades of research attempting to explain schizophrenia in terms of the dopamine hyperactivity hypothesis have produced disappointing results. A new hypothesis focusing on hypofunction of the NMDA glutamate transmitter system is emerging as a potentially more promising concept. In this article, we present a version of the NMDA receptor hypofunction hypothesis that has evolved from our recent studies pertaining to the neurotoxic and psychotomimetic effects of PCP and related NMDA antagonist drugs. In this article, we examine this hypothesis in terms of its strengths and weaknesses, its therapeutic implications and ways in which it can be further tested.
Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty of measuring dopamine transmission in the living human brain. This situation is rapidly changing. Recent developments in positron emission tomography and single-photon emission tomographic techniques enabled measurement of acute fluctuation of synaptic dopamine in the vicinity of D2 receptors. Using this technique, we, and others, measured the increase in dopamine transmission following acute amphetamine challenge in untreated patients with schizophrenia and matched healthy subjects. Following a brief overview of these new brain imaging techniques, the main results derived with this method in patients with schizophrenia are described: (1) amphetamine-induced dopamine release is elevated in patients with schizophrenia, supporting the idea that schizophrenia is associated with dysregulation of dopamine transmission; (2) following amphetamine, hyperactivity of dopamine transmission is associated with activation of psychotic symptomatology; (3) this dysregulation of dopamine release is not a long-term consequence of previous neuroleptic treatment, and is detected in never-medicated patients experiencing a first episode of the illness; and (4) in contrast, this exaggerated response of the dopamine system to amphetamine exposure is not detected in patients studied during a period of illness stabilization, suggesting that the hyperdopaminergic state associated with schizophrenia fluctuates over time. In conclusion, a hyperdopaminergic state might be present in schizophrenia during the initial episode and subsequent relapses, but not during periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.
A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease.
Context: Schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment. Starting point: H Stefansson and colleagues (Am J Hum Genet 2002; 71: 877-92) showed association of the neuregulin (NRG1) gene with schizophrenia. Other recent papers describe six additional susceptibility genes. Replications are already being reported for some of them. The genes are biologically plausible, and may have convergent effects on glutamatergic and other synapses. We review the evidence for each gene, the possible pathogenic mechanisms, and the implications of the findings. WHERE NEXT? Given earlier failures to replicate apparent breakthroughs, the results should be viewed with caution. Unequivocal replications remain the top priority. The respective contributions of each gene, epistatic effects, and functional interactions between the gene products, all need investigation. Confirmation that any of the genes is a true susceptibility gene for schizophrenia could trigger the same rapid therapeutic progress as has occurred recently in Alzheimer's disease.
Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors with modest striatal D(2) receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D(2)/D(3) dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D(2)/D(3) receptor blockade in vivo. Five hours of dynamic single photon emission tomography data were acquired after injection of [(123)I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D(2)/D(3) receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D(2)/D(3) receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D(2) receptor occupancy and preferential occupancy of limbic cortical dopamine D(2)/D(3) receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT(2A) receptor antagonism.