CHAPTER TEN

The Enduring Centrality ofDopamine in the Pathophysiologyof Schizophrenia: In Vivo Evidencefrom the Prodrome to the FirstPsychotic EpisodeIlaria Bonoldi*,†,{,1, O.D. Howes*,†*Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, United Kingdom†Psychiatric Imaging Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital,London, United Kingdom{Section of Psychiatry, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy1Corresponding author: e-mail address: ilaria.bonoldi@kcl.ac.uk

Contents

1.

AdvISShttp

Introduction

ances in Pharmacology, Volume 68 # 2013 Elsevier Inc.N 1054-3589 All rights reserved.://dx.doi.org/10.1016/B978-0-12-411512-5.00010-5

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2. Indirect Evidence for DA Dysfunction in Psychosis 201 3. Molecular Imaging Evidence for DA Dysfunction in Psychosis 203 4. The Link Between DA and Psychotic Symptoms 205 5. Molecular Imaging Evidence for DA Dysfunction in the Prodrome to Psychosis 206 6. The Link Between DA and Other Symptoms 209 7. DA Dysfunction: The Final Common Pathway? 210 8. What We Do Not Know 212 9. Conclusion 213 Conflict of Interest 214 References 214

Abstract

Dopamine has been thought to be central to the pathophysiology of schizophrenia forthe last four decades. However, the last decade or so has seen a considerable advance inunderstanding of dopamine’s role in the neurobiology of schizophrenia. This has beeninformed by advances in neuroimaging, preclinical models, and the study of the pro-drome to schizophrenia. Studies using these approaches have identified that the majorlocus of dopaminergic dysfunction is presynaptic, characterized by elevated dopaminesynthesis and release capacity. Moreover, this is seen in the prodrome to the illness, islinked to the symptoms, and increases with the onset of frank symptoms. It has alsobecome clear that there is no marked alteration in dopamine transporter or D2/3 recep-tor availability in schizophrenia in general, and, similarly, there do not seem to be D2/3

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200 Ilaria Bonoldi and O.D. Howes

receptor alterations in people at high clinical risk of psychosis. These findings highlightthe enduring role of dopamine in the onset of schizophrenia. They suggest that presyn-aptic dopamine dysregulation underlies the onset of psychosis and are in line with anintegrative model accounting for many of the genetic and environmental risk factorsfor schizophrenia.

1. INTRODUCTION

Schizophrenia is one of the most complex and severe psychiatric con-

ditions, profoundly and dramatically affecting the individual’s experience of

the self and the outer world (Bleuler, 1950). The syndrome is characterized

by heterogeneous clinical dimensions including positive (usually defined

as psychotic) symptoms, such as hallucinations and delusions; negative

symptoms (e.g., alogia, avolition/aphasia, social isolation, and affective dis-

turbances); disorganization (e.g., formal thought disorder and bizarre behav-

ior); and cognitive impairment (e.g., deficits in memory, attention, and

executive functions) (Andreasen, Arndt, Alliger, Miller, & Flaum, 1995;

Arndt, Andreasen, Flaum, Miller, & Nopoulos, 1995; Barch, 2009).

Schizophrenia has a lifetime prevalence almost reaching 1% (Perala et al.,

2007) in the general population, and the peak of onset tends to occur in late

adolescent or early adulthood (Saha, Chant, Welham, & McGrath, 2005).

Despite individual differences, the illness usually displays a chronic course

with alternating phases of remission and aggravation of psychotic symptoms

(an der Heiden & Hafner, 2000). Kraepelin’s first descriptions of the illness

discussed how the full-blown expression of the symptoms is often preceded

by a prodromal phase, lasting from months to years, in which nonspecific or

attenuated psychotic symptoms insidiously emerge (Klosterkotter, Schultze-

Lutter, & Ruhrmann, 2008). This clinical state is generally termed a clinical

high-risk (HR) syndrome, and specific operational criteria have been cre-

ated for its identification (Klosterkotter, Hellmich, Steinmeyer, &

Schultze-Lutter, 2001; Miller et al., 2003; Yung et al., 2005). Compared

to the general population (1%) (Perala et al., 2007), the HR syndrome is

associated with an increased risk of a psychotic disorder ranging from

18% after 6 months up to 36% after 3 years (Fusar-Poli, Bonoldi, et al.,

2012). A recent meta-analysis has shown that the majority (73%) of HR

individuals transiting to psychosis will develop a schizophrenia spectrum dis-

order (Fusar-Poli, Bechdolf, et al., in press). Subjects in this putatively

201Dopamine and the Onset of Psychosis

prepsychotic phase show significant cognitive impairments (Fusar-Poli,

Deste, et al., 2012) and deficits in social functioning and poor quality of life

(Fusar-Poli, Borgwardt, et al., in press). These HR features are associated

with a number of neurobiological abnormalities. In particular, gray matter

(GM) volume reductions have been reported in temporoparietal, bilateral

prefrontal, and limbic cortex in HR subjects (Pantelis et al., 2003; Wood

et al., 2005; Yucel et al., 2003). HR also show altered brain function—

particularly in prefrontal cortical regions—which has been linked to the risk

of developing frank psychosis (Allen et al., 2012; Broome et al., 2010), as

well as altered striatal dopaminergic function (Howes et al., 2011a,

2011b; Howes et al., 2009; Mizrahi et al., 2012). Different psychopatholog-

ical approaches with related assessment instruments have been developed to

characterize the HR condition. The current two main ones are the

ultrahigh-risk (UHR) criteria (Nelson, Yuen, & Yung, 2011; Yung,

Fusar-Poli, & Nelson, 2012), focusing mainly on attenuated positive symp-

toms and the basic symptoms (BS) criteria (Huber &Gross, 1989), based on a

detailed phenomenological approach to describing subtle subjective distur-

bances (Huber & Gross, 1989). Although there is variation across different

centers and inclusion criteria, the HR construct has proved to be a valid and

consistent predictor of transition to psychosis (Fusar-Poli, Bonoldi,

et al., 2012).

2. INDIRECT EVIDENCE FOR DA DYSFUNCTIONIN PSYCHOSIS

The hypothesis that DA dysfunction could play a key role in the origin

and development of psychotic symptoms is rooted in indirect evidence

emerging from pharmacology in the second half of last century

(Carlsson & Lindqvist, 1963; Carlsson, Lindqvist, & Magnusson, 1957).

The discovery of the antipsychotic properties of chlorpromazine and the

subsequent in vitro studies on the mechanism of action of antipsychotic drugs

led to the understanding that they are all dopamine D2-like receptor

antagonists and that their clinical potency was directly correlated with their

affinity for these receptors (Creese, Burt, & Snyder, 1976; Seeman & Lee,

1975). The DA hypothesis at this time, in the 1970s and early 1980s, was

predominantly concerned with dopamine receptor alterations in schizo-

phrenia without regional specification.

202 Ilaria Bonoldi and O.D. Howes

Further studies showed that the administration of amphetamine, a psy-

chostimulant drug that increases extracellular DA concentrations, induced

psychotic symptoms similar to those seen in schizophrenic patients in

healthy volunteers (Lieberman, Kane, & Alvir, 1987; Lieberman,

Kinon, & Loebel, 1990). Another drug, reserpine, was found to act on

DA by blocking its reuptake and thus depleting the presynaptic store and

to reduce psychotic symptoms in patients. These pharmacological studies

provided further indirect evidence for DA’s involvement in psychosis

(Carlsson et al., 1957). Based on these findings, researchers hypothesized that

a hyperdopaminergic activity was the mechanism responsible for the clinical

manifestation of psychosis (Creese et al., 1976; Howes & Kapur, 2009).

However, this theory of a general excess of DA activity was not con-

firmed by studies measuring DA metabolite levels in the cerebrospinal fluid

(Widerlov, 1988) of schizophrenic patients that showed that the increase in

DA metabolite levels was not seen in all patients, particularly not in chronic

patients with marked negative symptoms. Moreover, in some schizophrenic

patients, DA metabolites were reduced but still correlated with symptom

severity and response to antipsychotic treatment. Around this time, studies

showed that dopamine receptors have different levels of expression in dif-

ferent brain areas: D2 receptors were found to be more concentrated in

subcortical areas, while D1 receptors were predominant in cortical regions

(Hall et al., 1994). Based on this evidence, the DA dysfunction hypothesis

was then revised (Davis, Kahn, Ko, & Davidson, 1991). According to

Davis et al. (1991), dysregulation in dopamine function varied by brain

region, with increased dopaminergic function in subcortical regions but

predominant hypodopaminergia in the frontal cortex. Subcortical hyper-

dopaminergia, they proposed, explained the positive symptoms, since more

severe positive symptoms were associated with better response to antipsy-

chotic treatment and elevated metabolite level (Davis et al., 1991). On

the other hand, frontal hypodopaminergia was thought to be responsible

for negative symptoms, resistant to D2 receptor-blocking medications. Sup-

port for this idea came from the observation that humans with frontal lobe

lesions showed behavioral alterations similar to negative symptoms of

schizophrenia (Davis et al., 1991). However, this hypothesis had a number

of limitations. It was mostly based on indirect evidence and animal studies

and lacked a theoretical framework to organize the clinical expressions of the

symptomatology and the etiology of the neurochemical disturbances. More-

over, in vivo research was still needed to clarify which element of DA trans-

mission was altered in psychosis.

203Dopamine and the Onset of Psychosis

3. MOLECULAR IMAGING EVIDENCE FOR DADYSFUNCTION IN PSYCHOSIS

The role of DA dysfunction in psychosis can be tested in vivo thanks to

neurochemical imaging techniques such as positron emission tomography

(PET) and single positron emission computerized tomography (SPECT).

These methods allow the molecular assessment of DA neurotransmitter

activity, in terms of release (Laruelle et al., 1996), depletion (Kegeles

et al., 2010), transport and reuptake (Laruelle et al., 2000), synthesis

(Meyer-Lindenberg et al., 2002), and receptor expression and availability

(Hirvonen et al., 2005).

Molecular imaging studies starting in the mid-1990s employed agents

to either release (e.g., amphetamine) or deplete (e.g., alpha-methyl-

paratyrosine (AMPT), an inhibitor of tyrosine hydroxylase) tissue stores

of DA. They found that the baseline levels of striatal synaptic DA and the

DA release in response to amphetamine challenge were increased in patients

with schizophrenia as compared to controls (Laruelle et al., 1996). More-

over, the magnitude of that increase was related to the severity of

amphetamine-induced psychotic symptoms and the response to subsequent

antipsychotic treatment (Laruelle et al., 1996).

Subsequent studies have confirmed that drug-naıve/free psychotic

patients present higher DA release induced by amphetamine compared to

controls (Abi-Dargham et al., 1998; Abi-Dargham, van de Giessen,

Slifstein, Kegeles, & Laruelle, 2009; Breier et al., 1997; Laruelle, Abi-

Dargham, Gil, Kegeles, & Innis, 1999; Villemagne et al., 1999). Depletion

studies confirmed the link between DA manipulation and psychotic symp-

toms and found that AMPT challenge led to a significant decrease in severity

of psychotic symptoms (Abi-Dargham et al., 2009). It also induced signifi-

cant behavioral changes in schizophrenic patients (dysphoria, akathisia,

akinesia, and rigidity) as would be expected from dopamine depletion

(Voruganti & Awad, 2006).

Another locus of potential DA alterations in psychosis is DA transport

and uptake. In presynaptic terminals, cytoplasmic DA is moved into synaptic

vesicles for storage and subsequent release through the vesicular monoamine

transporter 2 (VMAT2). The dopamine transporter (DAT) is the major

mechanism terminating dopamine transmission in the striatum. Further-

more, numerous drugs that have been implicated in psychosis have impor-

tant pharmacological interactions with DAT, affecting dopamine transport

204 Ilaria Bonoldi and O.D. Howes

(e.g., cocaine and methylphenidate) or serving as substrates for transport

(e.g., dopamine, amphetamine, and 3,4-methylenedioxymethamphetamine

(MDMA or “ecstasy”)) (Piccini, 2003).

Over the past years, a number of studies have attempted to investigate

DAT and VMAT2 alterations in psychosis. There have now been fourteen

studies of striatal DAT in schizophrenia, including one with nearly fifty

drug-naıve first episode patients (Chen et al., 2013). Meta-analysis of the

studies in drug-naıve patients shows no alterations, and this is also the case

when drug-treated patients are included in meta-analyses (Fusar-Poli &

Meyer-Lindenberg, 2013a; Fusar-Poli, Stone, et al., 2011; Howes,

Kambeitz, et al., 2012). Similarly, there is little evidence to suggest there

are alterations in VMAT2 in schizophrenia (Taylor, Koeppe, Tandon,

Zubieta, & Frey, 2000).

Dopamine synthesis capacity has also been investigated in schizophrenia.

In these studies, a precursor of dopamine, L-dihydroxyphenylalanine

(L-DOPA), is radiolabeled to [18F]-DOPA or [11C]-DOPA) and, in the

brain, converted into dopamine and stored in nerve terminals (Moore,

Whone,McGowan, & Brooks, 2003). Therefore, the degree of radiolabeled18F/11C-L-DOPA uptake allows a measure of presynaptic dopamine synthe-

sis capacity. The complex molecular basis of DA synthesis capacity has been

detailed elsewhere (Kumakura & Cumming, 2009). A number of [11C] and

[18F]-DOPA studies in schizophrenia have been published to date, with

both significant and inconclusive outcomes. However, as indicated earlier,

a first meta-analysis has clearly found that there is an overall pathological

increase in presynaptic dopamine synthesis capacity in schizophrenic

patients over controls with a large effect size (Cohen’s d¼0.8) (Howes,

Kambeitz, et al., 2012). A second independent meta-analysis confirmed

the findings in the preceding text with a similar effect size (Fusar-Poli &

Meyer-Lindenberg, 2013b).

Presynaptic DA synthesis capacity is not elevated in patients with

other psychiatric conditions such as affective illnesses without psychotic

features (Martinot et al., 2001; Yatham et al., 2002) or in people with

subclinical psychotic experiences in the general population (Howes,

Shotbolt, et al., 2012), suggesting specificity to psychosis. Furthermore,

DA synthesis capacity, measured using PET to index the uptake of18F/11C-L-DOPA uptake and its conversion to radiolabeled DOPA, can

be used to identify people with schizophrenia, with high specificity

(90%) and sensitivity (89%) (Bose et al., 2008), suggesting it could be used

to aid diagnosis.

205Dopamine and the Onset of Psychosis

Since all available drugs effective in psychosis act on D2/D3 receptors,

D2/3 receptors have been the target of the majority of neuroreceptor studies

aiming to investigate whether in psychotic patients the DA receptor density

was elevated compared to controls. There have now been well over twenty

studies to investigate D2/3 receptor availability in drug-naıve/free schizo-

phrenia. The results of the D2/3 receptor studies are inconsistent, with a

small, at most, elevation evident on meta-analysis (Howes, Kambeitz,

et al., 2012). Overall, there is converging meta-analytical evidence indicat-

ing the locus of the largest dopaminergic abnormality in schizophrenia is

presynaptic, affecting dopamine synthesis capacity, baseline synaptic dopa-

mine levels, and dopamine release (Howes, Kambeitz, et al., 2012). Unfor-

tunately, current drug treatments fail to target these abnormalities (Howes,

Kambeitz, et al., 2012).

4. THE LINK BETWEEN DA AND PSYCHOTIC SYMPTOMS

Several lines of evidence suggest there is a link between dopamine and

psychotic symptoms. The exacerbation of positive symptoms induced by

amphetamines is associated with the change in D2/3 receptor radioligand

binding after the challenge (Laruelle et al., 1996). Amphetamines lead to

an increase in extracellular DA. For radioligands such as raclopride and123I-iodobenzamide [123I]IBZM, the increased DA leads to a reduction in

radioligand binding. Furthermore the change in radioligand binding has

been shown to be related to the change in DA levels (Breier et al., 1997;

Laruelle et al., 1996). The extent of DA release, as indirectly estimated by

measuring displacement of the SPECT D2/D3 receptor radiotracer123I-iodobenzamide [123I]IBZM, is significantly larger in patients experienc-

ing acute psychotic symptoms compared to those in remission (Laruelle

et al., 1999). Moreover, the magnitude of the radiotracer displacement is

related to the severity of amphetamine-induced psychotic symptoms

(Laruelle et al., 1996).

Increased baseline striatal extracellular dopamine levels have also been

detected in patients experiencing acute psychotic symptoms (Abi-

Dargham et al., 1998; Hietala et al., 1999, 1995; Lindstrom et al., 1999).

Furthermore, the higher the level of baseline synaptic DA, the better is

the subsequent response to antipsychotic medications (Abi-Dargham

et al., 2000).

It is worth noting that psychotic symptoms per se are not unique to

schizophrenia and can be found in other psychiatric disorders (e.g., affective

206 Ilaria Bonoldi and O.D. Howes

disorder with psychotic features) (APA, 2000). In fact, antipsychotic med-

ications appear to be effective for psychotic symptoms regardless of diagnos-

tic boundaries. However, it remains to be determined if DA abnormalities

underlie psychosis in affective disorders.

In order to link neurochemical dysfunctions and clinical manifestation of

psychosis, a theory involving salience and reward has been proposed

(Howes & Kapur, 2009; Kapur, 2003). This was based on evidence that sub-

cortical DA system plays a key role in reward prediction, marking relevant

context-driven stimuli and their association as being salient and facilitating

goal-directed behavior (Berridge & Robinson, 1998; Kapur, Mizrahi, & Li,

2005; Martin-Soelch et al., 2001; Robbins & Everitt, 1996; Schultz, 2002;

Schultz, Dayan, & Montague, 1997; Wise, 2004). In psychosis, dys-

regulation of the dopamine system may lead to context-inappropriate firing

of DA neurons. The abnormal subcortical DA release could thus contribute

to the assignment of salience to innocuous stimuli and the formation of inap-

propriate associations (Kapur et al., 2005), creating an increasing sense of

perplexity and confusion. Clinically, this phase could correspond to the

predelusional mood “Wahnstimmung” originally described by Karl Jaspers

(Jaspers, 1959/1963) in 1913. Psychotic symptoms such as hallucinations

and delusions are thought to gradually arise, colored by existing cognitive

and sociocultural schemas, as the individual’s own explanation of the expe-

rience of aberrant salience (Heinz & Schlagenhauf, 2010; Howes & Kapur,

2009). As a result, the same neurochemical dysregulation could have differ-

ent clinical manifestations in different subjects and diverse cultures (Kapur

et al., 2005).

5. MOLECULAR IMAGING EVIDENCE FOR DADYSFUNCTION IN THE PRODROME TO PSYCHOSIS

Over the past two decades, a growing amount of clinical and research

effort has focused on individuals expressing putatively prodromal symptoms

of psychosis.

Although theHR state can be variably defined by using different psycho-

metric instruments, the overall clinical presentation includes the presence of

subthreshold psychotic symptoms and decreased social functioning (Yung

et al., 2003, 2005). As compared to controls, subjects at high risk for psycho-

sis show reduced GM volume in the right superior temporal gyrus, left

precuneus, left medial frontal gyrus, right middle frontal gyrus, bilateral

parahippocampal/hippocampal regions, and bilateral anterior cingulate

207Dopamine and the Onset of Psychosis

(Pantelis et al., 2003; Wood et al., 2005; Yucel et al., 2003). Baseline GM

volume reductions in the right inferior frontal gyrus and in the right superior

temporal gyrus are associated with later transition to psychosis (Pantelis et al.,

2003). A recent meta-analysis demonstrated that relative to controls HR are

impaired on tests of general intelligence, executive function, verbal and

visual memory, verbal fluency, attention and working memory, and social

cognition. More marked deficits in the verbal fluency and memory domains

are associated with later transition to psychosis (Fusar-Poli, Deste, et al.,

2012). Altered frontal (Broome et al., 2009) and temporal lobe (Allen

et al., 2012) activation has been reported in HR subjects during a number

of cognitive tasks, indicating that altered brain function is likely to underlie

these cognitive impairments. A recent study showing increased hippocampal

resting cerebral blood volume provides further evidence of altered brain

function in HR subjects (Schobel et al., 2013). Furthermore, they show

an altered relationship between striatal DAergic function and activation in

frontal and medial temporal regions (Allen et al., 2012; Fusar-Poli et al.,

2010; Fusar-Poli, Howes, et al., 2011). Furthermore, HR show altered

medial temporal lobe (MTL) function, which is linked to subcortical DA

dysfunction (Crossley et al., 2009). In addition to altered striatal dopaminer-

gic function (Howes et al., 2011a, 2011b, 2009;Mizrahi et al., 2012), a num-

ber of other neurochemical alterations have been reported in HR subjects,

in particular altered glutamate in thalamus and striatum (de la Fuente-

Sandoval et al., 2013; Stone & Fusar-Poli, 2009; Stone et al., 2010).

Molecular imaging evidence from studies of individuals in the putative

prodromal phase of psychosis shows that dopaminergic abnormalities pre-

date the onset of the full-blown psychotic disorder, being already present

in HR individuals. The first study used [18F]-DOPA PET and found that

HR individuals show higher striatal dopamine synthesis capacity compared

to controls (Howes et al., 2011b, 2009) to an intermediate degree compared

to patients with schizophrenia (Howes et al., 2009). The increase in striatal

dopamine synthesis capacity in HR is predominantly localized in the asso-

ciative striatum and it is correlated with the severity of prodromal symptoms

and neurocognitive dysfunction (Howes et al., 2009). Increased DA synthe-

sis capacity appears to be specific to prodromal symptoms, since it did not

correlate with the severity of anxiety or depressive symptoms (Howes

et al., 2009). Interestingly, there were no dopaminergic alterations in healthy

controls experiencing auditory hallucinations, suggesting that altered dopa-

mine synthesis capacity is unlikely to underlie subclinical hallucinations

within the psychosis continuum (Howes, Shotbolt, et al., 2012).

208 Ilaria Bonoldi and O.D. Howes

The finding of elevated dopamine synthesis capacity in HR subject has

been recently replicated by the same researchers in a second independent

cohort (Egerton et al., 2013).

The altered presynaptic dopamine synthesis capacity appears to be related

to other alterations seen in the prodrome to schizophrenia. In particular,

dopamine synthesis capacity was found to be linked to cortical functioning

during cognitive processes in HR subjects, linking subcortical DAergic dys-

function to the cortical alterations seen in the development of psychosis

(Allen et al., 2012; Fusar-Poli et al., 2010; Fusar-Poli, Howes, et al.,

2011). The interplay between glutamate (GLU) and striatal dopamine func-

tion has also been investigated in HR subjects (Stone et al., 2010). This study

indicated that the relationship between hippocampal glutamate and striatal

dopamine systems is altered in HR people and the degree to which it is

changed may be related to the risk of transition to psychosis, further indicat-

ing the importance of cortical and subcortical interactions in the develop-

ment of psychosis.

The prospective follow-up of HR subjects has found that dopamine syn-

thesis capacity is greater in those who later transition to psychosis (Howes

et al., 2011b) and that DA synthesis capacity increases as patients develop

frank psychosis (Howes et al., 2011a).

While further longitudinal neuroimaging studies are required to confirm

the results in the preceding text, these findings suggest that neuroimaging

methods may have additional predictive value for detecting patients in their

early phase of psychosis.

D2/3 receptor availability has also recently been investigated in HR sub-

jects. Not surprisingly, given the meta-analytic evidence for little alteration

in D2/3 receptors in schizophrenia, both studies found no evidence of an

alteration in D2/3 receptors in HR subjects (Bloemen et al., 2013;

Mizrahi et al., 2012). Mizrahi et al. (2012) did, however, find evidence

for increased stress-evoked alteration in radioligand binding in schizophre-

nia and HR risk subjects, consistent with stress resulting in greater DA

release in schizophrenia and people at risk of schizophrenia. A sample of

HR subjects has been recently studied using AMPT to deplete synaptic

DA levels and measuring the change in [123]-IBZM binding (Bloemen

et al., 2013). However, this study failed to find any difference in change

in radiotracer binding potential in HR as compared to controls. However,

the study found that AMPT was effective in reducing the severity of atten-

uated positive symptoms, similar to findings from depletion studied in

schizophrenic patients (Abi-Dargham et al., 2009). Moreover, the reduction

209Dopamine and the Onset of Psychosis

of attenuated positive symptoms following depletion was greater in HR

subjects with higher synaptic DA concentration. This finding is in line with

the hypothesis that DA is specifically related to positive symptom severity

(Bloemen et al., 2013) and in particular to delusion formation. Another

group at increased risk of schizophrenia is first-degree relatives of patients

with schizophrenia. One study has found that first-degree relatives of

patients with schizophrenia showed increased dopamine synthesis capacity

(Huttunen et al., 2008). However, this has not been found in another study,

possibly because the subjects in this study were less symptomatic (Shotbolt

et al., 2011).

6. THE LINK BETWEEN DA AND OTHER SYMPTOMS

How does DA dysfunction explain other symptom dimensions in

schizophrenia, such as negative symptoms and cognitive impairment?

As mentioned in the preceding text, in 1991, Davis et al. (1991) put forth

the hypothesis of a regionally specific DA dysfunction in schizophrenia.

They suggested that while striatal hyperdopaminergia was linked to positive

symptoms, frontal hypodopaminergia was responsible for negative symp-

toms. This was based on observation that animals and humans with frontal

lobe lesions showed behaviors similar to schizophrenic patients with nega-

tive symptoms. Indirect support for this hypofrontality theory came from

studies on DA metabolite levels and the different distribution of D1 and

D2 receptors in the brain (Hall et al., 1994). Moreover, negative symptoms

appeared to be resistant to, or even worsened by, D2 receptor-blocking

medications (Howes, Kambeitz, et al., 2012). The link between hypofrontal

and hyper-subcortical dopaminergia was supported by animal studies show-

ing that lesions of DA neurons in the prefrontal cortex (PFC) induced an

increase in DA, DA metabolite levels, and D2 receptors density in the stri-

atum (Pycock, Kerwin, & Carter, 1980). However, no direct evidence con-

firmed this hypothesis and no framework explained the origin of symptoms

from neurochemical dysfunctions.

More recently, theoretical frameworks that attempt to explain the link

between neurobiology and phenomenology of positive and negative symp-

toms have been proposed (Howes &Kapur, 2009; Kapur et al., 2005; Roiser

et al., 2009). These suggest that abnormal firing of DA neurons may increase

the noise in the system, “submerging” dopaminergic signals linked to reward

(Heinz & Schlagenhauf, 2010; Roiser et al., 2009). Such a mechanism

would create reduce motivational drive, eventually resulting in anhedonia

210 Ilaria Bonoldi and O.D. Howes

and social withdrawal. Evidence supporting this hypothesis has shown that

in schizophrenic patients, there is a diminished ventral striatal response to

reward and the magnitude of this reduction correlates with severity of neg-

ative symptoms (Juckel et al., 2006).

Cognitive impairment has been frequently observed in schizophrenia,

particularly involving working memory and other executive functions

(Callicott et al., 2003; Glahn et al., 2005; Tan, Callicott, & Weinberger,

2009). Functional imaging studies have shown reduced PFC activation dur-

ing working memory tasks in patients with schizophrenia (Glahn et al.,

2005), and this was correlated with increased DA synthesis capacity in the

striatum (Meyer-Lindenberg et al., 2002). Poor performance on cognitive

tasks is also associated with striatal dopamine abnormalities (Howes et al.,

2009; McGowan, Lawrence, Sales, Quested, & Grasby, 2004; Meyer-

Lindenberg et al., 2002). At this stage, it is not clear if the primary process

leading to dysfunctions arises from striatal or frontal changes, although pre-

clinical models show that striatal changes in dopaminergic neurotransmis-

sion are sufficient to induce cognitive impairments (Kellendonk et al., 2006).

7. DA DYSFUNCTION: THE FINAL COMMON PATHWAY?

The etiology and pathophysiology of schizophrenia are far from being

fully understood. However, an increasing amount of evidence from animal

studies and in vivo human studies has demonstrated that many of the risk fac-

tors associated with the development of schizophrenia have an impact on the

dopamine system. Childhood abuse, migration, urban upbringing, lack of

close relationships, and unemployment are associated with an increased risk

of developing schizophrenia (Cantor-Graae, 2007). These experiences are

often markers of social isolation or subordination (van Winkel,

Stefanis, & Myin-Germeys, 2008). Evidence from animal studies has shown

that social isolation/subordination can induce dopamine DA overactivity

(Hall et al., 1998; Hall, Wilkinson, Humby, & Robbins, 1999; Morgan

et al., 2002). Moreover, animal studies have also shown that pre- and peri-

natal factors can lead to hyperactivity of mesostriatal DA function (Boksa,

2004; Boksa & El-Khodor, 2003). These findings suggest these risk factors

for schizophrenia may result in DA dysfunction, in line with the increased

presynaptic dopaminergic activity associated with schizophrenia. A recent

twin study found that environmental factors explain more of the variance

in striatal dopaminergic function than heritable factors, suggesting that

211Dopamine and the Onset of Psychosis

dopaminergic function is sensitive to environmental influence (Stokes

et al., 2013).

Another robust pathophysiological finding associated with psychosis is

MTL dysfunction (Ragland, Yoon, Minzenberg, & Carter, 2007). The rela-

tionship between this and the dopamine alterations needs further investiga-

tion, but animal models of psychosis suggest that hyperactivity in MTL,

particularly in the hippocampal subfields, underlies the subcortical dopamine

dysregulation (Lodge & Grace, 2011), via glutamatergic projections from

the hippocampus to the striatum (Law & Deakin, 2001; Lisman & Grace,

2005; Lodge & Grace, 2007; Pilowsky et al., 2006). According to Lodge

and Grace’s model, the ventral hippocampus modulates dopamine neurons

projecting from the ventral tegmental area (VTA) to the striatum via a poly-

synaptic pathway involving a glutamatergic input to the nucleus accumbens

that increases GABAergic activity to the ventral pallidum (VP). This

enhancement in GABA activity decreases tonic VP activity, resulting in a

disinhibition of dopamine neuron activity in the VTA (Lodge &

Grace, 2011).

This model of psychosis is based on animal studies in which a disruption

of the normal brain development has been produced in rats with the

administration of mitotoxin methylazoxymethanol acetate (MAM) at ges-

tational day 17 (GD17), causing anatomical, behavioral, and neurochemical

deficits that are consistent with those observed in schizophrenia patients.

MAM-treated rats show altered striatal dopaminergic activity, which can

be normalized by inactivating an output region of the MTL (Lodge &

Grace, 2007). This model highlights that, while DA dysfunction may

underlie the development of psychotic symptoms, alterations in several

synapses upstream may be critical to the DA alterations. Increasing evi-

dence corroborates the hypothesis that abnormalities in glutamatergic

transmission, mediated by N-methyl-D-aspartate (NMDA) receptor hyp-

ofunctioning, may be associated with schizophrenia (Javitt & Zukin,

1991; Olney, Newcomer, & Farber, 1999; Schwartz, Sachdeva, & Stahl,

2012; Stone et al., 2010). Furthermore, NMDA receptor antagonists

(e.g., ketamine and phencyclidine) can induce behavioral effects in healthy

humans similar to negative and positive psychotic symptoms, as well as

many of the cognitive deficits associated with schizophrenia (Adler

et al., 1999; Javitt & Zukin, 1991).

It has been proposed that GLU neurocircuitry system impacts on dopa-

minergic transmission to lead to the emergence of psychosis (Olney et al.,

1999; Schwartz et al., 2012).

212 Ilaria Bonoldi and O.D. Howes

Reduced functioning of NMDA glutamate receptors (Olney et al.,

1999) has been proposed to lead to disinhibition of cortical pyramidal cells.

According to this model, enhanced activity in pyramidal neurons in the

MTL would then result in increased glutamate (GLUT) release in the stri-

atum, stimulating GABAergic neurons that project from the striatum to the

VP. This would create an excessive inhibition of VP GABAergic neurons,

leading to the disinhibition of midbrain DAergic neurons and thus increased

DA release in the striatum. Moreover, dopaminergic neurons in the mid-

brain project back to the MTL, potentially producing further disinhibition,

reinforcing the positive feedback loop (Lodge & Grace, 2011).

Alternatively, Schwartz et al. (2012) highlight the potential role of a faulty

glutamatergic system in the PFC, focusing on glutamate pathways projecting

from the frontal cortex to the midbrain and regulating neurotransmitter

release. They propose that DA neuronal activity in the midbrain and limbic

structures could be controlled by GLU neurons in the frontal cortex with a

GLU–GABA–GLU–DA neurocircuit loop. Thus, disinhibited cortical

GLU neuronal tone, controlling mesolimbic DA neurons via descending

pathways, would result in excessive DA firing, manifesting in positive psy-

chotic symptoms. According to this model, negative symptoms of schizophre-

nia are due to hypofunction of DAergic projections to frontal regions and

consequent inefficient performance in the dorsolateral prefrontal cortex/ven-

tromedial prefrontal cortex (DLPFC/VMPFC) (Schwartz et al., 2012). These

two models are not mutually exclusive, and it is possible that both play a role.

8. WHAT WE DO NOT KNOW

Although convincing evidence from molecular imaging studies has

shown that schizophrenia and its prodromal phase are characterized by

altered presynaptic dopaminergic activity, the whole picture is far from

being fully understood. For instance, it is not yet clear which local presyn-

aptic element is responsible for the altered dopamine synthesis capacity.

Alterations could potentially occur at one or more steps involved in DOPA

uptake, DA synthesis and storage, such as the large amino acid transporter,

responsible for DOPA uptake in the dopaminergic neuron, or the enzyme,

L-aromatic acid decarboxylase that converts DOPA into dopamine. More-

over, it is not yet clear if the underlying pathophysiology is the same for all

subtypes of schizophrenia. Some [18F]-DOPA findings (Hietala et al., 1999,

1995) seem to suggest that the catatonic subtype of schizophrenia might be

associated with abnormally low levels of striatal DA, although these results

213Dopamine and the Onset of Psychosis

were drawn from only three subjects, and further work is needed to confirm

this hypothesis (Lyon et al., 2011). Another subtyping that has clinical impli-

cations is that into treatment responders and nonresponders. A recent [18F]-

DOPA study has linked DA alterations to treatment response. In this study,

treatment-resistant patients showed a lower DA synthesis capacity compared

to responders (Demjaha, Murray, McGuire, Kapur, & Howes, 2012). Con-

sistent with this, high-affinity D2 antagonists are less effective for treatment-

resistant patients than clozapine, a drug that has a relatively low affinity for

D2 receptors (Farde, Wiesel, Nordstrom, & Sedvall, 1989; Kapur,

Zipursky, &Remington, 1999; Nordstrom et al., 1995) and actions at a large

number of other receptors.

9. CONCLUSION

After almost half a century of investigation, dopamine still occupies a

central role in the pathophysiology of schizophrenia. Recent in vivo imaging

studies have shown that elevated striatal DA synthesis and release capacity is

associated with schizophrenia (Howes et al., 2007). Moreover, elevated DA

synthesis capacity predates the onset of full-blown psychosis and is already

evident in HR individuals (Howes et al., 2009). Specifically, striatal hyper-

dopaminergia is greater in those who later transition to psychosis (Howes

et al., 2011b) and progressively increases with the development of the first

episode of the illness (Howes et al., 2011a). In contrast, alterations in DAT or

D2/3 receptor availability are not marked in schizophrenia. Striatal dopa-

mine abnormalities appear to be associated with poor cognitive performance

in tasks such as working memory (Howes et al., 2009; McGowan et al.,

2004; Meyer-Lindenberg et al., 2002), and higher striatal DA synthesis

capacity seems linked to functional abnormalities in the related cortical areas

(Fusar-Poli, Howes, et al., 2011; Meyer-Lindenberg et al., 2002). Although

it is not yet clear where the primary change lays, cortical impairments may be

a consequence of striatal dysfunction (Kellendonk et al., 2006). It is likely

that multiple neurotransmitter systems are involved in the cognitive impair-

ment and negative symptoms of schizophrenia, as outlined in the circuit

models briefly reviewed earlier.

Further research is needed to explain in detail if, and how, the genetic

and environmental risk factors for schizophrenia impact on the DA system

and how this affects other brain systems.

All the currently licensed antipsychotic medications are based on block-

ade of dopamine D2 receptors. Therefore, they fail to target the major

214 Ilaria Bonoldi and O.D. Howes

presynaptic dopaminergic dysfunctions or upstream mechanisms leading to

the DAergic alterations. The identification of presynaptic dopaminergic dys-

function as the major locus of dopaminergic abnormalities in schizophrenia

suggests that future drug development should address presynaptic dopami-

nergic modulation or focus on upstream regulation of DA system, targeting

other altered neurotransmitter function such as glutamate (Patil et al., 2007)

or GABA (Lodge & Grace, 2011).

CONFLICT OF INTERESTNo relevant conflicts of interest.

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