Phenotype of schizophrenia: a review and formulation
CA Tamminga1and HH Holcomb2
1Department of Psychiatry, UT Southwestern Medical School, Dallas, TX, USA;2Maryland Psychiatric Research Center,
University of Maryland School of Medicine, Baltimore, USA
The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational
treatment directions for this brain disorder. Firm knowledge about this illness is limited to
areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of
dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions
remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is
an illness ripe for molecular characterization using a rational approach with a confirmatory
strategy; drug discovery based on knowledge is the only way to advance fully effective
treatments. This paper reviews the status of general knowledge in this area and proposes an
approach to discovery, including identifying brain regions of dysfunction and subsequent
localized, hypothesis-driven molecular screening.
Molecular Psychiatry (2005) 10, 27–39. doi:10.1038/sj.mp.4001563
Published online 31 August 2004
Keywords: schizophrenia; psychosis; limbic cortex; brain imaging; signs and symptoms
Schizophrenia is a brain disease that has afflicted
humans since the beginning of written history. Its
distinctive clinical features are easily recognized in
early Greek and Hebrew literature, and have not
changed remarkably over the millennia. However, the
formulation of the presentation has changed during
this time reflecting sociopolitical orientations and
often nonmedical formulations. During various his-
torical periods, psychotic persons were called pro-
phets or seers; occasionally, manifestations of the
devil, sometimes saints; but until modern times,
rarely ill. It was not until the last half of the 19th
century that compassionate treatment was invoked for
the mentally ill. At the turn of the 20th century,
schizophrenic psychosis was distinguished from
affective psychosis on the basis of outcome. In the
early 1930s, schizophrenia was treated with unusual
and unlikely procedures such as ‘fever therapy,’
adrenalectomy, and vasectomy, all tested on specula-
tion, but carried out in response to overwhelming
medical need.1It was not until the end of World War
II that reserpine was used with some efficacy, but
with considerable side effect burden. Chlorpromazine
was the first effective, selective, oral antipsychotic
drug; it was identified without a known tissue target
by informed clinical serendipity.2Its use spread
quickly throughout the western world. Identification
of its mechanism of action as dopamine receptor
blockade3allowed industry laboratories to develop
additional effective antidopaminergic compounds in
a timely fashion.
While the early literature reported ‘cures,’ it
gradually became apparent that these drugs act to
diminish psychotic symptoms, but not to cure the
illness or to fully restore health.4Today, with both
first- and second-generation antipsychotic drugs, the
situation of persons with schizophrenia is vastly
improved, but all still suffer considerable residual
symptom burden and lifelong psychosocial impair-
ments. In total, 10–20% of persons with the illness
recover rather fully to approximate preillness levels of
function (very good outcome) and another 15–20%
are treatment resistant (highly troublesome outcome);
the middle group suffers a range of ongoing mental
impairments (cognitive, affective and psychotic im-
pairments) despite medications.
The biggest impediment to progress in therapeutics
is the lack of firm knowledge of disease pathophy-
siology. Without known molecular targets, therapeu-
tics can advance only by serendipity, chance, or
modifications of existing treatments. Hope for identi-
fying the pivotal molecular targets for schizophrenia
rests on the application of modern concepts and
techniques of neuroscience to clearly diagnosed and
characterized populations of persons with schizo-
phrenia, supported by genetic information where
relevant. Bold advances made in clinical assessment
techniques, especially in brain imaging modalities,
allow clinical scientists to make regional in vivo
observations of brain structure, chemistry, and func-
tion in persons with the illness and compare outcome
measures between ill and nonill populations and
What is known with greatest certainty about
schizophrenia is its clinical phenomenology with its
Received 09 June 2004; revised 09 June 2004; accepted 22 June
Correspondence: CA Tamminga, MD, Department of Psychiatry,
UT Southwestern Medical School, 5323 Harry Hines Blvd.,
Dallas, TX 75390-9070, USA.
Molecular Psychiatry (2005) 10, 27–39
& 2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00
behavioral presentation, cognitive characteristics, and
electrophysiologic profile. This could be aptly called
its clinical phenotype. The clinical picture is com-
plex, and no one knows yet how the disease
characteristics sort to individual phenotypes that are
reflective of a single set of molecular target changes.
Several aspects of the phenotype are distinctive and
are presumed to be informative about schizophrenia
course, genetics, cognitive and task-activated brain
activation patterns, postmortem tissue characteristics,
and schizophrenia pharmacology will all contribute.
Symptoms and course
Several meta-analyses of large schizophrenic popula-
tions have demonstrated the clustering of symptoms
into at least three distinct symptom domains in
hallucinations, delusions, and thought disorder, and
paranoia; (2) cognitive dysfunction, especially in
attention, working memory, and executive function;
(3) negative symptoms with anhedonia, social with-
drawal, and thought poverty.5–11Symptom clusters
characteristically occur together; one cluster may
predominate; one domain is not exclusive of another.
Whether these symptom domains are multiple man-
ifestations of a single disease pathophysiology or are
each a partially independent disease construct re-
mains unknown. However, heterogeneity is more
often presumed about the illness, certainly with
respect to etiology. There are therapeutic implications
to heterogeneity: does one treatment exist for schizo-
phrenia? Or are there several symptom or syndrome-
specific treatments for the illness? This question
remains open, but taking clues from other illness,
one would guess that several treatments will emerge.
The course of schizophrenia is life-long. Occasion-
ally, the illness has a fast onset, is episodic in nature,
has symptoms first occurring in late teen and early
adult years, and shows satisfactory recovery between
episodes. However, often other patterns of illness
occur with an insidious onset, partial recovery, or a
remarkable lack of recovery between episodes.12,13In
most affected persons, a profound deterioration in
psychosocial function occurs within the first few
years of the illness.14After the initial deteriorating
years, the further course of illness settles at a low,
flatter plateau. Surprisingly, symptoms can improve
in later life after 50 years of age. The Vermont study
found considerable heterogeneity in outcome in later
life, including frank late improvers.15,16These data are
consistent with several other outcome studies, in
Europe and the US, which report frequent good
outcome in later years for individuals with schizo-
phrenia12,13,17,18even though divergent descriptions
exist.19Whether elder years are merely less demand-
ing periods or whether the normal aging process is
therapeutic in the illness is not known. The disease
course of schizophrenia can be easily distinguished
from traditional neurodegenerative disorders where
the course is progressively downhill (like Parkinson’s
disease or Alzheimer’s dementia) and from traditional
neurodevelopmental disorders (like mental retardation)
where the course is low and steady from early years.
Certain epidemiologic factors have been regularly
associated with a propensity toward the illness.
Genetic predisposition is certain.20,21Prevalence of
schizophrenia is 1% in the general population, but
approximately 8–10% in persons with a schizophre-
nic sibling, 12% in those with a schizophrenic parent,
and 40–50% in identical twins. While a genetic
constitution is influential, it does not inevitably
result in the illness. Moreover, schizophrenia occurs
without obvious family history. Both prenatal mater-
nal illness during the second trimester and perinatal
birth complications have been associated with schi-
zophrenia as predisposing risk factors, and winter
birth (summer conception) of the proband is asso-
ciated with a small, but clear increase in risk for
schizophrenia. Each risk factor confers a modest risk
alone; genetics is the strongest risk factor. Possibly
when factors occur together, these risks may be
multiplicative.22–25Moreover, the risk factors as a
group suggest the importance of very early life events
in the onset of an illness whose florid symptoms
appear much later in life.
Psychologic assessment of brain activity in schizo-
phrenia might be expected to provide the highly
relevant clues to abnormalities in the illness, because
the core symptoms of schizophrenia are of a cognitive
variety. Even though it is difficult to distinguish a
schizophrenic from a normal brain by traditional
anatomic or biochemical features, several psychologic
and physiologic measures are able to provide distin-
guishing features between the two groups. Any ability
to account for these differences with a compelling
biologic explanation would certainly enable advances
in our concepts of mechanisms in the illness.
Persons with schizophrenia perform poorly on most
neuropsychological tests when compared to normals.
This poor performance may be partly caused by
symptoms of schizophrenia (eg, poor motivation or
distraction from psychotic symptoms), but also
negative effects of early onset of the illness and
chronic institutionalization leading to the generalized
deficits in these patients.26Several kinds of cognitive
defects are particularly prominent in persons with the
illness: working memory defects, attentional dysfunc-
tion, verbal and visual learning and memory, proces-
sing speed, and social learning.27–32No cognitive
domains are entirely spared, and deficits in perfor-
mance are highly intercorrelated within persons.33
However, schizophrenic subjects in many of the
studies show a pattern of deficits, ruling out a
complete lack of motivation as a factor in perfor-
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
To date, neuropsychological characteristics of schi-
zophrenia have not served to localize disease patho-
physiology. For example, in schizophrenic persons,
memory deficits for recurring digit occur that are
consistent with temporo-hippocampal dysfunction.27
Functions that are ascribed to frontal cortex are
abnormal (for example, verbal fluency, spatial perfor-
mance, pattern recognition), and long-term memory is
affected. Besides, persons with schizophrenia also
perform tasks poorly that require sustained attention
or vigilance characteristically associated with the
anterior cingulated.34Deficits in memory possibly
involving hippocampus occur, including explicit
memory, verbal memory, and working memory.35,36
Deficits in working memory may explain a part of the
disorganization and functional deterioration observed
in the illness, since the ability to hold information
‘on-line’ is critical for organizing future thoughts and
actions in the context of the recent past.37These
characteristics of cognition in schizophrenia suggest
broad cortical dysfunction.
In addition to cognition, other manifestations of
brain function are abnormal in schizophrenia. Several
phenotypic expressions of provoked behaviors are
known to be altered in the illness, including smooth
and saccadic eye movements,38,39prepulse inhibi-
tion,40,41and P50 after auditory evoked potential.42
These are spontaneous behaviors of the brain occur-
ring in response to external cues that have known
neural anatomies, and hence may be more direct
reflections of neural pathology.43,44The ability of
some probands (60–70%) with schizophrenia to
follow a smooth pendulum movement with their eyes
is deficient.45Instead of describing smooth move-
ments following a pendulum stimulus, some show
jerky and irregular (delayed and catch-up movements)
tracking patterns. Also, antisacade eye movements
(those directed away from a stimulus) are also
abnormal in persons with the illness.45,46Prepulse
inhibition (PPI) is a normal phenomena evident
across all sensory modalities, where a small initial
(‘pre’) stimulus decreases the electrophysiological
response to a second higher intensity stimulus. In
schizophrenia, many probands show abnormal PPI, as
do unaffected family members. The neural systems
influencing both oculomotor movements and PPI
have been well described in the animal and are
believed to be highly conserved in the human.47,48P50
is an electrophysiologic measure produced when two
equal auditory stimuli are presented 500ms apart and
their evoked potential is measured. Healthy persons
show a reduced response (in amplitude) to the second
signal; whereas persons with schizophrenia (esti-
mated at 80%) show less or no suppression. Leonard
et al49used an alteration in P50 suppression to
describe a susceptibility locus on chromosome 15 in
First-degree relatives of schizophrenic probands
demonstrate many of these same cognitive and
neurophysiologic deficits described in schizophrenia,
even though these individuals do not manifest overt
psychosis.50–54,39,45These deficits include predomi-
nately impairments in different dimensions of atten-
tion, language comprehension, verbal fluency, verbal
memory, and spatial working memory, as well as
abnormalities of eye tracking, PPI and P50. This has
recently been documented by two comprehensive
studies of schizophrenia relatives.55,56Even after
adjusting for IQ, measures of auditory attention,
abstraction, and verbal memory differentiated rela-
tives of persons with schizophrenia from the compar-
ison groups. It is not clear whether the observed
neurocognitive impairments in relatives are asso-
symptoms. Some studies show that relatives meeting
criteria for definite or probable schizotypal person-
ality disorder have the most pronounced impairment,
although not all cognitively impaired relatives met
the diagnostic criteria for the probable or definite
schizotypal personality disorder.57,58Besides, other
investigators59–61with diverse instruments (Wiscon-
sin Card Sorting Test, Trail making, verbal fluency,
Symbol Digit, and/or WAIS variables) also have
documented cognitive change among relatives of a
schizophrenic probands, independent of schizotypal
Clinical genetics and phenotypes
The heritability of schizophrenia is approximately
80%, but is not a simple pattern. There are thought to
be multiple susceptibility genes, each of small effect
along with influential epigenetic and environmental
factors. Since schizophrenia has failed to show
monogenetic forms and has no molecular or cellular
markers, research has been slow. Nonetheless, repli-
cated linkages to several chromosomal regions have
been made, including to 8p, 22q, 2, 3, 5q, 6p, 11q, 13q,
and 20p,20and there are several genes within these
regions that have been associated with the ill-
D-amino-acid oxidase (DAAO),
regulator of G protein-signaling-4 (RGS4),65proline
transferase (COMT).67,68Each of these genes codes
for a protein that can be rationally linked with a
purported illness mechanism69but no clear disease
pathophysiology has yet emerged. The goal of
confirming a susceptibility gene for schizophrenia is
to acquire molecular information about disease
mechanisms, which could potentially lead to a
broader understanding of the illness and be a basis
for novel treatment development.
Investigators argue that one important road block in
identifying genetic correlates of schizophrenia is
disease heterogeneity and/or diagnostic imprecision.
Schizophrenia is an illness diagnosed entirely on
phenomenology characteristics, and these may be an
insufficient database to properly categorize homoge-
neous disease states. Therefore, investigators have
been attempting to define more homogeneous pheno-
types of schizophrenia in persons with the illness and
in family members (‘endophenotypes’) and test these
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
genetically.21The features most often used to develop
phenotypes in the illness are neurocognitive char-
acteristics, eye movements, PPI abnormalities, P50
changes, and human brain imaging features (reviewed
in Gottes and Gould21). While there has been only
modest progress in this area, the orientation is just
beginning to be applied and studies have only been
In vivo structural brain characteristics
Early MRI studies reported a reduction in overall
brain size, an increase in ventricular size, and
variable cortical wasting in schizophrenia.70–72These
reports confirmed and extended older literature using
the computerized axial tomography (CAT) examina-
tion of schizophrenia that demonstrated ventricular
enlargement.73The suspicion that a portion of these
findings could be caused by antipsychotic treatment
was raised by the results of a recent study showing
haloperidol-associated increases in ventricular size
and decreases in neocortical mass in first break
schizophrenia over the first 3 months of treatment
in a study where second-generation drug treatment
produced none of these alterations (Lieberman,
More recently, MRI studies have consistently
reported a volume reduction in medial temporal
cortical structures (hippocampus, amygdala, and
parahippocampal gyrus).74–77New analytic techni-
ques for shape analysis show regional shape differ-
volume of the superior temporal gyrus may be
reduced in schizophrenia, a change that correlates
with the presence of hallucinations75,79and with
regional EEG changes.80Reports of other structural
brain changes in schizophrenia have been less
consistent. Increases in sulcal size are reported, along
with decreases in gray matter volume and altered
gyral patterns.81Even white matter volume increases
have been seen.77Neocortical volume reductions have
been reported in symptomatic subgroups of schizo-
phrenic subjects, for example middle frontal cortex
volume reduction in negative symptom schizophre-
nia.82The extent to which the overall volume of a
brain structure reflects any internal pathology, espe-
cially if the pathology is subtle, is necessarily limited.
Also, while positive MRI data identifies a brain area
for further study, negative results do not rule out areas
as pathologic. The use of functional imaging techni-
ques has also been productive and will be reviewed
In vivo functional brain characteristics
Early positron emission tomography (PET) studies
reported relative hypometabolism in frontal cortex, a
finding consistent with even earlier SPECT blood
flow studies.83,84Subsequent PET/FDG studies in
schizophrenia produced inconsistent detection of
frontal cortex hypometabolism, with some studies
continuing to find it,85others reporting no change in
the measure,86and still others finding frontal hyper-
metabolism.87These controversies now can be par-
tially explained by two potential confounds: a
neuroleptic effect and a skewed target population
effect. Neuroleptics reduce cerebral metabolism in
frontal cortex,88thus likely producing a confound in
those early studies which compared neuroleptic-
treated schizophrenic persons with untreated normal
controls. We also know that frontal cortical dysfunc-
tion is associated with deficit (negative) type schizo-
phrenia, seemingly selectively. The composition of a
patient group with neuroleptic-treated, deficit-type
schizophrenics (which are often available for study)
will skew the results. What component of the frontal
hypometabolism is due to this confound and what to
disease is difficult to say. Recently, we (reviewed in
next section) and others have found evidence for
limbic abnormalities in schizophrenia both at rest86
and with cognitive challenge.89–91Heckers et al92
found reduced hippocampal activation in schizo-
phrenic subjects during a memory retrieval task of
previously studied words. These findings comple-
ment other postmortem and structural imaging stu-
structures of schizophrenics.93,94
In an attempt to relate rCBF to symptoms, Liddle
et al95reported that negative symptoms were nega-
tively associated with rCBF in left frontal cortex and
left parietal areas. Hallucinations/delusions were
positively associated with flow in the left parahippo-
campal gyrus and the left ventral striatum. Disorga-
cingulate and mediodorsal thalamus. This study
shows that different brain areas are differently
involved in symptom manifestations in schizophre-
nia, perhaps either as a cause or effect of the disorder.
Recently, a PET/H2
phrenic persons noted several CNS regions which
activated in the subjects associated with hallucina-
tions; these were the left and right thalamus, right
putamen, left and right parahippocampal area, and
right anterior cingulate. Cortical activations were
present, but their cortical localizations were highly
variable between the subjects and not significant in
group analysis.96Further work from this group has
shown that apomorphine (which is antipsychotic in
schizophrenia, despite being a dopamine agonist)
improves (that is, ‘normalizes’) the anterior cingulate
blood flow of schizophrenic persons during verbal
fluency task performance.97
Abnormal functional connections between brain
regions has been suggested as the cause of abnormal
rCBF pattens seen in schizophrenia.86,98,99In studies
of verbal fluency100and semantic processing,101a
network analysis revealed a functional disconnection
between the anterior cingulate and prefrontal regions
of schizophrenic subjects. Frontal lobe functional
connectivity was abnormal in the schizophrenic
subjects even though they had significantly activated
the regions and their behavior on the tasks was not
impaired. These findings suggest that the abnormal-
ities seen in the frontal lobes of schizophrenics may
with flowin anterior
15O study of hallucinating schizo-
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
be a problem of integration across regions and not a
specific regional abnormality.
Most recently in fMRI studies using cognitively
demanding tasks, such as working memory tasks, the
fMRI results are also diverse. Manoach et al102,103used
the Sternberg Item Recognition working memory
paradigm which required the subjects to remember
either two or five digits. Unlike many PET studies of
working memory, they found an increase instead of a
decrease in prefrontal rCBF in the schizophrenic
volunteers as compared to the normal controls.
Callicott et al104using the N-back task and Stevens
et al105using the Word and Tone serial position task
found decreases of rCBF in inferior frontal regions of
schizophrenic subjects. The task performance of the
schizophrenic subjects was significantly worse on the
N-back and word serial position task, but was
matched on the tone task. Research has shown that
although rCBF increases in prefrontal regions with
greater working memory demands, if working memory
capacity is exceeded, the activation decreases.106
Manoach suggests that the discrepant findings in sch-
izophrenia may be explained by an overload of work-
ing memory in schizophrenic subjects for some tasks.
Characteristics of postmortem tissue
It is widely accepted that schizophrenia lacks
identifiable neuropathologic lesions as occur in
Parkinson’s disease or Alzheimer’s dementia. Cer-
tainly a more subtle tissue pathology must be
expected. The possible confounds of tissue artefact,
agonal state, chronic neuroleptic treatment, lifelong-
altered mental state, and relevant demographic factors
must always be considered in evaluating postmortem
brain tissue studies. Many modern postmortem
studies of pathology in schizophrenia tissue are
available.94,107,108The application of multiple techni-
ques in the face of incomplete guiding hypotheses has
left the postmortem literature of schizophrenia very
broad and often fragmented.
Several studies report a predominant expression of
pathologic change in the illness in limbic cortex, but
not necessarily a common neuropathologic feature.94
Regions including the hippocampus, anterior cingulate
cortex, thalamus, and mammillary bodies and their
intimately associated cortical areas (entorhinal cortex)
are regularly associated with abnormalities. Abnorm-
alities of cell size,109cell number,110area,111neuronal
organization,112gross structure,113and neurochemistry
are cited.93The entorhinal cortex shows abnormalities
of cellular organization in Layer II neurons.114It is
interesting to recall that both structural changes on
MRI111and (as will be described shortly) functional
changes in PET86have targeted these same areas for
interest in schizophrenia pathophysiology. The modest
consistency of this localizing pathology, despite
heterogeneity in concrete findings, is striking for the
field across technically different studies.
However, limbic structures are not the only ones
affected in postmortem studies. The neocortex espe-
cially frontal areas are associated with reports of cell
or tissue loss: one study reported gray matter volume
reductions,115two did not,116,117and one reported
increased neuronal packing in frontal cortex.118Gold-
berg found that schizophrenic twins performed more
poorly than their unaffected identical co-twin on all
performance measures. Specifically, abnormalities
involved assessments of intelligence, memory, atten-
tion, verbal fluency, and pattern recognition. The
nonill twins failed to differ in performance from
unrelated normal control persons except for their
reductions in ‘logical memory’ (Wechsler Scale) and
in Trails A performance.28Akbarian et al119and Volk
et al120report decreased expression of glutamic acid
decarboxylase (GAD) mRNA in schizophrenic pre-
frontal cortex (PFC) without significant cell loss. It is
thought that chiefly one of the GABA-containing
cortical neurons may be reduced in schizophrenia,
the chandelier cell.121The alterations in GABA
system activity may be the basis of the already
observed frontal hypometabolism repeatedly reported
in functional imaging studies of the illness.
Several studies report cell loss and reduced tissue
volume in thalamus,122,123while others are nega-
tive.124For this cerebral region, it is possible that
restricting analyses to symptom cognitive dysfunction
domains could reduce outcome variability and pro-
vide sharper answers.
Regional studies of neocortical tissue have gener-
ated persuasive observations consistent with the idea
that developmental mistakes in migratory pattern may
be associated with schizophrenia.125–128Specifically,
Akbarian et al reported a reduction in nicotinamide-
(NADPH)-staining neurons in the higher cortical
layers of the schizophrenic dorsolateral PFC and an
increase (‘trailing’) in these neurons in underlying
white matter layers.129These findings are consistent
with the idea of an impairment of neuronal migration
of these particular cells into upper layers of frontal
cortex during their critical developmental period
(second trimester) in schizophrenia. Even earlier
studies reported alterations in superficial cellular
organization (for example, in Layer II) in entorhinal
cortex, with Layer II cell ‘trailing’ in the lower cortical
layers, again consistent with a neuronal migratory
failure in this area of cortex.114,130,131
Postmortem tissue studies in schizophrenia have not
yet led us to a specific pathology or even to an exclusive
region where pathology occurs. Certainly, reports of
abnormalities in hippocampus and frontal cortex pre-
dominate. Taking into account that these are the areas
most often examined, and that artifact abounds in all
postmortem tissue studies, few firm conclusions can be
drawn. It may be that postmortem tissue will be most
useful for focused hypothesis testing.
Monoamine and glutamate system pharmacology
Studies of biochemical markers of the dopamine
system in schizophrenia was stimulated by the early
pharmacologic observation that blockade of dopa-
mine receptors in the brain reduces psychotic
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
symptoms.3The hypothesis derived from this obser-
vation that dysfunction of the CNS dopaminergic
system either in whole or in part accounts for
psychosis in schizophrenia has been explored in all
body fluids and in various conditions of rest and
stimulation over the last half –century,132,133with
little real support except for the recent studies that
show possible changes in DA release in acute illness
phases.134More recently, because of its ubiquitous
and prominent location in the CNS, and because the
antiglutamatergic drugs phencyclidine (PCP) and
ketamine cause a schizophrenic-like reaction in hu-
mans, the glutamate system and its interactions with
dopamine have become a focus of study.
Human brain imaging ligand binding studies done
in vivo have been carried out with D2 dopamine
receptor ligands to look for D2 dopamine receptor
defect(s). An early study reported increases in D2-
family receptors in neuroleptic-naive and neurolep-
tic-free schizophrenia,135and a later report suggested
its presence in psychotic nonschizophrenics136; but
subsequent studies using various other D2ligands and
replications with the initial ligand have been unable
to replicate this finding.137–140All schizophrenic
individuals do not have increased D2-family receptors
in the caudate–putamen, but an alteration in D2
density may be characteristic of a subgroup of
schizophrenic patients, perhaps those with a long
duration of illness, or other special clinical character-
istics.141The question remains whether D2-family
receptors are elevated in a subgroup of schizophrenic
patients or reflect a confound of medication effect in
the initial report.
More recently, Laruelle et al142have measured
dopamine release into the synapse using SPECT or
PET imaging with low-affinity dopamine receptor
ligands. He reported that persons with schizophrenia
have an increased release of dopamine into the synapse
during the acute phases of their illness in response to
amphetamine challenge, compared to healthy con-
trols.143Increased release seems not secondary to
chronic antipsychotic treatment, since augmented
release also occurs in first-episode patients and some
family members.134This is one of the first replicated
findings of dopaminergic dysfunction in schizophrenia.
While D2 dopamine receptors in striatum are
associated with psychosis, the D1 dopamine receptors
in frontal cortex have been more recently associated
with the cognitive dysfunctions in the illness,
especially working memory.144,145Consistent with
this idea, human brain imaging ligand studies suggest
abnormalities in D1 receptor density in the frontal
cortex of persons with schizophrenia.146,147Support of
this idea also derives from postmortem studies
showing that dopaminergic transmission may be
abnormal in parts of neocortex.148,149This has lead
to speculations that an agonist at the D1 receptor may
be therapeutic in treating cognitive dysfunctions in
The introduction of the new antipsychotic drugs
over the last decade, and their generally superior
action, has generated questions about the role of the
serotonin system in the treatment and perhaps in the
pathophysiology of the illness. Years ago, serotonin
was hypothesized to be central to the pathophysiol-
ogy of schizophrenia, because of the psychotomimetic
actions of serotonergic drugs, like LSD.151Postmortem
studies have failed to find consistent change in
measures of the serotonin system in schizophrenia,
including in receptors (in vivo and postmortem) or in
metabolites.152Since serotonin has been shown to
modify dopamine release in striatum,153,154the aug-
mented antipsychotic action of the new drugs may be
mediated through modulation of dopamine release
into the synapse. Indeed, drugs without any dopa-
mine receptor affinity, but with only 5 HT2a receptor
antagonism, do behave as antipsychotic drugs in
animal models and show antipsychotic activity in
humans.155Since the serotonin system has diverse
receptors and functions, it is not surprising that this
aspect is not yet fully explicated.
In support of the involvement of glutamate in
schizophrenia, the early report of reduced glutamate
levels in spinal fluid of schizophrenic patients was
interpreted to suggest neuronal hypoglutamatergic
function in the illness.156Although, this report was
not consistently replicated,157–159(because the frac-
tion of CSF glutamate considered to come from the
transmitter pool is so small (o5%), the method was
not considered sensitive enough to reliably find
changes. However, Kornhuber’s idea156of reduced
glutamatergic transmission in schizophrenia has
continued to capture the interest of the field. The
demonstration of the antiglutamatergic action of
phencyclidine (PCP),160a drug with potent psychoto-
mimetic (perhaps schizophrenia-like) properties act-
ing at the N-methyl-D-aspartate (NMDA) receptor,161
provided further support. Putatively, PCP has its
psychotomimetic properties secondary to its antiglu-
tamatergic actions, with this being the mechanism of
its endogenous psychosis.162
The literature on glutamate in schizophrenia is
suggestive, but not yet consistent in pointing to a
specific defect. It is important to note that many
assessments for the glutamate system in mammalian
brain are early and lack sensitivity and selectivity.
And, an understanding of the physiology of glutama-
tergic transmission is incomplete. Techniques and
strategies to assess this function in schizophrenia are
improving. Thus, technical and conceptual issues
may be relevant to the failure to replicate findings.
Perhaps the variety of disparate hippocampal gluta-
matergic findings themselves may be important as
suggested by Ulas and Cotman,163leading to a final
common blockade or inhibition of hippocampal
efferent pathway activity in schizophrenia.
A Working hypothesis
For limbic cortex involvement in schizophrenia
The development of a progressive tract of research,
within a laboratory with studies built on previous
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
findings, can demonstrate the development of a
theme for disease pathophysiology. Studies in our
laboratory over the last several years have been
directed toward identifying the regions of functional
pathology in schizophrenia that may contain critical
molecular targets underlying schizophrenia, as a
background for enabling the rational development of
therapies for the illness. We have developed experi-
ments based on the iterative strategy of starting with
in vivo functional imaging studies in schizophrenia
volunteers with unbiased regional analysis to identify
regions of dysfunction in schizophrenia during
various task conditions and drug treatments. Then,
we have followed up these results using postmortem
human tissue analysis within those identified regions
to exhaustively study human protein markers of
It is easy to say that overall, the body of biological
work in schizophrenia lacks replicated findings
across laboratories, thus, making it particularly
difficult to build a consistent story across all of the
findings in the literature. Why this is the case is not
clear, but most would ascribe it to differences in
patient populations, in illness stages, in medication
status, and in disease state, rather than in the
technical measures used. In the research story
described here, a modestly consistent line of findings
have emerged: namely, the involvement of the limbic
cortex in mediating the positive symptoms of schizo-
phrenia. This may be because of several prospectively
selected clinical characteristics of the studies: pa-
tients were relatively young; they were characteristi-
cally medication-free when studied in vivo; they were
symptomatic with positive symptoms (negative symp-
tom persons were excluded); and rigorous perfor-
mance criteria were imposed for participation in the
task-activated rCBF studies. These criteria all served
to create a more homogenous (even though less
generalized) set of patient participants and might
have diminished variance on outcome measures
enough to allow findings to emerge.
The early studies in this series of experiments
asked the simple question: which brain areas are
involved in positive symptom pathology in schizo-
phrenia. Volunteers were medication-free for 4–8
weeks. PET scans with fluorodeoxyglucose (FDG)
were performed with both patient and normal
volunteers at rest. All comorbidities, other CNS drugs,
and other diagnoses were excluded. Under these
conditions, two brain areas showed glucose utiliza-
tion (rCMRglu) differences between the normal and
the schizophrenia groups, the anterior cingulate
cortex (ACC) and the hippocampus (Hipp) (Figure
1).86A follow-up study of similar design tested the
regional associations of positive symptoms and
showed that as long as patient volunteers were
medication-free, there was a significant association
between rCMRglu in the limbic cortex (ACC plus
Hipp) and the magnitude of positive symptoms in the
illness (Figure 2); this correlation did not obtain when
patients were medicated or with other symptom
domains.164These studies allowed us to speculate
that it was the limbic cortex which is associated with
the positive symptoms of the illness, while the PFC
cortex may support negative and/or cognitive symp-
As a next experimental step, we put the schizo-
phrenic brain to work on an effortful task and
assessed the CNS functional activation patterns in
schizophrenia. The schizophrenia volunteers had
positive symptoms and were medication-free; and
they were tested on an effortful auditory discrimina-
tion task involving learning, attention, and working
memory. All of the volunteers were trained on the
task with performance fixed to 80% correct. These
performance features of the experimental design were
necessary because the schizophrenia group, perform-
ing naively, did not perform anywhere near the level
of the normal group, but could perform comparably
with normalsaftertraining. Consequently,we
with schizophrenia were compared with a matched normal
group. Of more than 40 ROIs compared between groups,
only two, the anterior cingulate cortex (ACC) and the
hippocampus (Hippo) differed between groups.
A group of young, drug-free psychotic persons
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
collected a relatively high-performing group of vo-
lunteers, not different on general neuropsychological
measures from other groups of research subjects, but
likely better performing on attention tasks and other
measures of cognition than an average person with
schizophrenia. In comparing these groups of volun-
teers, the only brain region whose function during the
decision part of the task differed between the normals
and schizophrenics was the ACC (Figure 3).165In this
comparison, the only schizophrenics who were in the
data analysis were those whose performance was
similar to the normals. When all of the patients were
allowed into the analysis who performed the task at
all levels (even though not up to the level of normals),
then the area of defect extended to include the PFC
along with the ACC suggesting that a performance
confound might account for PFC hypofunction. It was
not only that the ACC showed decreased rCBF in
schizophrenia, but the rCBF was not correlated with
the difficulty of the task. In normals, as the difficulty
of the task increased, the ACC showed a linearly
related increase in rCBF (Figure 4). This did not occur
in the schizophrenia group, suggesting that the ACC
may be cut off from the context of task performance.
The remaining defect that we identified in the rCBF
of this schizophrenia group was an increase in
hippocampal rCBF that occurred not only with the
task, but across all the task conditions of Rest,
Sensorimotor control (SMC), and Decision. The
hippocampus, but only the anterior portion, showed
an elevated rCBF (Figure 5).166That elevated rCBF
was diminished toward normal with antipsychotic
treatment (possibly ‘normalized’).
Having identified Hipp and ACC dysfunction in
schizophrenic illness using in vivo functional brain
imaging, we have now isolated these regions from
postmortem tissue, schizophrenia, and control, and
are analyzing basic histologic and neurochemical
changes in the illness. Although a plethora of
previous studies have reported a variety of changes,
the reports have not used a consistent set of tissue and
have not analyzed all parts of the regions within a
single brain structure (eg, anterior vs posterior
regions). Since functional change may be regionally
specific, even within an organ, multiple segments
must be assessed. Some of our early data, while
showing no change in ionotropic glutamate receptor
binding (AMPA, NMDA, or kainate), did show an
alteration in NR1 subunit mRNA and in NR2B
mRNA93. In preliminary analysis, we checked out
this subunit expression in the anterior (abnormal
rCBF) vs the posterior (normal rCBF) schizophrenia vs
normal hippocampus. We have found differences,
even in this preliminary analysis. No differences
between anterior and posterior levels of NR1mRNA
were obtained; NR2B mRNA was higher in anterior
all of whom were drug free, there was a significant
correlation between the psychosis score (vertical axis) and
the magnitude of glucose utilization in the ACC and Hippo
(horizontal axis). This correlation disappeared when the
same individuals were treated with antipsychotic medica-
In another group of persons with schizophrenia,
Persons with schizophrenia showed decreased rCBF in the ACC during the performance of an auditory
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
than in posterior hippocampus, but these differences
were similar across normal and schizophrenia tissue;
but it was the NR2AmRNA levels in entorhinal cortex
and in the CA3 subfield that were elevated in the
anterior hippocampal sections but not in posterior
parts, only in the schizophrenia tissue. Since the NR1/
NR2Atype of NMDA receptor is now thought to be the
predominant form at the cerebral synapse, these
results suggest functional relevance. Although much
work remains, we are now attempting to distinguish
anterior from posterior hippocampal defects in schi-
zophrenia as a clue to isolating and identifying the
molecules possibly associated with generating psy-
chosis in schizophrenia.
This tract of investigation suggests that in schizo-
phrenia itself, the positive symptoms and possibly the
cognitive dysfunction of the illness (including learn-
ing and memory disruptions and possibly attentional
abnormalities) may emanate from the functional and
chemical changes we have described in hippocampus
and the downstream systems changes these primary
lesions exert in ACC and PFC. We reported the limbic
association with positive symptoms but have yet to
study the cognitive illness manifestations and their
possible association with limbic dysfunction. How-
ever, other laboratories associate frontal cortex dys-
function with the cognitive symptoms of illness,
including memory, attentional, and executive func-
These data as a whole implicate the functional
alteration in limbic cortex as potentially meaningful
in the pathophysiology of the psychosis of schizo-
phrenia. They suggest that the neural input from the
hippocampus to its efferent structures, ACC and PFC,
is disordered in the illness and may account for
positive symptoms. However, the specific molecular
mechanisms leading to the functional change still
need to be identified. Still, with localization clues
derived from rCBF studies, these molecular changes
associated with putative surrogate psychosis markers
(ie, altered rCBF) can be screened for involvement in
Schizophrenia continues to be an illness without
known pathophysiology or etiology. However, clues
to pathophysiology are emerging along with a mean-
ingful anatomy. Furthermore, the need to sort these
characteristics by reduced phenotypes in order to
associate molecular change with functional expres-
sion is becoming clear. The phenotypes of schizo-
electrophysiologic, biochemical, or physiologic (ie,
rCBF) characteristics are being proposed. The sorting
of these phenotypes into biologically and pharmaco-
logically meaningful groups is ongoing. The overall
importance of this task lies in defining the molecular
targets of the illness to facilitate rational drug
discovery. Targeting the exact pathophysiology of
of the auditory discrimination task. However, in the schizophrenia group (right panel), no such correlation obtains in ACC
during the task.
In the healthy group (left panel), a correlation exists between task difficulty and ACC rCBF during the performance
rCBF in Hippocampus during Decision Condition
% rCBF Change From NV
abnormally elevated, unrelated to task, but only in the
rCBF in the hippocampus in schizophrenia is
Phenotype of schizophrenia
CA Tamminga and HH Holcomb
schizophrenia for pharmacologic treatment could
deliver substantial improvements in outcome to
persons with schizophrenia.
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