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Copyright 2014 American Medical Association. All rights reserved.
Antipsychotic Treatment and Functional Connectivity
of the Striatum in First-Episode Schizophrenia
Deepak K. Sarpal, MD; Delbert G. Robinson, MD; Todd Lencz,PhD; Miklos Arg yelan,MD, MSc;
Toshikazu Ikuta, PhD; KatherineKarlsgodt, PhD; Juan A . Gallego, MD, MS; John M. Kane, MD;
Philip R. Szeszko, PhD; Anil K. Malhotra, MD
IMPORTANCE Previous evidence has implicated corticostriatal abnormalities in the
pathophysiology of psychosis. Although the striatum is the primary target of all efficacious
antipsychotics, the relationship between its functional connectivity and symptomatic
reduction remains unknown.
OBJECTIVE To explore the longitudinal effect of treatment with second-generation
antipsychotics on functional connectivity of the striatum during the resting state in patients
experiencing a first episode of psychosis.
DESIGN, SETTING, AND PARTICIPANTS This prospective controlled study took place at a clinical
research center and included 24 patients with first-episode psychosis and 24 healthy
participants matched for age, sex, education, and handedness. Medications were
administered in a double-blind randomized manner.
INTERVENTIONS Patients were scanned at baseline and after 12 weeks of treatment with
either risperidone or aripiprazole. Their symptoms were evaluated with the Brief Psychiatric
Rating Scale at baseline and follow-up. Healthy participants were scanned twice within a
12-week interval.
MAIN OUTCOMES AND MEASURES Functional connectivity of striatal regions was examined via
functional magnetic resonance imaging using a seed-based approach. Changes in functional
connectivity of these seeds were compared with reductions in ratings of psychotic
symptoms.
RESULTS Patients had a median exposure of 1 day to antipsychotic medication prior to being
scanned (mean [SD] = 4.5 [6.1]). Eleven patients were treated with aripiprazole and 13
patients were treated with risperidone.As psychosis improved, we observed an increase in
functional connectivity between striatal seed regions and the anterior cingulate, dorsolateral
prefrontal cortex, and limbic regions such as the hippocampus and anterior insula (P< .05,
corrected for multiple comparisons). Conversely, a negative relationship was observed
between reduction in psychosis and functional connectivity of striatal regions with structures
within the parietal lobe (P< .05, corrected for multiple comparisons).
CONCLUSIONS AND RELEVANCE Our results indicated that corticostriatal functional
dysconnectivity in psychosis is a state-dependent phenomenon. Increased functional
connectivity of the striatum with prefrontal and limbic regions may be a biomarker for
improvement in symptoms associated with antipsychotic treatment.
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.1734
Published online November 5, 2014.
Author Audio Interview at
jamapsychiatry.com
Supplemental content at
jamapsychiatry.com
Author Affiliations: Department of
Psychiatry,Zucker Hillside Hospital,
North Shore-LIJ Health System, Glen
Oaks, New York (Sarpal, Robinson,
Lencz, Argyelan, Karlsgodt, Gallego,
Kane, Szeszko, Malhotra); Center for
Psychiatric Neuroscience, Feinstein
Institute for Medical Research,
Manhasset, New York (Robinson,
Lencz, Karlsgodt, Gallego, Kane,
Szeszko, Malhotra); Department of
Psychiatry,Hofstra North Shore–Long
Island Jewish School of Medicine,
Hempstead, New York (Robinson,
Lencz, Gallego, Kane, Szeszko,
Malhotra); School of Applied
Sciences, Department of
Communication Sciences and
Disorders, University of Mississippi,
University (Ikuta).
Corresponding Author: Anil K.
Malhotra, MD, Division of Psychiatry
Research, Zucker Hillside Hospital,
North Shore-LIJ Health System,
75-59 263rd St, Glen Oaks, NY 11004
(amalhotra@nshs.edu).
Research
Original Investigation
E1
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Disruptions in corticostriatal circuitry have been impli-
cated in the pathophysiology of schizophrenia. Early
proposals linked schizophrenia with decreases in dopa-
mine in the prefrontal cortex and excessive dopamine in the
striatum.
1,2
Although elevated striatal dopamine has been
shown in patients with schizophrenia,
3
their unaffected
relatives,
4
and individuals who are at risk for developing psy-
chotic symptoms,
5
corticostriatal relationships have also been
demonstrated to play a central role in psychosis. Early posi-
tron emission tomography work found that the severityof psy-
chotic symptoms correlated with abnormal patterns of blood
flow in limbic and prefrontal cortical regions.
6
Studies in schizo-
phrenia using functional magnetic resonance imaging (fMRI)
have reported abnormal corticostriatal activation during
reward
7,8
and executive processing.
9,10
Evidence from func-
tional connectivity and multimodal studies have shown al-
tered corticostriatal circuitry in patients with chronic
schizophrenia
11,12
and in patients with prodromal psychotic
symptoms.
13,14
A previous family-based study suggested that
altered functional connectivity between striatum and corti-
cal regions may represent a risk phenotype in patients with
first-episode psychosis (FEP) and their relatives.
15
Despite the evidence implicating corticostriatal links in psy-
chosis, there is a paucity of data directly examining the rela-
tionship between corticostriatal functional connectivity and
the clinical effects of antipsychotic agents. Structures of the
striatum are of particular interest when considering the ef-
fects of treatment because they harbor the largest density of
dopamine D2 receptors.
16
Although antipsychotic drugs vary
in their potency and effect on cortical and subcortical func-
tions, all known antipsychotic agents bind tothe D2 receptor.
17
A few studies have used a longitudinal study design to exam-
ine the effects of antipsychotic treatment with network-
based analyses
18-20
and during reward processing
21
but did not
directly address the question of symptom-related changes in
striatal connectivity.
In the present study, we examined the relationship be-
tween changes in striatal circuitry and reduction in psychotic
symptoms after treatment with antipsychoticmedic ations. We
used a prospective study design in which resting-state fMRI
scans were collected in a cohort of patients with first-episode
schizophrenia and a matched healthy comparison (HC) group
at 2 points. Scans in the patient group were collected at base-
line and after 12 weeks of treatment with a second-
generation antipsychotic; HC participants were also scanned
within a 12-week interval.
To interrogate the functional networks of the striatum,we
used a seed-based approach first proposed by Di Martino et al.
22
We tested the effect of antipsychotic treatment on the func-
tional circuitry of the striatum by comparing changes in con-
nectivity of our striatal seed regions and changes in psychotic
symptoms. Our primary hypothesis was that functional con-
nections with cortical regions would be strengthened and nor-
malized as psychotic symptoms resolved, specifically with pre-
frontal and limbic regions that had been impaired in
schizophrenia. To test this hypothesis, we first needed to cre-
ate functional maps from our HC group at baseline. We hy-
pothesized that our functional maps would replicate the an-
teroposterior separation of positive and negative striatal
correlations previously observed.
22
At baseline, we expected
to see frontostriatal decoupling in our patients relative to the
HC group, which would then normalize as a function of suc-
cessful treatment. By contrast, we did not expect to see changes
associated merely with the passage of time.
Methods
Participants
Patients aged 15 to 40 years old with FEP underwent resting-
state fMRI scanning and symptom ratings at baseline and after
12 weeks of treatment, with either risperidone or aripiprazole
as part of a National Institute of Mental Health (NIMH)–funded
double-blind, randomized clinical trial. First-episode psycho-
sis includes a variety of diagnostic categories; our investigation
was limited to patients with first-episode schizophrenia spec-
trum disorders (ie, schizophrenia, schizophreniform disorder,
schizoaffective disorder,or a psychotic disorder not otherwise
specified). All patients were required to have 2 weeks or less of
cumulative lifetime exposure to antipsychoticsto enter the clini-
cal trial. An HC group was also scanned at 2 points within a 12-
week interval (Table 1). Patient diagnoses were based on the
Structured Clinical Interview for DSM-IV Axis I Disorders,
supplemented by information from clinicians and, when avail-
able, family members. After a complete description of the study
was given to the participants, written informed consent (writ-
ten assent and written parental/guardian consent for individu-
als younger than 18 years)was obtained per a protocol that was
approved by the institutional review board of the North Shore–
Table 1. Baseline Demographics and Clinical Ratings
Characteristic
Mean (SD)
First-Episode
Psychosis
(n = 24)
Healthy Comparison
Group
(n = 24)
Age, y 21.4 (5.0)
a
20.0 (3.1)
Sex, No.
Male 17
b
17
Female 7 7
Education 12.3 (1.8)
a
13.0 (2.5)
Handedness (Edinburgh) 0.76 (0.32)
a
0.51 (0.58)
Interval between scans, d 87.3 (4.9)
a
89.1 (6.7)
Prior antipsychotic
exposure, d
4.5 (6.1) NA
BPRS total score
Baseline 43.3 (9.3) NA
Follow-up 27.3 (6.9)
a
NA
PSx rating
Baseline 11.0 (2.6) NA
Follow-up 5.6 (2.6)
a
NA
Abbreviations: BPRS, Brief Psychiatric Rating Scale; NA, not applicable; PSx,
psychotic symptoms.
a
No significant difference (P< .05) from values for the comparison group
(2-tailed ttest).
b
No significant difference (P< .05) from values for the comparison group
(χ
2
test).
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nectivity with posterior regions. These regions in the superior
parietal lobe and supramarginal gyrus were negatively con-
nected with striatal regions at the baseline in our HC group
(Figure 1).
As hypothesized, our results demonstrated that sympto-
matic improvement of psychosis was associated with altera-
tions in functional connections of the striatum, a structure con-
sistently implicated in the pathophysiology of psychosis and
a shared site of D2 receptor binding of all antipsychoticagents.
17
One region that showed robust changes in functional interac-
tions as psychosis improved was the dorsal caudate, also known
as the associative caudate. This region has been shown to be
anatomically and functionally connected to the dorsolateral
prefrontal cortex.
22,25,26
A large body of evidence has linked
the striatum with the dorsolateral prefrontal regions in
psychosis.
12-15
Our results extended these findings and dem-
onstrated that this link was modulated by pharmacologic in-
tervention in a manner that correlated with symptom reduc-
tion. Additionally, our finding of significantly increased
connectivity between striatal regions and the dorsal anterior
Figure 3. Functional Connectivity Changes With Less Improvementin Psychotic Symptoms
–0.2
–0.1
–0.3
–0.4
0.4
0
0.2
0.1
0.3
0.6
0
0.2
0.4
–0.2
–0.4
–0.6
0–1
–0.8
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right ventral caudate/nucleus accumbens and left supramarginal gyrus
Improvement of Psychosis
z
=
40
0.8
–0.2
0
0.2
0.6
0.4
–0.4
0–1
–0.6
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right ventral caudate/nucleus accumbens and left superior parietal lobule
Improvement of Psychosis
z
=
52
0
–1
–0.5
–2 1 2 3 4 6
5 7 8 109 1211 13
Change in Functional Connectivity
Left ventral caudate and superior parietal lobule
Improvement of Psychosis
z
=
48
Key regions that show significant
(false discovery rate P<.05,
corrected) negative correlation
between the change in functional
connectivity and symptom
improvement, with seed regions in
the right ventral caudate/nucleus
accumbens and left ventral caudate.
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Figure 1. Locations of Seed Regions and Their RepresentativeConnec tivity Maps
Dorsal caudate
z
=
8
Dorsal caudate putamen
z
=
4
Dorsal rostral putamen
z
=
6
Ventral rostral putamen
z
=
–2
Ventral caudate/nucleus accumbens
z
=
–8
Ventral caudate
z
=
0z
=
–16 z
=
0z
=
12 z
=
36 z
=
56
Both left and right seed regions of interest are displayed in green in the first
column. The corresponding positive (red) and negative (blue) functional
connectivity maps of each of these seeds from the right hemisphere in the
healthy comparison group at baseline are displayed in subsequent columns.
Maps are shown with a threshold of P< .001, uncorrected for the purpose of
visualization.
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Both positive and negative masks were created from all
12 connectivity maps in our HC group at baseline with a
threshold of P< .05, uncorrected. Our subsequent analyses
that involved psychotic symptom ratings were limited
within these reference masks.
Between-Group Comparisons
In our between-group analyses, we compared connectivity
maps of all 12 ROIs at baseline in our FEP and HC groups. No
results in either masked or whole-brain analyses were
observed at our level of significance (P< .05, corrected for
false discovery rate).
Between-Scan Comparisons
Our HC group showed no significant changes in functional
connectivity in masked or whole-brain analyses of all 12 of
our seed ROIs when baseline scans were compared with
follow-up scans in a paired manner. Our FEP group showed
only 1 significant masked finding between baseline and
follow-up scans in paired comparisons; the right ventral cau-
Figure 2. Functional Connectivity Changes With Improvement in PsychoticSymptoms
0.4
–0.2
–0.1
0
0.1
0.2
0.3
–0.3
–0.4
–0.5
0–1
–0.6
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right dorsal caudate and anterior cingulate
Improvement of Psychosis
z
=
14
0.8
–0.2
0
0.2
0.6
0.4
–0.4
0–1
–0.6
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right dorsal caudate and right dorsolateral prefrontal cortex
Improvement of Psychosis
z
=
22
0.6
–0.2
0
0.2
0.4
–0.4
0
–1
–0.6
–2 1 2 3 4 6
5 7 8 109 1211 13
Change in Functional Connectivity
Right ventral caudate/nucleus accumbens and left hippocampus
Improvement of Psychosis
z
=
12
Key regions that show significantly
(false discovery rate P<.05,
corrected) increased functional
connectivity as symptoms improve,
with seed regions in the right dorsal
caudate and the right ventral
caudate/nucleus accumbens.
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date showed increased connectivity with the thalamus on
the left side and a cluster of voxels adjacent to the seed
within the nucleus accumbens on the right side (see the
eTable in the Supplement for details).
Increase in Striatal Functional Connectivity
With Treatment Response
Antipsychotic treatment in our cohort of patients with FEP
resulted in an overall significant reduction in positive symp-
toms (Mean [SD] PSx score at baseline = 11 [2.6], 12
weeks = 5.6 [2.6]; t= 7.35; P< .001), as measured by our PSx
score, a composite of items reflective of psychosis from the
Brief Psychiatric Rating Scale. We performed multiple
regression analyses in our FEP group to compare PSx at
baseline and follow-up, as well as the reduction in PSx with
changes in functional connectivity of each of our seed ROIs.
No significant correlations were observed between PSx and
the functional connectivity of our ROIs at baseline or
follow-up. Greater reduction in PSx showed a robust posi-
tive correlation with increased functional connectivity
between the right dorsal caudate and prefrontal regions that
included the orbitofrontal cortex, anterior cingulate, and
the right dorsolateral prefrontal cortex (Figure 2;Table 2).
As psychosis resolved, the right ventral caudate/nucleus
accumbens seed showed a significant increase in connectiv-
ity with a cluster of voxels located in the left hippocampus
(Figure 2; Table 2). Similarly, as symptoms improved, the
right ventral rostral putamen seed showed increased func-
tional connectivity with the anterior cingulate and right
anterior insula (Figure 2; Table 2). No other seed regions
showed results that survived correction for multiple com-
parisons. We observed no significant findings at the whole-
brain level outside of the space within our masks derived
from our HC group.
Decrease in Striatal Functional Connectivity
With Treatment Response
Conversely, in several ROIs, we observed significant negative
correlations between symptom improvement and changes in
functional connectivity with posterior regions. This pattern
mirrored the negative correlation maps we observed with our
seeds in the HC group at baseline (Figure 1). With improve-
ment in PSx, we observed significantly less connectivity be-
tween the right ventral caudate/nucleus accumbens and bi-
lateral superior parietal lobule and supramarginal gyrus
(Figure 3; Table 2). Similarly, as psychosis improved, the left
ventral caudate showed less connectivity with the superior pa-
rietal lobe (Figure 3; Table 2). No additional findings were ob-
served at the whole-brain level outside of the space within our
masks.
Discussion
We used resting-state fMRI to examine the effects of treat-
ment with either aripiprazole or risperidone on functional net-
works of striatal regions in a unique cohort of patients with FEP.
Scans were collected in a longitudinal study design before and
after 12 weeks of controlled treatment. With improvement of
psychosis, we observed a significant increase in functional con-
nectivity between the right dorsal caudate and several pre-
frontal regions including the anterior cingulate, right dorso-
lateral prefrontal cortex, and orbitofrontalcortex. Additionally,
as psychotic symptoms resolved, we observed an increase in
functional connectivity between the right ventral caudate/
nucleus accumbens and hippocampus, as well as between a
seed region placed within the ventral putamen with the ante-
rior insula. Finally, we also found that as symptoms im-
proved, the ventral caudate showeddec reased functional con-
Table 2. Significant Differences in Functional Connectivity From Multiple Regression With Changes in Psychotic Symptoms
Seed Region
Direction of
Correlation Correlated Region Brodmann Area
Montreal Neurological
Institute Coordinates
(x,y,z)
Score FDR-Corrected P
ValueTZ
Right DC
Positive Right dorsolateral
prefrontal cortex
9 30, 46, 22 4.98 4.03 .006
Positive Anterior cingulate 32 −6, 38, 14 7.16 5.09 .004
Positive Right orbitofrontal
cortex
47 24, 26, −12 4.56 3.79 .02
Positive Left thalamus −6, −8, −4 4.18 3.55 .01
Right VRP
Positive Bilateral anterior
cingulate
32 14, 44, 4 4.72 3.88 .04
Positive Right insula 13 40, 14, −10 4.74 3.9 .04
Right VC/NA
Positive Left hippocampus −34, −26, −12 6.17 4.65 .03
Negative Left superior parietal
lobule
7 −32, −46, 50 5.96 4.55 .03
Negative Left supramarginal gyrus 40 −52, −32, 44 5.96 4.55 .03
Negative Right superior parietal
lobule
7 22, −56, 56 5.18 4.14 .04
Negative Right supramarginal
gyrus
40 58, −28, 42 5.23 4.17 .04
Left VC Negative Right superior parietal
lobule
7 38, −58, 48 6.01 4.57 .03
Abbreviations: DC, dorsal caudate; FDR, false discovery rate; VRP, ventral rostral putamen; VC, ventral caudate; VC/NA, ventral caudate/nucleus accumbens.
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nectivity with posterior regions. These regions in the superior
parietal lobe and supramarginal gyrus were negatively con-
nected with striatal regions at the baseline in our HC group
(Figure 1).
As hypothesized, our results demonstrated that sympto-
matic improvement of psychosis was associated with altera-
tions in functional connections of the striatum, a structure con-
sistently implicated in the pathophysiology of psychosis and
a shared site of D2 receptor binding of all antipsychoticagents.
17
One region that showed robust changes in functional interac-
tions as psychosis improved was the dorsal caudate, also known
as the associative caudate. This region has been shown to be
anatomically and functionally connected to the dorsolateral
prefrontal cortex.
22,25,26
A large body of evidence has linked
the striatum with the dorsolateral prefrontal regions in
psychosis.
12-15
Our results extended these findings and dem-
onstrated that this link was modulated by pharmacologic in-
tervention in a manner that correlated with symptom reduc-
tion. Additionally, our finding of significantly increased
connectivity between striatal regions and the dorsal anterior
Figure 3. Functional Connectivity Changes With Less Improvementin Psychotic Symptoms
–0.2
–0.1
–0.3
–0.4
0.4
0
0.2
0.1
0.3
0.6
0
0.2
0.4
–0.2
–0.4
–0.6
0–1
–0.8
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right ventral caudate/nucleus accumbens and left supramarginal gyrus
Improvement of Psychosis
z
=
40
0.8
–0.2
0
0.2
0.6
0.4
–0.4
0–1
–0.6
–2 1 2 3 4 65 7 8 109 1211 13
Change in Functional Connectivity
Right ventral caudate/nucleus accumbens and left superior parietal lobule
Improvement of Psychosis
z
=
52
0
–1
–0.5
–2 1 2 3 4 6
5 7 8 109 1211 13
Change in Functional Connectivity
Left ventral caudate and superior parietal lobule
Improvement of Psychosis
z
=
48
Key regions that show significant
(false discovery rate P<.05,
corrected) negative correlation
between the change in functional
connectivity and symptom
improvement, with seed regions in
the right ventral caudate/nucleus
accumbens and left ventral caudate.
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cingulate implicated a role for error monitoring and cognitive
control in recovery from psychotic symptoms.
27
Our work sup-
ported previous results that demonstrated second-
generation antipsychotic treatment–based alterations in blood
flow to the anterior cingulate.
28
Psychosis has been characterized as the result of abnor-
mal assignment of salience to internal and external stimuli.
29,30
Several brain regions from the present study that demon-
strated increased striatal connectivity in response to treat-
ment were implicated in the normal attribution of salience. Spe-
cifically, as psychotic symptomsremitted, the ventral putamen
showed increased connectivity with the anterior insula and an-
terior cingulate, regions that have been linked to the salience
network.
11
Findings in the present study suggested thatchanges
in the functional coordination between the striatum and pre-
frontal and limbic systems may influence salience processing
as psychotic symptoms are reduced. In support of this hypoth-
esis, induction of psychosis by cannabis has been shown to
modulate activation of the caudate and prefrontal cortex dur-
ing salience processing.
31
We did not observe significant baseline differences in func-
tional connectivity of the striatum between healthy individu-
als and patients with psychosis. A previous study by Fornito and
colleagues
15
suggested that frontostriatal dysconnectivity is an
endophenotype for psychosis by showing decreased coupling
between the striatum and dorsolateral prefrontal cortex in un-
affected relatives of patients. While our study did not address
familiality, baseline differences in connectivity patterns between
studies may be related to differences in clinical variables,
imaging parameters, and statistical approaches.
While previous fMRI studies have reported cross-
sectional evidence linking reduced striatal signal and psy-
chotic symptoms,
32-34
our study used a longitudinal ap-
proach to examine the effects of antipsychotic medications on
network-based functional connectivity measures. To our
knowledge, only 1 resting-state fMRI study has been reported
that examines antipsychotic treatment and functional con-
nectivity in first-episode schizophrenia. Lui and colleagues
18
observed treatment-based disruption in connectivity be-
tween brain regions and functional circuits in conjunction with
altered low-frequency fMRI signals within the cortical re-
gions and striatum. They did not report changes in functional
circuitry that correlated with treatment efficacy; further-
more, the study did not specifically examine corticostriatal con-
nectivity with an anatomically driven approach. Addition-
ally, 1 longitudinal positron emission tomography study
observed decreased connectivity of the medial frontal cortex
with the hippocampus and ventral striatum after treatment,
19
while a task-based fMRI study reported alterations in default
mode network connectivity after olanzapine treatment.
20
Other
neuroimaging studies have also taken a longitudinal ap-
proach to test the effects of antipsychotic treatment on task-
based activation and generally report normalization of the sig-
nal after treatment.
35,36
The present study contributes to the evolving field of bio-
markers for psychotic disorders and treatment response. Pre-
vious studies have shown differential neuroimaging signals
based on treatment response.
37
Additionally, differences in the
response to treatment with antipsychotic medications have
been associated with polymorphisms in the gene coding for
the D2 receptor.
38,39
Independently, variation in the DRD2 gene
has been shown to be related to functional engagementof f ron-
tostriatal circuits.
40
Further studies are required to clarify the
association between our finding of treatment-related modu-
lation of corticostriatal interactions and genetic variation.
Limitations of the present study included a relativelymod-
est sample size; however,our sample size was comparable with
other recent studies that examined patients with first-
episode schizophrenia at 2 points
21
or used functional
connectivity.
15,41,42
Larger sample sizes would have been use-
ful to examine differential effects of various antipsychotic
agents. Additionally, we examined a select group of psy-
chotic patients and were unable to extend our results to other
groups of patients experiencing psychosis. Future studies are
required to examine striatal connectivity in illnesses such as
bipolar disorder. By examining changes in psychotic symp-
toms, our results focused on state-dependent changes in cor-
ticostriatal circuitry that are reflective of successful treat-
ment rather than the effect of treatment alone. Further studies
are required to separate trait-related abnormalities in cir-
cuitry.
Conclusions
The present study provided evidence that the efficacy of treat-
ment of psychosis with second-generation antipsychoticmedi-
cations is associated on a neurophysiological level with altera-
tions in functional corticostriatal circuitry. To the extent that
psychosis successfully improves, functional connectivity be-
tween the striatum and the prefrontal—as well as limbic re-
gions—are strengthened. These data further characterize the
pathophysiology of psychosis and support the role of neuro-
imaging as a potential biomarker for clinical response.
ARTICLE INFORMATION
Submitted for Publication: March 8, 2014; final
revision received July 16, 2014; accepted July 21,
2014.
Published Online: November 5, 2014.
doi:10.1001/jamapsychiatry.2014.1734.
Author Contributions: Dr Sarpal had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Sarpal, Robinson, Lencz,
Karlsgodt, Kane, Szeszko, Malhotra.
Acquisition, analysis, or interpretation of data:
Sarpal, Robinson, Lencz, Argyelan, Ikuta, Karlsgodt,
Gallego, Szeszko, Malhotra.
Drafting of the manuscript: Sarpal, Robinson, Lencz,
Malhotra.
Critical revision of the manuscript for important
intellectual conte nt: All authors.
Statistical analysis: Sarpal, Lencz, Argyelan, Ikuta,
Karlsgodt.
Obtained funding: Robinson, Kane, Malhotra.
Administrative, technical, or material support:
Robinson, Kane, Malhotra.
Study supervision: Lencz, Szeszko, Malhotra.
Conflict of Interest Disclosures: Dr Robinson has
been a consultant to Asubio and Shire and has
received grants from Bristol-Myers Squibb, Janssen,
and Otsuka. Dr Lencz is a consultant to Eli Lilly.Dr
Kane is a shareholder in Medvante, Inc; has been a
consultant for Amgen, Alkermes, Bristol-Myers
Squibb, Eli Lilly,Forrest Pharmaceuticals,
Genentech, H. Lundbeck Intracellular Therapeutics,
Janssen Pharmaceutica, Jazz Pharmaceuticals,
Research Original Investigation Antipsychotic Treatmentand the Striatum
E8 JAMA Psychiatry Published online November 5, 2014 jamapsychiatry.com
Copyright 2014 American Medical Association. All rights reserved.
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Copyright 2014 American Medical Association. All rights reserved.
Johnson and Johnson, Lundbeck, Merck, Novartis,
Otsuka, Pierre Fabre, Proteus, Reviva,Roche and
Sunovion; and has been on the speaker’s bureau for
Bristol-Myers Squibb, Eli Lilly, Janssen, and Otsuka.
Dr Malhotra is a consultant to Genomind Inc. No
other disclosures were reported.
Funding/Support: This study was supported by
grants P50MH080173 to Dr Malhotra,
P30MH090590 to Dr Kane, R01MH060004 to
Dr Robinson, and R01MH076995to Dr Szeszko
from the National Institute of Mental Health.
Role of the Funder/Sponsor:The National
Institute of Mental Health had no role in the design
and conduct of the study; collection, management,
analysis, and interpretation of the data;
preparation, review,or approval of the manuscript;
and decision to submit the manuscript for
publication.
REFERENCES
1. Weinberger DR. Implications of normal brain
development for the pathogenesis of
schizophrenia. Arch Gen Psychiatry. 1987;4 4(7):
660-669.
2. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine
in schizophrenia: a review and reconceptualization.
Am J Psychiatry. 1991;148(11):1474-1486.
3. Howes OD, Kambeitz J, Kim E, et al. The nature
of dopamine dysfunction in schizophrenia and what
this means for treatment. Arch Gen Psychiatry.
2012;69(8):776-786.
4. Huttunen J, Heinimaa M, Svirskis T, e t al. Striatal
dopamine synthesis in first-degree relatives of
patients with schizophrenia. Biol Psychiatry. 2008;
63(1):114-117.
5. Fusar-Poli P, Howes OD, Allen P, et al. Abnormal
frontostriatal interactions in people with prodromal
signs of psychosis: a multimodal imaging study.
Arch Gen Psychiatry. 2010;67(7):683-691.
6. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones
T,Frackowiak RS. Patterns of cerebral blood flow in
schizophrenia. Br J Psychiatry. 1992;160:179-186.
7. Nielsen MØ, Rostrup E, Wulff S, et al. Alterations
of the brain reward system in antipsychotic naïve
schizophrenia patients. Biol Psychiatry. 2012;71(10):
898-905.
8. Koch K, Wagner G, Nenadic I, et al.
Fronto-striatal hypoactivation during correct
information retrieval in patients with schizophrenia:
an fMRI study.Neuroscience. 2008;153(1):54-62.
9. Quidé Y, Morris RW,Shepherd AM, Rowland JE,
Green MJ. Task-related fronto-striatal functional
connectivity during working memory performance
in schizophrenia. Schizophr Res. 2013;150(2-3):468-
475.
10. Tu PC, Lee YC, Chen YS, Li CT, Su TP.
Schizophrenia and the brain’s control network:
aberrant within- and between-network
connectivity of the frontoparietal network in
schizophrenia. Schizophr Res. 2013;147(2-3):339-347.
11. Orliac F, Naveau M, Joliot M, et al. Links among
resting-state default-mode network, salience
network, and symptomatology in schizophrenia.
Schizophr Res. 2013;148(1-3):74-80.
12. Meyer-Lindenberg A, Miletich RS, Kohn PD,
et al. Reduced prefrontal activity predicts
exaggerated striatal dopaminergic function in
schizophrenia. Nat Neurosci. 2002;5(3):267-271.
13. Fusar-Poli P, Howes OD, Allen P, et al. Abnormal
prefrontal activation directly related to pre-synaptic
striatal dopamine dysfunction in people at clinical
high risk for psychosis. Mol Psychiatry. 2011;16(1):
67-75.
14. Dandash O, Fornito A, Lee J, et al. Altered
striatal functional connectivity in subjects with an
at-risk mental state for psychosis. Schizophr Bull.
2014;40(4):904-913
15. Fornito A, Harrison BJ, Goodby E, et al.
Functional dysconnectivity of corticostriatal
circuitry as a risk phenotype for psychosis. JAMA
Psychiatry. 2013;70(11):1143-1151.
16. Hall H, Sedvall G, Magnusson O, Kopp J, Halldin
C, Farde L. Distribution of D1- and D2-dopamine
receptors, and dopamine and its metabolites in the
human brain. Neuropsychopharmacology. 1994;11
(4):245-256.
17. Kapur S, Mamo D. Half a century of
antipsychotics and still a central role for dopamine
D2 receptors. Prog Neuropsychopharmacol Biol
Psychiatry. 2003;27(7):1081-1090.
18. Lui S, Li T, Deng W, et al. Short-term effects of
antipsychotic treatment on cerebral function in
drug-naive first-episode schizophrenia revealed by
“resting state” functional magnetic resonance
imaging. Arch Gen Psychiatry. 2010;67(8):783-792.
19. Bolding MS, White DM, Hadley JA, Weiler M,
Holcomb HH, Lahti AC. Antipsychotic drugs alter
functional connectivity between the medial frontal
cortex, hippocampus, and nucleus accumbens as
measured by H215O PET. Front Psychiatry. 2012;3:
105.
20. Sambataro F, Blasi G, Fazio L, et al. Treatment
with olanzapine is associated with modulation of
the default mode network in patients with
schizophrenia. Neuropsychopharmacology. 2010;35
(4):904-912.
21. Nielsen MO, Rostrup E, Wulff S, et al.
Improvement of brain reward abnormalities by
antipsychotic monotherapy in schizophrenia. Arch
Gen Psychiatry. 2012;69(12):1195-1204.
22. Di Martino A, Scheres A, Margulies DS, et al.
Functional connectivity of human striatum:
a resting state FMRI study. Cereb Cortex. 2008;18
(12):2735-2747.
23. Hedlund JL, Vieweg BW. The Brief Psychiatric
Rating Scale (BPRS): a comprehensive review.
J Oper Psychiatr. 1980;11:48-65.
24. Genovese CR, Lazar NA, Nichols T.
Thresholding of statistical maps in functional
neuroimaging using the false discovery rate.
Neuroimage. 2002;15(4):870-878.
25. Alexander GE, DeLong MR, Strick PL. Parallel
organization of functionally segregated circuits
linking basal ganglia and cortex. Annu Rev Neurosci.
1986;9:357-381.
26. Postuma RB, Dagher A. Basal ganglia functional
connectivity based on a meta-analysis of 126
positron emission tomography and functional
magnetic resonance imaging publications. Cereb
Cortex. 2006;16(10):1508-1521.
27. Polli FE, Barton JJ, Thakkar KN, et al. Reduced
error-related activation in two anterior cingulate
circuits is related to impaired performance in
schizophrenia. Brain. 2008;131(pt 4):971-986.
28. Lahti AC, Holcomb HH, Weiler MA, et al.
Clozapine but not haloperidol re-establishes normal
task-activated rCBF patterns in schizophrenia
within the anterior cingulate cortex.
Neuropsychopharmacology. 2004;29(1):171-178.
29. Kapur S. Psychosis as a state of aberrant
salience: a framework linking biology,
phenomenology, and pharmacology in
schizophrenia. Am J Psychiatry. 2003;160(1):13-23.
30. Jensen J, Willeit M, Zipursky RB, et al. The
formation of abnormal associations in
schizophrenia: neural and behavioral evidence.
Neuropsychopharmacology. 2008;33(3):473-479.
31. Bhattacharyya S, Crippa JA, Allen P, et al.
Induction of psychosis by Δ9-tetrahydrocannabinol
reflects modulation of prefrontal and striatal
function during attentional salience processing.
Arch Gen Psychiatry. 2012;69(1):27-36.
32. Juckel G, Schlagenhauf F, Koslowski M, et al.
Dysfunction of ventral striatal reward prediction in
schizophrenia. Neuroimage. 2006;29(2):409-416.
33. Menon M, Schmitz TW, Anderson AK, et al.
Exploring the neural correlates of delusions of
reference. Biol Psychiatry. 2011;70(12):1127-1133.
34. Sorg C, Manoliu A, Neufang S, et al. Increased
intrinsic brain activity in the striatum reflects
symptom dimensions in schizophrenia. Schizophr Bull.
2013;39(2):387-395.
35. Nejad AB, Ebdrup BH, Glenthøj BY, Siebner HR.
Brain connectivity studies in schizophrenia:
unraveling the effects of antipsychotics. Curr
Neuropharmacol. 2012;10(3):219-230.
36. Abbott CC, Jaramillo A, Wilcox CE, Hamilton
DA. Antipsychotic drug effects in schizophrenia:
a review of longitudinal FMRI investigations and
neural interpretations. Curr Med Chem. 2013;20(3):
428-437.
37. Lahti AC, Weiler MA, Holcomb HH, Tamminga
CA, Cropsey KL. Modulation of limbic circuitry
predicts treatment response to antipsychotic
medication: a functional imaging study in
schizophrenia. Neuropsychopharmacology. 2009;
34(13):2675-2690.
38. Lencz T, Robinson DG, XuK, et al. DRD2
promoter region variation as a predictor of
sustained response to antipsychotic medication in
first-episode schizophrenia patients. Am J Psychiatry.
2006;163(3):529-531.
39. Zhang JP, Lencz T, Malhotra AK. D2 receptor
genetic variation and clinical response to
antipsychotic drug treatment: a meta-analysis. Am J
Psychiatry. 2010;167(7):763-772.
40. Bertolino A, Fazio L, Caforio G, et al. Functional
variants of the dopamine receptor D2 gene
modulate prefronto-striatal phenotypes in
schizophrenia. Brain. 2009;132(Pt2):417-425.
41. Konova AB, Moeller SJ, TomasiD, Volkow ND,
Goldstein RZ. Effects of methylphenidate on
resting-state functional connectivity of the
mesocorticolimbic dopamine pathways in cocaine
addiction. JAMA Psychiatry. 2013;70(8):857-868.
42. Schmidt A, Smieskova R, Aston J, et al. Brain
connectivity abnormalities predating the onset of
psychosis: correlation with the effect of medication.
JAMA Psychiatry. 2013;70(9):903-912.
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