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Am J Psychiatry
June 1998

Increased Striatal Dopamine Transmission in Schizophrenia:

Confirmation in a Second Cohort

Anissa Abi-Dargham, M.D., Roberto Gil, M.D., John Krystal, M.D., Ronald M. Baldwin, Ph.D.,
John P. Seibyl, M.D., Malcom Bowers, M.D., Christopher H. van Dyck,
Dennis S. Charney, M.D., Robert B. Innis, M.D., Ph.D., and Marc Laruelle, M.D.

Objective: The authors previously observed an increase in striatal dopamine transmission

following amphetamine challenge in 15 untreated patients with schizophrenia compared to
15 matched healthy subjects. The purpose of this study was to replicate this finding in a new
cohort of schizophrenic patients and healthy subjects. Method: Fifteen patients with schizo-
phrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeco-
nomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia,
had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a
minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction
in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg,
intravenous bolus). Reduction in D2 receptor availability was measured with single photon
emission computed tomography and the D2 receptor radiotracer [123I]IBZM. Results: No
differences were observed between patients with schizophrenia and the comparison group in
D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger
reduction in D2 receptor availability following acute amphetamine challenge than the com-
parison group. In this study, the effect size was smaller than in the first study. Excess dopamine
release following amphetamine was associated with transient emergence or worsening of posi-
tive symptoms. Conclusions: In this new cohort of subjects the authors replicated their initial
observation of a dysregulation of striatal dopamine release in schizophrenia.
(Am J Psychiatry 1998; 155:761767)

C onventional in vivo neuroreceptor imaging with

positron emission tomography (PET) or single
photon emission computed tomography (SPECT) pro-
mitters in the vicinity of these receptors (1, 2). Compe-
tition between radiotracers and transmitters for bind-
ing to neuroreceptors is the principle underlying this
vides noninvasive measurement of the density and af- application. This recent development of neuroreceptor
finity of a variety of neuroreceptors in the living brain. imaging allows direct measurement of regional synaptic
In addition, these techniques can be used to measure transmission in specific neurotransmitter systems, cor-
fluctuations in the concentration of endogenous trans- relation of these measurements with behaviors and
symptoms, and an exploration of the role of neuro-
Presented in part at the annual meeting of the Society for Neuro- chemical imbalances in the pathogenesis of neuropsy-
science, Washington D.C., Nov. 1621, 1996, and at the American chiatric disorders.
College of Neuropsychopharmacology, Puerto Rico, Dec. 913, Specifically, we developed a method to measure am-
1996. Received July 30, 1997; revision received Dec. 4, 1997; ac-
cepted Dec. 16, 1997. From the Departments of Psychiatry and Diag-
phetamine-induced dopamine release with SPECT and the
nostic Radiology, Yale University, New Haven; and the VA Medical radiotracer [123I](S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-
Center, West Haven, Conn. Address reprint requests to Dr. Abi-Dar- [(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM),
gham, New York State Psychiatric Institute, Unit 28, 177 West 168th an antagonist at the D2 and D5 receptors (3). We initially
St., New York, NY, 10032; aadar@neuron.cpmc.columbia.edu (e-
mail). observed that amphetamine challenge reduced the [123I]-
Supported by National Alliance for Research in Schizophrenia and IBZM binding potential in baboons. In vivo binding po-
Depression Young Investigator Award (Dr. Laruelle), NIMH grants tential is the product of the density and affinity of avail-
MH-54192 (Dr. Laruelle) and MH-30929 (Dr. Bowers), and the Vet-
erans Administration. able receptors, i.e., receptors not occupied by dopamine.
The authors thank Christine Fingado, Donna M. Damon, Melyssa Since amphetamine is devoid of significant affinity for D2
K. Madrak, Louis A. Amici, Richard Weiss, Lynn Pantages-Torok, receptors, we postulated that this effect was mediated by
and the staff of the NeuroSPECT Laboratory at Yale-New Haven increased dopamine release and displacement of [123I]-
Hospital for technical assistance and the staff of the Neuropsychiatric
Studies Unit at the West Haven VA Medical Center for the clinical IBZM specific binding by dopamine. This mechanism was
care of the patients. supported by the observation that pretreatment with the

Am J Psychiatry 155:6, June 1998 761


dopamine depleter alpha-methyl-para-tyrosine prevented chemical purity >95% was prepared by direct electrophilic radioiodi-
the effect of amphetamine on [123I]IBZM binding poten- nation of the desiodoprecursor BZM. A total mean [123I]IBZM dose
of 10.7 mCi (SD=2.5) was given as a bolus (mean=4.0 mCi, SD=0.9)
tial (4). In addition, we established the existence of a good followed by a continuous infusion at a mean rate of 1.0 mCi/hour
correlation between amphetamine-induced dopamine re- (SD=0.2) for the duration of the experiment (372 minutes). This pro-
lease measured with microdialysis and the amphetamine- tocol of administration (bolus plus constant infusion with bolus to
induced decrease in [123I]IBZM binding potential mea- hourly infusion rate ratio of 3.92 hours) has been shown to induce a
state of sustained binding equilibrium. In the absence of ampheta-
sured with SPECT (4). Therefore, measuring the reduc- mine injection, both the specific and nonspecific activity remained at
tion in [123I]IBZM binding potential following ampheta- a constant level (within plus or minus 5%) from 150 minutes to the
mine administration provides a noninvasive method to end of the experiment (5).
estimate the magnitude of amphetamine-induced dopa- SPECT data were acquired on the PRISM 3000 (Picker, Cleveland,
Ohio) with high-resolution fan beam collimators (resolution full
mine release. Extending this method to healthy volun- width at half maximum, 11 mm; 123I point source sensitivity, 16.5
teers demonstrated its feasibility in humans (5). counts/seconds/Ci). Two scanning sessions were obtained for each
We used this technique to study amphetamine-induced subject during the course of the [123I]IBZM infusion (before and after
dopamine release in patients with schizophrenia. In a first amphetamine injection). Each scanning session consisted of nine con-
cohort of 15 patients and 15 matched healthy subjects, secutive acquisitions of 8 minutes each. The first scanning session was
obtained from 180 to 252 minutes. After completion of the first scan-
we observed a significantly greater amphetamine-in- ning session, dextroamphetamine sulfate was injected intravenously
duced decrease in the [123I]IBZM binding potential in the at a dose of 0.3 mg/kg over 30 seconds. During the 45 minutes fol-
schizophrenic group (mean=19.5%, SD=15.7%) than lowing the amphetamine injection, subjects were outside the scanner
in the healthy group (mean=7.6%, SD=8.0%) (two- in order to evaluate the psychiatric response to amphetamine. The
second scanning session (i.e., after amphetamine injection) was ob-
tailed t test, F=6.87, df=1, 28, p<0.05) (6). These data tained from 300 to 372 minutes.
provided the first in vivo evidence for a dysregulation of The clinical response to the amphetamine challenge was evaluated
striatal dopamine release in schizophrenia. This result with the Positive and Negative Syndrome Scale (9). Baseline ratings
was independently replicated by Breier et al. (7) using were obtained 60 minutes before the first scanning session. Postam-
PET, the radiotracer [11C]raclopride, and a smaller dose phetamine ratings were obtained 30 minutes after the injection of
amphetamine (i.e., during the interval between the first and second
of amphetamine (0.2 mg/kg). scanning sessions). For positive and negative subscales, a change of at
In the present investigation, we attempted to replicate least 4 points from baseline was considered clinically significant.
these findings in a new cohort of 15 drug-free schizo- Plasma metabolite-corrected [123I]IBZM steady-state concentration
phrenic subjects and 15 matched healthy subjects. We was measured by extraction followed by high pressure liquid chroma-
tography on four venous samples collected at 20-minute intervals from
kept the experimental conditions similar to those of the 180 to 260 minutes (5). Determination of the plasma [123I]IBZM free
first study in order to allow subsequent meta-analysis fraction was performed by ultrafiltration (10). Plasma [123I]IBZM clear-
of the pooled data. ance was calculated as the ratio of steady-state concentration to infusion
rate. Amphetamine plasma concentration was measured by gas chroma-
tography on three venous samples obtained at 10, 20, and 40 minutes
after amphetamine injection. To measure peripheral effects of ampheta-
METHOD mine on dopamine metabolism, plasma levels of the dopamine metabo-
lite homovanillic acid (HVA) were measured on six samples: three pre-
Subjects amphetamine samples were collected at 20-minute intervals during the
first scanning session (180, 200, and 220 minutes), and three postam-
phetamine samples were collected during the second scanning session
Inclusion criteria for patients were as follows: 1) diagnosis of schizo- (300, 320, and 340 minutes). Plasma HVA levels were assayed as pre-
phrenia according to DSM-IV; 2) no other DSM-IV axis I diagnosis; viously described by gas chromatography and mass spectrometry; deu-
3) no history of alcohol or substance abuse or dependence; 4) absence terated internal standards were used (11).
of any psychotropic medication for at least 21 days before the study
(with the exception of lorazepam, which was allowed at a maximal
dose of 3 mg/day up to 24 hours before the study); 5) no concomitant Data Analysis
or past severe medical conditions; 6) no pregnancy; 7) no current
suicidal or homicidal ideation; and 8) ability to provide informed con- SPECT images were analyzed as previously described (6). Unless
sent. After explanation of the nature and risks of the study, the ability otherwise specified, between-group comparisons were performed
of the patient to provide informed consent was formally evaluated by with two-tailed unpaired t tests. Relationships between continuous
asking the patient to complete a multiple-choice questionnaire (avail- variables were analyzed with the Pearson product-moment correla-
able from Dr. Abi-Dargham on request). According to the recommen- tion coefficient. A probability value of 0.05 was selected as the sig-
dations of the National Alliance for the Mentally Ill (Arlington, Va.), nificance level. Effect size was calculated as the mean for schizo-
assent from involved family members was also obtained. All patients phrenic patients minus the mean for healthy subjects divided by the
were admitted to a research ward for the duration of the study, in- standard deviation for healthy subjects. Because of lack of a second
cluding the washout period. intravenous line, plasma [123I]IBZM and amphetamine were not col-
Inclusion criteria for the comparison group were as follows: 1) ab- lected for three patients and two healthy subjects.
sence of past or present neurological or psychiatric illnesses; 2) no
concomitant or past severe medical conditions; 3) no pregnancy; and
4) ability to provide informed consent. Groups were matched for age, RESULTS
gender, race, and parental socioeconomic level, assessed by the
Hollingshead scale (8).
Scan Protocol
The groups did not significantly differ in age, gender,
SPECT experiments were carried out as previously described (5). ethnicity, or parental socioeconomic status (table 1).
Briefly, [123I]IBZM with specific activity >5,000 Ci/mmol and radio- Patients had significantly lower socioeconomic status

762 Am J Psychiatry 155:6, June 1998


TABLE 1. Demographic Characteristics of Healthy Comparison FIGURE 1. Baseline (Preamphetamine) [123I]IBZM Binding Poten-
Subjects and Schizophrenic Patients tial to Striatal D2 Receptors in Healthy Subjects (N=13) and Patients
With Schizophrenia (N=12)a
Comparison Schizophrenic
Subjects Patients
Characteristic (N=15) (N=15)
Male 12 12
Female 3 3
Caucasian 9 9
African American 4 4
Hispanic 2 2

Mean SD Mean SD

Age (years) 40 11 41 9
Socioeconomic statusa
Parental 37 10 34 18
Subjectb 42 9 29 9
aAssessed by Hollingshead scale (8).
bPatients had significantly lower
socioeconomic status than compari-
son subjects (t=3.72, df=28, p<0.001; unpaired two-tailed t test).

aNo significant between group difference was observed. The variance

than subjects in the comparison group (F=13.8, df=1, in the schizophrenic group was larger than in the comparison group.
28, p<0.001). Two patients were experiencing a first The horizontal line is the group average.
psychotic episode and were considered neuroleptic
naive (one had never received a neuroleptic; the other
had less than 1 week of lifetime exposure). The other was negligible and did not differ between the groups
13 patients had a mean duration of illness of 17 years (schizophrenic patients: mean=0.5%/hour, SD=3.6%;
(SD=7). Antipsychotics were discontinued in three pa- healthy subjects: mean=0.6%/hour, SD=2.9%). None
tients for the purpose of participation in this study of these slope distributions had a mean value signifi-
(for 2238 days). Ten patients were noncompliant cantly different from zero (one-sample t test), indicating
with antipsychotic treatment at the time of recruit- that an adequate steady-state input function was
ment. For these patients, the average neuroleptic-free achieved in both groups. Plasma [123I]IBZM clearance
interval was 169 days (SD=145) (an index of 365 days or free fraction did not differ between the groups
was used for patients drug free for more than 1 year (plasma [123I]IBZM clearance: schizophrenic patients,
[N=3]). After completion of the study, all patients mean=63 liters/hour, SD=21; healthy subjects, mean=
were offered antipsychotic medication and clinical fol- 71 liters/hour, SD=10; plasma [123I]IBZM free fraction:
low-up. schizophrenic patients, mean=3.2%, SD=0.7%; healthy
Five patients received lorazepam at doses lower than subjects, mean=3.6%, SD=0.9%).
3 mg/day up to 24 hours before the scan. At the time of
the scan, baseline scores were 44 (SD=11) on the Brief Baseline [123I]IBZM Binding Potential
Psychiatric Rating Scale (BPRS) (12) and 18.5 (SD=5.1)
and 19.6 (SD=7.0), respectively, on the positive and No differences were observed in baseline [123I]IBZM
negative symptom subscales of the Positive and Nega- binding potential between patients (mean=239 ml g1,
tive Syndrome Scale. SD=115) and healthy subjects (235 ml g1, SD=46) (fig-
ure 1). The variability of [123I]IBZM binding potential
Scan Parameters was significantly larger in patients (F=6.10, df=11, 12,
p<0.005). Baseline [123I]IBZM binding potential was
As previously reported, the bolus plus constant infu- significantly correlated with age (r2=0.18, F=5.2, df=1,
sion paradigm used in this study, with a bolus to hourly 23, p<0.05), showing a mean decline of 14% (SD=6%)
infusion ratio of 3.92 hours, induced steady-state per decade. The interaction between age and diagnosis
[123I]IBZM plasma levels by the time of the scan. The was not significant, showing no differences in the rate
steady-state quality of the plasma input function was of [123I]IBZM binding potential decrease with age be-
evaluated by the slope of the metabolite-corrected tween schizophrenic and healthy subjects. In the schizo-
plasma [123I]IBZM concentration from 180 to 260 min- phrenic group, baseline [123I]IBZM binding potential
utes. This slope was small and not different between was not correlated with baseline clinical symptoms (to-
groups (schizophrenic patients: mean=1.7%/hour, tal BPRS and positive and negative subscales of the
SD=7.3%; healthy subjects: mean=2.3%/hour, Positive and Negative Syndrome Scale), the neuroleptic-
SD=3.5%). Similarly, the slope of the occipital activity free interval, or lifetime neuroleptic exposure.

Am J Psychiatry 155:6, June 1998 763


FIGURE 2. Transaxial Slice at the Level of the Caudate Nucleus FIGURE 3. Amphetamine-Induced Reduction in [123I]IBZM Binding
Showing the Distribution of Activity During Constant Infusion of the Potential in Healthy Subjects (N=15) and Schizophrenic Patients
Selective D2 Receptor Radiotracer [123I]IBZM, Before (A) and After (N=15)a
(B) Amphetamine Injection (0.3 mg/kg bolus) in a 38-Year-Old
Healthy Subjecta

aBoth images represent the sum of nine consecutive acquisitions of 8

minutes and were decay corrected to the beginning of the experiment.
The amphetamine injection induced a decrease in the specific to non-
specific activity ratio. This effect is due to the synaptic release of aThe amphetamine effect was significantly larger in schizophrenic pa-
dopamine following amphetamine. Increased dopamine concentra-
tion leads to increased D2 receptor occupancy by dopamine, and tients (mean reduction of 13.8%, SD=10%, relative to baseline) than
fewer available receptors for [123I]IBZM binding. in healthy subjects (mean=7.1%, SD=6.2%) (F=4.64, df=1, 28,
p<0.05). The horizontal line is the group average.

Amphetamine Peripheral Effects age and amphetamine-induced [123I]IBZM displace-

ment was observed in the two groups (patients and
Amphetamine plasma levels were similar between healthy subjects) combined (r2<0.01, N=30, p=0.71) or
groups (schizophrenic patients: mean=23 ng/ml, SD=7; analyzed separately (schizophrenic patients: r2<0.01,
healthy subjects: mean=23 ng/ml, SD=10). Ampheta- N= 15, p=0.91; healthy subjects: r2=0.02, N=15,
mine induced a marked but transient increase in systolic p=0.58). No relationship was observed between am-
and diastolic blood pressure. No between-group differ- phetamine plasma levels and [123I]IBZM displacement,
ences were observed in the blood pressure response to either in the entire study group (r2<0.01, N=30, p=0.98)
amphetamine (peak increase in systolic blood pressure: or in each group considered separately (schizophrenic
schizophrenic patients, mean=36 mm Hg, SD=12; patients: r2<0.01, N=15, p=0.68; healthy subjects: r2=
healthy subjects, mean=41 mm Hg, SD=14; peak in- 0.03, N=15, p=0.58). No correlations were observed
crease in diastolic blood pressure: schizophrenic pa- between amphetamine-induced [123I]IBZM displace-
tients, mean=20 mm Hg, SD=24; healthy subjects, ment and other indices of peripheral amphetamine ac-
mean=18 mm Hg, SD=6). Plasma HVA levels at base- tivity, such as changes in systolic blood pressure (r2=
line were not different between groups (schizophrenic 0.03, N=30, p=0.33) or changes in plasma HVA (r2=0.05,
patients: mean=9.7 ng/ml, SD=2.7; healthy subjects: N=30, p=0.28).
mean=9.7 ng/ml, SD=3.9). Mean postamphetamine In the schizophrenic group, amphetamine-induced
plasma HVA levels were 3.6 ng/ml (SD=1.1) and 3.2 [123I]IBZM displacement was not associated with dura-
ng/ml (SD=0.6) in healthy subjects and schizophrenic tion of the neuroleptic-free interval (r2=0.03, N=13, p=
patients, respectively. No differences between groups 0.50), lifetime neuroleptic exposure (r2<0.01, N=13, p=
were observed in the reduction of plasma HVA induced 0.88), duration of illness (r2=0.03, N=15, p=0.54), or
by amphetamine (schizophrenic patients: mean=60%, the use of lorazepam in the week preceding the study
SD=10%; healthy subjects: mean=63%, SD=13%). (patients taking lorazepam [N=5]: mean=20%, SD=
12%; patients without lorazepam [N=10]: mean=11%,
Amphetamine Effect on [123I]IBZM Binding Potential SD=1%) (F=3.10, df=1, 13, p=0.10). The two neuro-
leptic-naive patients had an amphetamine-induced
Amphetamine-induced reduction in [123I]IBZM bind- [123I]IBZM binding potential decrease of 7% and 35%,
ing potential was larger in schizophrenic patients respectively. The baseline [123I]IBZM binding potential
(mean=13.8%, SD=10.3%) than in healthy subjects was not associated with the amphetamine-induced
(mean=7.1%, SD=6.2%) (F=4.64, df=1, 28, p<0.05) [123I]IBZM reduction, either in the groups analyzed to-
(figures 2 and 3). A nonsignificant higher variability in gether (r2=0.04, N=30, p=0.31) or separately (schizo-
the response was observed in the schizophrenic group phrenic patients: r2=0.06, N=15, p=0.40; healthy sub-
(F=2.71, df=14, 14, p=0.07). No relationship between jects: r2<0.01, N=15, p=0.85).

764 Am J Psychiatry 155:6, June 1998


FIGURE 4. Significant Relationship Between Changes in Positive Scale). No significant relationship was observed between
Psychotic Symptoms, Measured With the Positive and Negative Syn- improvement in negative symptoms and [123I]IBZM
drome Scale, and the Increase in Striatal Dopamine Transmission
Following Amphetamine, Measured as the Amphetamine-Induced displacement (r2=0.07, N=15, p=0.31). Amphetamine-
Reduction in [123I]IBZM Binding Potentiala induced changes in positive and negative symptoms
were not correlated (r2<0.01, N=15, p=0.76).

Comparison With First Study

Results in this second cohort of subjects are compa-

rable to the results obtained in the first cohort (6) (table
2). Both cohorts were relatively similar in terms of clini-
cal and demographic composition. In each study, no
between-group differences were observed in baseline
[123I]IBZM binding potential. In comparison subjects,
the amphetamine effects on [123I]IBZM binding poten-
tial were identical in studies 1 and 2. In both studies,
the amphetamine effect on [123I]IBZM binding poten-
tial was larger in schizophrenic patients than in healthy
subjects. However, in this study, the effect size was
lower (1.06) than in the first study (1.49), and the sig-
nificance level of the group difference was lower
(p=0.04 for this study and p=0.01 for the first study).
Since the study protocols were identical, results of both
studies can be combined. When the results were com-
bined, the effect size was 1.32 and the p value was
0.001 (F=11.4, df=1, 58, p=0.001).
F=9.6, df=1, 13, p<0.001. Solid bars indicate the threshold
of clinically significant changes (plus or minus 4 points).

Relationship Between Clinical and Biochemical Response
In a new cohort of 15 schizophrenic subjects and 15
No psychotic reaction was observed in the comparison matched healthy subjects, we replicated the observation
group (healthy subjects). In the schizophrenic group, six of a larger decrease in [123I]IBZM binding potential fol-
patients experienced a psychotic reaction to the ampheta- lowing amphetamine challenge in schizophrenic pa-
mine injection (i.e., increase of 4 or more points on the tients than in healthy subjects. Findings from these two
positive subscale of the Positive and Negative Syndrome studies, together with the independent replication by
Scale), eight patients showed no significant change in Breier et al. (7) and the preliminary results recently pre-
positive symptoms, and one patient significantly im- sented by a third group (13), clearly indicate abnormal
proved (i.e., decrease of 4 or more points on the positive reactivity of dopaminergic transmission to ampheta-
subscale of the Positive and Negative Syndrome Scale). mine exposure in the brain of schizophrenic subjects.
Amphetamine-induced dopamine release was signifi- We also replicated the observation that this excessive
cantly larger in the patients who had a psychotic reaction reaction is associated with behavioral consequences,
(mean=23%, SD=9%, N=6) than in the patients who i.e., worsening or emergence of psychotic symptoms.
did not have a psychotic reaction (mean=8%, SD=5%, As in the first study, the increased stimulation of do-
N=9) (F=16.6, df=1, 13, p<0.005). The increase in positive pamine transmission observed in the striata of schizo-
symptoms was significantly correlated with the reduction phrenic patients could not be attributed to differences
in [123I]IBZM binding potential (r2=0.42, F=9.6, df=1, in plasma amphetamine levels. The measurement of
13, p<0.001) (figure 4). Baseline [123I]IBZM binding po- plasma HVA before and after amphetamine was a new
tential was not different between schizophrenic patients feature of this study. Since HVA is formed mainly inside
who had a psychotic reaction (mean=216 ml g1, SD=95, the cell, the decrease in plasma HVA following am-
N=6) and those who did not (mean=255 ml g1, SD=132, phetamine is generally attributed to depletion of the do-
N=9). The severity of positive symptoms at baseline was pamine cytoplasmic pool (1416). Thus, the decrease in
not associated with the magnitude of the amphetamine plasma HVA is an indirect measure of the intracellular
effect on positive symptoms (r2=0.03, N=15, p=0.91) or effect of amphetamine in the peripheral nervous system.
[123I]IBZM displacement (r2=0.07, N=15, p=0.32). The similarity in plasma HVA response to ampheta-
Eleven patients showed no significant changes in mine indicates that the intracellular bioavailability of
negative symptoms following the amphetamine chal- amphetamine was comparable between the groups.
lenge, and four patients showed a clinically significant Thus, the observed group differences in striatal dopa-
improvement (i.e., decrease of 4 or more points on the mine response to amphetamine exposure are related to
negative subscale of the Positive and Negative Syndrome central nervous system factors.

Am J Psychiatry 155:6, June 1998 765


TABLE 2. Results of Two Studies of Amphetamine-Induced Decrease in [123I]IBZM Binding Potential in Healthy Comparison Subjects and
Schizophrenic Patients
Comparison Subjects Schizophrenic Patients
Decrease in Decrease in
Binding Binding
Potential (%) Potential (%) Analysis
Study N Mean SD N Mean SD Size F df p
Previous (4) 15 7.6 8.0 15 19.5 15.7 1.49 6.87 1, 28 0.01
Present 15 7.1 6.3 15 13.8 10.3 1.06 4.64 1, 28 0.04
Combined data 30 7.3 7.1 30 16.7 13.4 1.32 11.45 1, 58 0.001

As in the first study, we could not attribute the in- does not provide any information about the baseline
creased dopamine response in schizophrenic patients to dopamine concentration, i.e., concentration in the ab-
prior neuroleptic exposure, because of the lack of asso- sence of amphetamine. In this study we measured only
ciation between the amphetamine effect and previous the relative increase in dopamine concentration result-
neuroleptic exposure or duration of neuroleptic inter- ing from the amphetamine challenge. The observation
val. These results indicate that the effect is unlikely to of a normal D2 receptor availability at baseline does not
represent a long-term effect of previous neuroleptic imply that baseline dopamine levels are unaltered in
medication. Similarly, we were unable to link the effect schizophrenia (17). A study based on rapid induction of
with lorazepam exposure during the week preceding dopamine depletion with alpha-methyl-para-tyrosine is
the study. In conclusion, the effect seems to be associ- currently being conducted in our group to address this
ated with the illness process per se. issue (18).
Abnormal dopaminergic transmission has been sus- Finally, the low number of patients not previously ex-
pected in schizophrenia for a long time. These studies posed to antipsychotics makes it difficult to rule out the
represent the first direct demonstration of abnormal possibility that the observed effect might represent a
regulation of striatal dopaminergic transmission in long-term consequence of prolonged neuroleptic expo-
schizophrenia. The increase in dopaminergic transmis- sure. More neuroleptic-naive patients should be studied
sion following amphetamine might be due to an in- to address this important question.
creased affinity of D2 receptors for dopamine (for ex- The effect size in the second cohort (1.06) was lower
ample, due to a higher proportion of high versus low than that in the first cohort (1.49). The reasons for the
affinity sites), a larger or more prolonged dopamine re- lower effect size are unclear. The scan protocol was
lease (i.e., presynaptic factors), or a combination of identical, comparison subjects had similar effects (table
both. Additional studies are needed to better character- 2), and the clinical characteristics of the patients were
ize the exact mechanisms responsible for this increased similar (tables 1 in this article and in reference 6).
transmission (4, 6). Therefore, it is likely that the difference in effect size is
Several limitations of this study should be discussed. due to a sampling effect, possibly related to the large
This method has a relatively low sensitivity. We pre- variance of the amphetamine effect in the schizophrenic
viously examined in primates the relationship between group.
increase in extrastriatal dopamine, measured with mi- The mechanism, specificity, significance, and etiology
crodialysis, and decrease in [123I]IBZM binding poten- of this increased dopaminergic response in schizophre-
tial, measured with SPECT. An increase of 45% above nia remains to be elucidated. However, recent preclini-
baseline of striatal dopamine is needed to decrease cal studies do offer interesting hypotheses. Neonatal
[123I]IBZM binding potential by 1% (4). A similar ratio hippocampal lesions in rodents and primates provide a
(44:1) has been reported by Breier et al. (7) for [11C]- potential neurodevelopmental animal model for some
raclopride. In a previous study, we showed that in the clinical and biochemical features of schizophrenia (19).
absence of amphetamine, the reproducibility of [ 123I]- Regulations of striatal dopamine release were com-
IBZM binding potential measurement had an average pared with microdialysis between adult rhesus mon-
variability (test minus retest divided by the average) of keys who underwent ablation of the amygdala-hippo-
plus or minus 3.3% (SD=1.7%, range=5% to 5%). campal formation within 3 weeks of birth, comparison
The low signal to noise ratio of the method explains monkeys, and monkeys who underwent the same lesion
why two comparison subjects had an apparent increase ablation during adulthood (20). Local perfusion of am-
in [123I]IBZM binding potential following ampheta- phetamine in the prefrontal cortex induced a decrease
mine. On the other hand, the low sensitivity of the in striatal dopamine release in comparison monkeys
method implies that a very large difference in synaptic and in monkeys with adult lesions. This observation is
dopamine increase between patients and comparison consistent with the inhibition of subcortical dopamine
subjects corresponded to the measured differences in by prefrontal dopamine (21). In contrast, in monkeys
[123I]IBZM binding potential decrease. with neonatal lesions, prefrontal amphetamine perfu-
Another important limitation of the method is that it sion induced an increase in striatal dopamine release,

766 Am J Psychiatry 155:6, June 1998


i.e., a reversal of the normal effect (inhibition). Thus, a 7. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, deBar-
neonatal hippocampal lesion does affect prefrontal in- tolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckel-
man WC, Pickar D: Schizophrenia is associated with elevated
hibition of striatal dopamine release. The relevance of amphetamine-induced synaptic dopamine concentrations: evi-
this model to schizophrenia remains to be established. dence from a novel positron emission tomography method. Proc
Brain imaging techniques now provide the tools to di- Natl Acad Sci USA 1997; 94:25692574
rectly test these preclinical models in patients. 8. Hollingshead AB: Four-Factor Index of Social Status. New Ha-
ven, Conn, Yale University, Department of Sociology, 1975
In conclusion, we replicated in this second cohort our 9. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syn-
previous observation that schizophrenia is associated drome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;
with an increased dopamine transmission following 13:261276
acute amphetamine challenge (6). The results of both 10. Gandelman MS, Baldwin RM, Zoghbi SS, Zea-Ponce Y, Innis
studies were very similar, with the exception that the RB: Evaluation of ultrafiltration for the free fraction determina-
tion of single photon emission computerized tomography
effect size in the second study was less pronounced than (SPECT) radiotracers: -CIT, IBF and iomazenil. J Pharm Sci
that in the first study. These studies, as well as similar 1994; 83:10141019
results provided by other groups (7, 13), are consistent 11. Bacopoulos NG, Heninger G, Roth RH: Effects of haloperidol
in documenting this excessive neurochemical response and probenecid on plasma and CSF dopamine metabolites in the
rhesus monkey (Macacca mulatta). Life Sci 1978; 23:18051812
and provide direct evidence to support the hypothesis 12. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale. Psy-
of a dysregulation of central dopamine transmission in chol Rep 1962; 10:799812
schizophrenia. 13. Wong D, Gjedde A, Reith J, Grunder G, Szymanski S, Yokoi F,
Hong C, Nestadt G, Neufeld K, Pearlson G, Tune L, Angrist B:
Multiple lines of evidence for dopamine dysfunction in psychosis
REFERENCES by imaging (abstract). Schizophr Res 1997; 24:183
14. Zetterstrom T, Sharp T, Marsden CA, Ungerstedt U: In vivo
1. Logan J, Dewey SL, Wolf AP, Fowler JS, Brodie JD, Angrist B, measurement of dopamine and its metabolites by intracerebral
Volkow ND, Gatley SJ: Effects of endogenous dopamine on dialysis: changes after d-amphetamine. J Neurochem 1983; 41:
measures of [18F]N-methylspiroperidol binding in the basal gan- 17691773
glia: comparison of simulations and experimental results from 15. Zetterstrom T, Sharp T, Ungerstedt U: Further evaluation of the
PET studies in baboons. Synapse 1991; 9:195207 mechanism by which amphetamine reduces striatal dopamine
2. Innis RB, Malison RT, Al-Tikriti M, Hoffer PB, Sybirska EH, metabolism: a brain dialysis study. Eur J Pharmacol 1986; 132:
Seibyl JP, Zoghbi SS, Baldwin RM, Laruelle MA, Smith E, Char- 19
ney DS, Heninger G, Elsworth JD, Roth RH: Amphetamine- 16. Kuczenski R, Segal D: Concomitant characterization of behav-
stimulated dopamine release competes in vivo for [123I]IBZM ioral and striatal neurotransmitter response to amphetamine us-
binding to the D2 receptor in non-human primates. Synapse ing in vivo microdialysis. J Neurosci 1989; 9:20512065
1992; 10:177184 17. Farde L, Wiesel F, Stone-Elander S, Halldin C, Nordstrm AL,
3. Kung HF, Kasliwal R, Pan S, Kung M-P, Mach RH, Guo Y-Z: Hall H, Sedvall G: D2 dopamine receptors in neuroleptic-naive
Dopamine D-2 receptor imaging radiopharmaceuticals: synthe- schizophrenic patients: a positron emission tomography study
sis, radiolabeling, and in vitro binding of R-(+)- and S-(-)-3-iodo- with [11C]raclopride. Arch Gen Psychiatry 1990; 47:213219
2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benz 18. Hietala J, Syvlahti E, Vuorio K, Ngren K, Lehikoinen P, Ruot-
amide. J Med Chem 1988; 31:10391043 salainen U, Rkklinen V, Lehtinen V, Wegelius U: Striatal D2
4. Laruelle M, Iyer RN, Al-Tikriti MS, Zea-Ponce Y, Malison R, dopamine receptor characteristics in neuroleptic-naive schizo-
Zoghbi SS, Baldwin RM, Kung HF, Charney DS, Hoffer PB, In- phrenic patients studied with positron emission tomography.
nis RB, Bradberry CW: Microdialysis and SPECT measurements Arch Gen Psychiatry 1994; 51:116123
of amphetamine-induced dopamine release in nonhuman pri- 19. Lipska B, Weinberger D: Cortical regulation of the mesolimbic
mates. Synapse 1997; 25:114 dopamine system: implication for schizophrenia, in Limbic Mo-
5. Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea- tor Circuits and Neuropsychiatry. Edited by Kalivas PW, Barnes
Ponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung CD. Boca Raton, Fla, CRC Press, 1993, pp 329349
HF, Innis RB: SPECT imaging of striatal dopamine release after 20. Kolachana BS, Saunders RC, Bachevalier J, Weinberger DR: Ab-
amphetamine challenge. J Nucl Med 1995; 36:11821190 normal prefrontal cortical regulation of striatal dopamine release
6. Laruelle M, Abi-Dargham A, Van Dyck CH, Gil R, DSouza CD, after neonatal medial temporal-limbic lesions in rhesus monkeys.
Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Bald- Abstracts of the Society for Neuroscience 1996; 22: 1974
win RM, Seibyl JP, Krystal JH, Charney DS, Innis RB: Single 21. Deutch AY: Prefrontal cortical dopamine systems and the elabo-
photon emission computerized tomography imaging of am- ration of functional corticostriatal circuits: implications for
phetamine-induced dopamine release in drug-free schizophrenic schizophrenia and Parkinsons disease. J Neural Transm 1993;
subjects. Proc Natl Acad Sci USA 1996; 93:92359240 91:197221

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