Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00209027 |
| Other study ID # |
IRB00024777 |
| Secondary ID |
570-024 |
| Status |
Terminated |
| Phase |
N/A
|
| First received |
September 13, 2005 |
| Last updated |
November 13, 2013 |
| Start date |
April 2005 |
| Est. completion date |
April 2011 |
Study information
| Verified date |
November 2013 |
| Source |
Emory University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Food and Drug Administration |
| Study type |
Interventional
|
Clinical Trial Summary
The objective of this study is to determine whether subjects with negative symptoms of
schizophrenia have abnormal functioning of brain circuits relevant to reward processing, and
to determine whether any such abnormalities are normalized by treatment with aripiprazole.
Description:
TITLE: Aripiprazole effects on reward processing in deficit syndrome schizophrenia Principal
Investigator: Erica Duncan, M.D.
Background- This is a study of the way people with schizophrenia may feel when they get
rewards. Certain parts of the brain play a part in people feeling happy when they win some
sort of reward or have a good thing happen to them. Some people with schizophrenia may have
trouble feeling pleasure because part of their brains, the frontal cortex, may not work
properly. We are doing this study to understand how the frontal cortex works in people with
and without schizophrenia when they are trying to win a reward. We will use a special kind
of brain scan called Functional Magnetic Resonance Imaging (fMRI) to show the brain working
in action. fMRI scanning uses a big magnet to take special pictures of the brain.
A new medicine called aripiprazole has been approved by the Food and Drug Administration for
treating symptoms of schizophrenia. This medicine has a new mechanism of action that helps
neural functioning in the part of the brain that is involved with planning and goal setting.
We think this new medication may help with brain processing of rewards. We are therefore
studying the brain with fMRI scans before and during treatment with this aripiprazole.
Objective- The objective of this study is to determine whether subjects with negative
symptoms of schizophrenia have abnormal functioning of brain circuits relevant to reward
processing, and to determine whether any such abnormalities are normalized by treatment with
aripiprazole.
Research Plan-Aim 1. Define impairments in the neural correlates of reward processing in
primary deficit syndrome schizophrenics compared to normal controls.
Ten stable outpatients with primary deficit syndrome schizophrenia will be compared to ten
normal controls in a BOLD contrast fMRI experiment constructed to assess in a parametric
design the recruitment of reward circuitry in response to increasing monetary reward. We
predict that frontal cortical areas important in reward processing such as the OFC and ACC
will have reduced activation in the schizophrenic subjects.
Aim 2. Assess the ability of aripiprazole to normalize reward circuit functioning in deficit
syndrome schizophrenia, and correlate fMRI changes with clinical changes in negative
symptoms.
The ten schizophrenic subjects in Aim 1 will be switched from standard antipsychotic
treatment to twelve weeks of open label aripiprazole and retested with the fMRI monetary
reward task. We predict that twelve weeks of aripiprazole treatment will normalize the
activation of OFC and ACC in response to monetary reward stimuli. We further predict that
the degree of normalization in fMRI activation will correlate with negative symptom
improvement on aripiprazole.
Methods- Up to 25 volunteers with schizophrenia and 25 volunteers without a psychiatric
disorder will participate in this study at the Atlanta VA Medical Center. Subjects will
first be interviewed about their medical and psychiatric history, and any current symptoms
they are having. They will receive an fMRI scan during which they will play a computer game
that rewards correct responses with money. This fMRI session will allow for the assessment
of which parts of the brain are functioning during rewarding conditions. The results will be
compared for subjects with and without schizophrenia.
The subjects with schizophrenia will have their antipsychotic medication tapered and
switched to aripiprazole during a twelve week treatment phase. They will be seen at the end
of Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, and Week 12. At the last visit the fMRI
scan will be repeated during the same reward task.
Clinical Relevance- The inability to experience pleasure and the inability to pursue goals
is an important symptom of schizophrenia. These symptoms probably play a huge role in
preventing many people with schizophrenia from leading full and fulfilling lives. A central
defect in reward processing pathways in the brain may account for these symptoms. If
aripiprazole can be demonstrated to improve functioning in these brain pathways, this would
greatly advance our understanding of schizophrenia and could bring greater functioning to
patients with schizophrenia.
Complete study Protocol:
ARIPIPRAZOLE EFFECTS ON REWARD PROCESSING IN DEFICIT SYNDROME SCHIZOPHRENIA
Principal Investigator: Erica Duncan, MD
Specific Aims
The chronic negative symptoms of schizophrenia remain poorly responsive to
psychopharmacologic treatment. The impaired motivation of primary deficit syndrome patients
prevents them from pursuing social and occupational goals and prevents them from developing
meaningful and productive lives. This proposal is based on the test of a hypothesis that
schizophrenic patients with enduring deficit symptoms suffer from impairments in reward
processing and the translation of perceived reward salience into goal-oriented behavior.
Preclinical and clinical research has revealed the functioning of a distributed neural
network in the processing of reward stimuli. Regions of the prefrontal cortex (PFC) such as
orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) are key frontal cortical
elements of a neural circuit that mediates reward salience, reward expectation, and reward
approach behavior. Aripiprazole, in virtue of its' activity as a dopamine (DA) partial
agonist, is uniquely suited to enhance functioning of these frontal areas crucial to reward
processing. We hypothesize that primary deficit syndrome schizophrenia is associated with
functional deficits in reward circuitry detectable by fMRI scanning during a monetary reward
task. We further hypothesize that treatment with aripiprazole will normalize reward circuit
function in these subjects and thus contribute to improvements in negative symptoms. The
following specific aims will test these hypotheses:
Aim 1. Define impairments in the neural correlates of reward processing in primary deficit
syndrome schizophrenics compared to normal controls.
Ten stable outpatients with primary deficit syndrome schizophrenia will be compared to ten
normal controls in a BOLD contrast fMRI experiment constructed to assess in a parametric
design the recruitment of reward circuitry in response to increasing monetary reward. We
predict that frontal cortical areas important in reward processing such as the OFC and ACC
will have reduced activation in the schizophrenic subjects.
Aim 2. Assess the ability of aripiprazole to normalize reward circuit functioning in deficit
syndrome schizophrenia, and correlate fMRI changes with clinical changes in negative
symptoms.
The ten schizophrenic subjects in Aim 1 will be switched from standard antipsychotic
treatment to twelve weeks of open label aripiprazole and retested with the fMRI monetary
reward task. We predict that twelve weeks of aripiprazole treatment will normalize the
activation of OFC and ACC in response to monetary reward stimuli. We further predict that
the degree of normalization in fMRI activation will correlate with negative symptom
improvement on aripiprazole.
Background and Significance
Negative Symptoms as a Deficit in Reward Processing Antipsychotic medications are often able
to relieve the positive symptoms of schizophrenia such as hallucinations, delusions, and
disorganization. However the response of deficit symptoms to psychopharmacology remains
disappointing. Many patients with minimal active psychotic symptoms are severely impaired in
their functioning because of enduring deficit syndrome features.
A key component of the deficit syndrome is a lack of motivation to pursue goals in
educational, occupational, social, and recreational domains. This proposal rests on the
hypothesis that a core feature of the amotivational component of the deficit state is a
deficiency in reward processing. This deficiency in turn fails to provide sufficient
stimulation of conditioning reinforcement of approach behavior serving the pursuit of
rewards. In most patients the impairment is not so severe that the patients fail to pursue
the primary rewards of food and drink. But motivation to pursue more complex secondary
reinforcers such as economic success, stable loving relationships, avocations, intellectual
fulfillment and other uniquely human goals are strikingly lacking in deficit syndrome
patients.
Frontal Cortical Hypofunction in Negative Symptoms Refinements in the DA hypothesis have
emphasized an imbalance between mesocortical and subcortical/mesolimbic DA activity.
Hyperactivity of the mesolimbic DA system has been implicated in the positive symptoms of
the illness; hypofunctioning of the mesocortical DA pathway has been implicated in the
pathophysiology of negative symptoms (Weinberger 1987; Davis et al.1991). The finding of
neurophysiologic hypofunction of the frontal cortex during cognitive activation studies in
schizophrenic subjects has given rise to the concept of hypofrontality (Weinberger et al.
1986; Berman et al. 1986; for review see Weinberger et al. 1994). Furthermore, frontal
hypofunction has been linked specifically to negative symptoms irrespective of the severity
of positive symptoms in unmedicated schizophrenics (Wolkin et al. 1992).
Neural Circuitry of Reward Processing Research into the neural correlates of reward
processing indicates the importance of midbrain dopamine (DA) neurons and distributed reward
circuits to the coding of reward anticipation and salience, and the translation of
motivation into approach behavior. Key structures that have been implicated in reward
processing on the basis of animal studies include DA neurons of the ventral tegmental area
(VTA) and substantia nigra and their target areas such as the nucleus accumbens (NAcc),
amygdala, and OFC (Wise 1980; Wise and Hoffman 1992; Koob 1992; Robbins and Everitt 1996;
see Schultz 2000, 2001 for review). Circuitry linking these areas is hypothesized to mediate
several aspects of reward processing such as the detection of primary or secondary reward
stimuli, prediction of expected future rewards, and the use of information to control
goal-directed or motivated behavior (Schultz 2000). Recently developed methods are being
used to study the reward pathways in normal humans and subjects with substance abuse
disorders in the fMRI environment. These studies implicate the mesocorticolimbic DA system
and functionally connected areas: OFC, ACC, dorsolateral PFC, amygdala, NAcc, and insula
(Grant et al. 1996; Childress et al. 1999; Maas et al. 1998; Garavan et al. 2000; Kilts et
al. 2001; Wexler et al. 2001). fMRI paradigms using money as a secondary reinforcer reveal
activations in many of these same areas: amygdala, NAcc, ventral striatum, and areas of PFC
(Thut et al. 1997; Elliott et al. 2000; Elliott et al. 2003). The fact that very similar
areas are activated by primary reinforcer paradigms in animal studies, drug cue studies in
substance abusers, and monetary reward paradigms in normal controls suggests that the study
of monetary reward processing is a valid strategy to assess the integrity of reward
circuitry in experimental paradigms.
Overlap of Reward Circuitry and Areas Implicated in Negative Symptoms As indicated above,
dopaminergic hypofunction in the PFC is strongly implicated in the pathophysiology of
negative symptoms. The presentation of reward or stimuli that predict reward stimulates the
phasic activation of dopaminergic neurons in the midbrain (Shultz 2000) that innervate the
PFC. Hence there is a critical overlap of circuitry implicated in negative symptoms and
circuitry that subserves reward processing. This overlap supports the use of reward
paradigms to explore the functional integrity of mesocortical DA inputs and PFC function.
Aripiprazole and Negative Symptoms The novel antipsychotic, aripiprazole, has a unique
pharmacological mechanism of action that makes it potentially unique for the amelioration of
negative symptoms. Aripiprazole is thought to increase DA activity in the PFC by virtue of
its' activity as a partial agonist at post-synaptic DA2 receptors (Burris et al. 2002). We
hypothesize that treatment with aripiprazole will normalize the function of PFC reward
circuitry through increased DA functioning in frontal cortical regions (OFC, ACC) that
subserve reward processing.
Potential Importance of Proposal for Treatment Indications of Aripiprazole The severe
impairment of motivated behavior in patients with deficit syndrome schizophrenia is strongly
suggestive of an abnormality in the neural circuits that mediate reward processing and the
translation of reward salience to motivated behavior. To date there are no published fMRI
studies of the functioning of reward circuits in subjects with deficit syndrome
schizophrenia. We hypothesize that negative symptom schizophrenics will exhibit impaired
fMRI estimated activation of reward circuitry compared to normal controls, and that
aripiprazole treatment will normalize functioning of this circuitry.
The demonstration of improvements in negative symptoms in medication trials has been
elusive. Even an agent capable of improving reward processing might not produce detectable
decreases in rating scales designed to measure negative symptoms over the short term. This
is because patients with chronic deficit states have compromised functioning due to the
cumulative effects of social and occupational dysfunction. In patients such as these, the
normalization of reward processing circuits by a medication such as aripiprazole would only
be the first step. These patients are likely to require considerable psychosocial
rehabilitation to recoup occupational and social functioning and achieve meaningful gains in
negative symptom rating scales. However, normalization of reward circuitry function would
strongly suggest that aripiprazole has potential to improve chronic negative symptoms when
combined with a supporting rehabilitative program. Significant changes in reward circuit
function would also strongly support the early intervention potential for aripiprazole to
prevent chronic deterioration in function if first break patients were treated with this
agent early in their course.
Materials and Methods
Subjects Ten male schizophrenic subjects ages 18-60 will be recruited. Diagnosis will be
confirmed by structured diagnostic interview (SCID-I). Primary deficit syndrome will be
confirmed by rating with the Schedule for the Deficit Syndrome (SDS), a scale that defines
schizophrenic subjects according to whether they have chronic negative symptoms even across
periods when positive symptoms are in remission (Kirkpatrick et al. 1989). This scale thus
allows for the differentiation of those patients who have negative symptoms consistently
across clinical states from those whose negative symptoms emerge when they are acutely
psychotic and remit when positive symptoms remit. Additionally, subjects must have a minimum
score of 30 on the SANS. Subjects will be excluded for clinically significant unstable
medical illness, history of neurological disease including head trauma with loss of
consciousness >5 minutes, active substance abuse or dependence within the prior three
months, any contraindication to fMRI, left handedness, mental retardation, color blindness,
antipsychotic treatment resistance, or known allergy to or nonresponse to aripiprazole.
Subjects with schizophrenia will be excluded if they do not have a working telephone.
Ten male normal comparison subjects will recruited, matched in mean age and ethnicity to the
schizophrenic group. Absence of psychopathology will be confirmed by SCID-I, NP version.
Subjects will be excluded for clinically significant unstable medical illness, history of
neurological disease including head trauma with loss of consciousness >5 minutes, active
substance abuse or dependence within the prior three months, any contraindication to fMRI,
left handedness, color blindness, or mental retardation. Normal controls will be matched to
schizophrenic subjects with regard to monthly income so that monetary rewards during the
task will have comparable reinforcement value.
Baseline Assessment Prior to fMRI scanning all subjects will be assessed for smoking status
by means of the Fagerstrom Smoking Tolerance Questionnaire (Fagerstrom 1978) and nicotine
dependent subjects will be instructed to smoke their usual amount prior to reporting for
scanning. Screening for intact vision (≥ 20/25 uncorrected or corrected with eyeglasses or
contact lenses) by means an eye chart will be conducted. Cognitive status will be assessed
in the following domains: attention (Continuous Performance Test), psychomotor reaction time
(finger tapping test), memory (California Verbal Learning Test), IQ (Weschler Abbreviated
Scale of Intelligence, vocabulary and matrices subtests), and executive function (Stroop
Task). The schizophrenic subjects will be rated for severity of psychopathology by means of
the PANSS, Abrams and Taylor Rating Scale for Emotional Blunting (A&T), SANS, Clinical
Global Impression Scale (CGI), and the Quality of Life Scale. Current side effects to
antipsychotics will be assessed by means of the Barnes Akathisia Scale and the Simpson Angus
Scale. Schizophrenic subjects will have 30cc of blood drawn for CBC and SMA-12 to ensure
stable baseline medical status prior to switching to aripiprazole.
Cognitive Task Meaningful comparisons of schizophrenic and non-schizophrenic subjects by a
cognitive task necessitates the use of a simple task to minimize confounds related to group
differences in cognitive ability. A parametric manipulation of reward contingency will
control for group differences in task performance. The proposed monetary incentive task,
adapted from that of Elliott et al. (2003), is chosen because of its simplicity and
parametric design. The subjects will be given a simple target detection task in which they
will be instructed to squeeze a response bulb when they see a red or blue square. Different
colored squares will be presented on a screen for 1.3 sec each. When they correctly signal
the target stimuli they will see a reward stimulus informing them of how much money they
have won on that trial. For trials with non-targets (paying no reward if the subject
squeezes the bulb) the subjects will see a neutral text telling them to wait. The reward
amounts will vary from 5¢ to $1 per trial (5¢, 25¢, 50¢, 75¢, or $1). The task will be
divided into five blocks separated by 30 sec rest periods. Each block will contain 40
trials. Trial types will be presented in randomized order within each block: 30% of trials
will contain one of the two target stimuli. Each block will pay correct responses at one of
the five monetary reward levels. The task is designed specifically to allow for both an
"on-off" assessment of activations in the presence or absence of reward, but also for a
parametric analysis of brain areas that increase their activation with increased reward
levels. The subjects will be told that their payment for participation in the fMRI scan will
be the total money they accumulate by correct responses during the task. This latter point
is important in that the money won during task performance has a real world salience more
likely to enhance reward-related activations than if all subjects automatically were paid
the same amount regardless of their accuracy. Thus the subjects receive actual rather than
simulated reward.
fMRI Scanning Blood oxygen level-dependent (BOLD) fMRI scanning will be performed on a
research dedicated Siemens 3T whole body MRI scanner located in the Emory Hospital MRI
Center. Foam padding will be used to restrict the subjects' head motion within the magnet.
30 axial slices of 3 mm thickness will be acquired parallel to the AC-PC line with a matrix
size of 64 x 64 over a field of view of 22 x 22 cm, using a TE of 30 msec. With this
protocol we have successfully imaged the orbitofrontal cortex with minimal magnetic
susceptibility artifacts. The functional images will be obtained using a T2* weighted
spiral-scan pulse sequence (TR 3000 msec, TE 25 msec, flip angle 60 deg). High resolution
anatomical T1-weighted MR images will be acquired for localization of task-related neural
activations (TR =10 msec, TE = 4.5 msec, TI=900 msec, FOV=24 cm, 256 x 256 matrix,
contiguous 3 mm slices covering the whole brain).
Aripiprazole Treatment After receiving the first scan, the schizophrenic subjects will be
started on open label aripiprazole 15 mg po qd. Over the subsequent six weeks they will be
titrated to a target dose of 30 mg po qd and maintained on this dose for the next six weeks.
The aripiprazole titration schedule will be as follows: 15 mg Weeks 1-2, 20 mg Weeks 3-6,
and then 30 mg. During the first six weeks of the treatment phase their prior antipsychotic
will be gradually tapered down (75% of total daily dose in Week 1 and 2, 50% of total daily
dose in Weeks 3 and 4, 25% of total daily dose in Week 5 and 6) and then discontinued.
The subjects will be brought in for study visits at the end of Week 1, Week 2, Week 4, Week
6, and Week 8, Week 10, and Week 12. At each study visit they will be rated with the PANSS,
SANS, CGI, and A&T. Extrapyramidal side effects and akathisia will be rated with the Simpson
Angus Scale and the Barnes Akathisia Scale respectively. The Quality of Life Scale, the
CVLT, CPT, and Stroop Test will be repeated at the end of Week 12.
Stopping Rules for Subjects with Schizophrenia There is a risk of symptom exacerbation when
antipsychotic medication is switched. For this reason, several safeguards will be put into
place.
1. Subjects will be excluded if they have a history of suicidal, or assaultive behavior
during psychotic decompensations.
2. The subjects will be given a cross-titration whereby their prior antipsychotic
medication is gradually tapered over six weeks while aripiprazole is being titrated to
maximum dose.
3. Subjects in the schizophrenia group will be closely monitored during the treatment
phase. They will be given reminder calls the day before each study visit. If they do
not come for a scheduled visit, the study staff will call and reschedule for the
soonest day they can come in. Subjects without a working telephone will be excluded.
4. At each visit subjects will be rated with the CGI. If the CGI Global Improvement Scale
is rated 6 (Much Worse) or 7 (Very Much Worse) at any visit, they will be dropped from
the study and their previous antipsychotic will be resumed at the dose prior to
enrollment.
fMRI Image Analysis Imaging data will be analyzed by means of MATLAB and statistical
parametric mapping software (SPM99). The images will be resliced and corrected for motion by
registration to the first functional image acquired for each subject using a 6 parameter
transformation (Friston et al 1995). Images will be spatially normalized to a Montreal
Neurological Institute template. A high-pass filter will be used to remove low frequency
noise. Image smoothing using a 6 mm Gaussian kernel will be used to enhance signal-to-noise
ratios and accommodate differences in neuroanatomy to facilitate group comparisons. The
delayed cerebral blood flow response to activation conditions will be modeled using the
standard hemodynamic response function. Statistical analysis will proceed using a random
effects model to examine outcomes of the parametric design of the experiment (Buchel et al.
1998). We will model both linear and nonlinear hemodynamic responses in regions of interest:
Nacc, amygdala, striatum, thalamus, OFC, ACC, and hippocampus.
Analysis of Behavioral Data For Aim 1, cognitive data will be analyzed with a between
subjects MANOVA to compare neurocognitive results between schizophrenics and normal
controls. For Aim 2, behavioral rating scale data and repeated cognitive test scores (for
CVLT, Stroop Test, CPT) will be analyzed with a repeated measures MANOVA model using
timepoint as a within subjects factor.
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