The Effects of Aripiprazole on the Processing of Rewards in Schizophrenia
The Effects of Aripiprazole on the Processing of Rewards in Schizophrenia
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.
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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Subjects with Schizophrenia:

 Inclusion Criteria:

 -  Diagnosed with schizophrenia

 -  Male

 -  Age 20-50

 -  Right handed

 Exclusion Criteria:

 -  No current or past drug or alcohol problems (dependance or abuse)

 -  Not color blind

 Control Subjects:

 Inclusion Criteria:

 -  Male

 -  Age 20-50

 -  Right handed

 Exclusion Criteria:

 -  No current psychiatric problems

 -  No current or past drug or alcohol problems

 -  Not color blind