Conditions: Attenuated Psychosis Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
We are conducting a randomized, 24-week, double-blind study, comparing fluoxetine with aripiprazole in 48 patients with attenuated positive symptoms at a level of at least moderate severity.

Detailed description:
To Compare Fluoxetine and Aripiprazole on All-cause Discontinuation/Need to Add Another Psychiatric Medication, Symptomatic Improvement, and Adverse Effects

Arms:
arm 1: To increase homogeneity and assure treatment with a clinically effective dose, patients will undergo a fixed titration phase during the first four weeks (2mg wk1, 5mg wk2, 10mg wk3, 5-30 mg wk4-24), with the option to slow or halt the titration or decrease the target dose if intolerability develops. After 3 weeks, dosing will be flexible and left up to clinical choice and need (5-30mg). arm 2: To increase homogeneity and assure treatment with a clinically effective dose, patients will undergo a fixed titration phase during the first four weeks (5mg wk1, 10mg wk2, 20mg wk3, 10-60mg wk3-24), with the option to slow or halt the titration or decrease the target dose if intolerability develops. After 3 weeks, dosing will be flexible and left up to clinical choice and need(10-60mg).

Interventions: intervention 1: Aripiprazole intervention 2: Fluoxetine
Intervention descriptions: intervention 1: see arm description intervention 2: see arm description

Protocol document:
Prot_SAP_000.pdf: 
Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    1  
 
 
COVER PAGE 
 
Study Title: 
 
The Role of Antidepressants or Antipsychotics in Preventing Psychosis: 
Fluoxetine vs Aripiprazole Comparative Trial (FACT) 
 
Clinicaltrials.gov PRS Record - NCT02357849 
 
Version date: 03/09/16 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    2  
 
The Role of Antidepressants or Antipsychotics in Preventing Psychosis: 
Fluoxetine vs Aripiprazole Comparative Trial (FACT)  
 
Principal Investigator: Christoph U. Correll, M.D. 
 
Specific Aims 
The early identification and prevention of schizophrenia has become a vital clinical and research goal. 
Research conducted over the past ten years, including work from our ACISR, has been instrumental in the 
development of effective criteria for the identification of young people at heightened risk for psychosis. 
Moreover, early data suggest that administration of antipsychotic drugs during the prepsychotic or “prodromal” 
illness phase (characterized by emerging attenuated positive symptoms) may reduce prepsychotic symptoms, 
improve functioning and reduce progression to full blown psychosis (Correll et al. 2010).  
 
In other areas of medicine, however, treatments for the prevention or amelioration of early illness expression 
may differ from those utilized in the full-blown disorder. Therefore, we conducted an open label, non-
randomized pilot study in which we compared treatment response to the class of antidepressants versus 
antipsychotic drug treatment on treatment response in 48 adolescents considered to be at high risk for 
schizophrenia. Our data (Cornblatt et al. 2007) suggested that the antidepressants, initiated naturalistically by 
treating physicians, were associated with less conversion to psychosis as compared with second-generation 
antipsychotic drug treatment. Of importance for our hypotheses, it appeared that that the advantage of 
antidepressants in preventing transition to psychosis was mediated by a significantly higher rate of non-
adherence associated with antipsychotic drug treatment. Moreover, relevant to the well-being of patients, 
adverse effect potentials between antidepressants and antipsychotics differ in youth, favoring antidepressants 
(Correll et al. 2011). 
 
While these first findings of a protective effect of antidepressants in prodromal individuals add to an intriguing 
line of primarily indirect evidence suggesting that antidepressants, which have a favorable risk-benefit ratio, 
may influence the development of psychosis, the lack of randomization and potential of prescriber bias reduce 
the interpretability of these early data. Therefore, we now propose to conduct a randomized, controlled 6-
month pilot study comparing the antidepressant fluoxetine with the second generation antipsychotic 
aripiprazole in 48 subjects aged 12-25 years with at least moderate attenuated positive symptoms that 
developed within the past five years. Since transition to psychosis can occur at a relatively low rate over a very 
variable and potentially long time frame, and since discontinuation rates in long-term studies of putatively 
prodromal cohorts have been very high, we have designed a randomized, double-blind study focusing on 
intermediate outcomes, including the composite of all-cause-discontinuation and/or addition of a major 
psychotropic medication (see below), symptom change, safety, and adherence. The specific aims are: 
 
Specific Primary Aim 1: To compare fluoxetine and aripiprazole on the likelihood of and time to all-cause 
discontinuation/need to add another psychiatric medication, symptomatic improvement, and adverse effects  
Primary Hypothesis 1: Compared to aripiprazole, significantly fewer patients on fluoxetine will either 
discontinue treatment or require the addition of an antipsychotic, mood stabilizer, antidepressant or of >3 
weeks of treatment with an anxiolytic/hypnotic  
Secondary Hypothesis 1: Compared to aripiprazole, time to all-cause discontinuation or need to add another 
psychiatric medication (as defined above) will be significantly longer with fluoxetine 
Secondary Hypothesis 2: Compared to aripiprazole, changes in attenuated positive, negative and general 
psychopathology will be similar with fluoxetine. 
Secondary Hypothesis 3: Compared to aripiprazole, fluoxetine will be associated with significantly lower rates 
of adverse effects. 
Specific Secondary Aim 1: To compare the effect of fluoxetine and aripiprazole on social and role functioning 
and subjective well-being in individuals at risk for schizophrenia. 
Primary Hypothesis 1: Compared to aripiprazole, fluoxetine will lead to significantly greater improvement in 
social and role functioning. 
Secondary Hypothesis 1: Compared to aripiprazole, fluoxetine will lead to greater subjective well-being. 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    3  
 
Exploratory Aim: To compare the effect of fluoxetine and aripiprazole on peripherally measured levels of brain 
derived neurotrophic factor (BDNF). 
Exploratory Hypothesis 1: Compared to aripiprazole, fluoxetine will lead to significantly greater increases in 
BDNF.  
 
Background and Significance 
Early Recognition and Prevention During the Psychotic Prodrome. After more than five decades of increasingly 
refined psychopharmacologic developments, schizophrenia has remained one of the most severe and 
disabling disorders in medicine. Since interventions after a first schizophrenia episode have not been able to 
alter the generally chronic and relapsing disease course (Robinson et al. 2004), early intervention and 
prevention of schizophrenia are a vital goal. Initial, retrospective studies that demonstrated presence of a 
symptomatic prepsychotic illness phase of clinically relevant severity and duration (Hafner et al. 1999) provided 
the practical basis for early identification efforts. Several lines of evidence further supported the potential utility 
of early interventions for the schizophrenia prodrome. These include an increasing appreciation that 
schizophrenia is a neurodevelopmental disorder characterized by early developmental delays and problems, 
and that is further associated with a significant functional decline and brain morphological changes (Correll and 
Kane 2004; Sawa and Snyder, 2002; Woods, 1998). Moreover, the duration of untreated psychosis (Marshall 
et al. 2005), and number of relapses have been associated with decreased grey matter and worse functional 
outcomes, even after controlling for potentially relevant confounders (Perkins et al. 2005). Importantly, brain 
morphological changes have also been demonstrated during the transition from prodromal psychosis to full 
blown psychosis (Pantelis et al. 2003), suggesting that early intervention may be a potential vehicle to 
effectively interrupt biological processes involved in the development of psychosis and its adverse functional 
consequences (Correll et al. 2010). 
 
Prodromal schizophrenia research conducted over the past ten years at our Center and others has further 
consolidated the evidence that early identification and intervention studies during the schizophrenia prodrome 
are possible (Correll et al. 2010). Early recognition programs have identified high risk samples with conversion 
rates to psychosis between 10 and 40% over one to two years (Yung et al. 2008). In the largest study to date 
by the North American Prodromal Longitudinal Study (NAPLS) group of which Dr. Cornblatt at our Center is 
one of the PIs, a conversion rate of 35.3% over 2.5 years was reported (Cannon et al. 2008). These 
conversion rates to psychosis are 10-40 times the prevalence rate observed in the general population and far 
greater than the expected incidence rate during such a brief time period (Eaton 1999).  
 
Evidence for the Potential Utility of Antipsychotics for the Prevention of Psychosis. Three randomized 
controlled intervention trials have been completed that included antipsychotics as the active treatment. These 
studies show that 6 months of treatment with low dose risperidone + CBT (McGorry et al. 2002) and 12 months 
of treatment with low dose amisulpride (Ruhrmann et al. 2007 and unpublished data) were associated with a 
significantly reduced transition to suprathreshold psychosis compared to needs based interventions that did not 
include antipsychotic drug treatment. The third trial showed a trend toward significance (p=0.08) comparing 12 
months of olanzapine treatment with placebo, allowing psychotherapy in both groups (McGlashan et al. 2006). 
However, both at 8 weeks (Woods et al. 2003) and 12 months (McGlashan et al. 2006) several symptom 
ratings improved significantly more in the olanzapine treated group. Non-adherence rates were high and group 
differences diminished during longer term follow-up off all interventions, primarily due to a relative increase in 
conversions to psychosis in the patients initially randomized to active treatment. 
 
Evidence for the Potential Utility of Antidepressants for the Prevention of Psychosis. Several lines of research - 
including epidemiologic, pharmacologic and clinical trials evidence - suggest that antidepressants may have a 
role in preventing psychotic disorders and psychotic relapses. Retrospective (Hafner et al. 1999; Hafner et al. 
2005) and prospective studies (Correll et al. 2005) have shown that depressive symptoms are an integral part 
of the psychotic prodrome, preceding the onset of attenuated positive symptoms by approximately five years 
(Hafner et al. 1999). Furthermore, antidepressants are increasingly recognized to have neuroprotective 
properties (Li et al. 2000; Malberg 2000; Sanchez et al. 2001; Salzman et al.1994), increasing levels of brain 
derived neurotrophic factor (Rantamaki et al. 2007 De Foubert et al. 2004; Calabrese et al. 2007), which has 
been found to be low in post-mortem studies of patient with schizophrenia (Hashimoto et al. 2005; Weickert et 
al. 2005) in plasma (Toyooka et al. 2002; Huang and Lee, 2006; Pirildar et al. 2004; Buckley et al. 2007) and in 
CSF (Pillai et al. 2008) of schizophrenia patients compared to controls. Finally, two naturalistic studies in 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    4  
 
individuals considered at high risk for the development of schizophrenia suggested that antidepressants might 
reduce conversion to psychosis (Cornblatt et al. 2007; Fusar-Poli et al. 2007), longer duration of 
antidepressant treatment was associated with full recovery of any syndromal or subthreshold positive or 
negative symptoms in patients with psychosis NOS (Correll et al. 2008), schizophrenia patients with 
postpsychotic depression randomized to imipramine were significantly less likely to relapse into depression as 
well as psychosis (0% vs. 50%, p<0.02) than patients randomized to placebo (Siris et al 1994). Furthermore, a 
recent meta-analysis of five small scale (n’s=25-30), randomized, placebo-controlled studies in patients with 
predominantly negative symptoms found a significant advantage of antidepressant treatment compared to 
placebo for the reduction of negative symptoms (Rummel et al. 2005). These data have attracted significant 
interest in the research and clinical community because the availability of a non-antipsychotic, low-risk 
intervention for the psychotic prodrome would enhance patient care, have profound implications for research 
on the pathophysiology of psychosis, and could provide leads for future drug development strategies. 
 
Potetntial Moderators of Psychosis Risk 
There is converging evidence that neuroinflammation (Miller et al. 2011), oxidative stress (Flatow et al. 2013) 
and low levels of neurogenesis promoting factors, such as  brain derived neurotrophic factor (BDNF) (Buckley 
et al. 2011) are involved in schizophrenia. These findings are of considerable interest in the context of the 
proposed study, as certain antidepressants seem to reduce markers of inflammation and oxidative stress on 
the one hand, and increase BDNF, on the other. In a meta-analysis of 20 studies, including 1,504 patients, the 
effect size for increasing peripherally measured BDNF levels was 0.62 (95% CI=0.36-0.88), which is 
considered a moderate effect and suggests that BDNF-mediated neurogenesis might be a critical factor 
involved in antidepressant efficacy (Brunoni et al. 2008).  
 
 
Preliminary Data 
In our open, naturalistic study of 48 patients (mean age: 15.8 years) followed for at least 6 months (mean: 30.5 
months), we observed significantly lower transition to psychosis in the group treated with antidepressants (0%) 
compared to those receiving antipsychotics (43%) (p<.007) (Cornblatt et al. 2007). However, we were cautious 
in the interpretation of these data because 10/11 conversions in the antipsychotic-treated group occurred after 
the antipsychotic agent had been discontinued, (mostly longer than 6 months prior to the full manifestation of 
psychosis) and adherence rates were significantly higher in the antidepressant treated group(61% vs 21%, 
p=.005). While improvement in positive symptoms was significant (p<.001) and similar in both treatment 
groups, disorganized symptoms did not improve with either treatment. The non-random treatment assignment 
in this study calls for a randomized controlled study to follow up on these intriguing results. 
 
Research Plan 
Study design. We will conduct a Randomized, 24-week, double-blind study, comparing fluoxetine with 
aripiprazole in 48 patients with attenuated positive symptoms at a level of at least moderate severity. In 
choosing the antidepressant and the antipsychotic medication for this trial, we sought medications that had 
strong available evidence for their efficacy and safety, a high benefit-to-risk ratio, current FDA approval for use 
in adolescents who will be a core patient group for this study, and a longer half life in order to minimize 
treatment gaps when doses are taken irregularly. Moreover, since patients in this study will not have 
suprathreshold psychotic symptoms, choosing an antipsychotic with the least short- and long-term safety 
concerns was important to increase patient and family acceptability and to be in equipoise about these two 
intervention strategies. Based on these criteria, we chose fluoxetine over other antidepressant alternatives and 
aripiprazole over other antipsychotic alternatives.  
 
Inclusion Criteria: 1) consent obtained from patients and their parents (assent for patients under 18); 2) age 
12-25 years (inclusive); 3) English-speaking; 4) at least one positive (Scale A) SOPS score of 3-5, i.e., 
moderate, moderately severe or severe. 
 
Exclusion Criteria: 1) lifetime diagnosis of an Axis I psychotic disorder, including: schizophreniform disorder, 
schizophrenia, schizoaffective disorder, bipolar disorder, or major depression with psychotic features; 2) 
current psychosis (any positive symptom SOPS score of 6, i.e., extreme); 3) current diagnosis of Major 
Depressive Disorder, single episode or recurrent, severe without psychotic features; 4) current stimulant 
treatment; 5) history of neurological, neuroendocrine or other medical condition known to affect the brain; 6) 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    5  
 
any significant medical condition that contra-indicates treatment with either aripiprazole or fluoxetine; 7) past or 
current substance dependence; sunstance abuse within the last 4 weeks; 8) IQ < 70.  
 
Recruitment. We will recruit patients utilizing the ACISR Trials Operation Unit, which has developed 
recruitment strategies within the child and adolescent as well as adult outpatient and emergency room services 
at Zucker Hillside Hospital, with additional referrals from the inpatient units. In addition, to increase the pool of 
potentially eligible patients, our ACISR maintains a Research Network that will liaise with local community 
mental health clinics offering a screening program for potentially prodromal symptoms in the clinic clientele. 
We will approach mental health clinics associated with Queens Child Guidance Center (5 clinics), North Shore 
Child Guidance Center (3 clinics), South Shore Child Guidance Center , Penninsula Counseling Center, 
Pederson-Krag Center, as well as the outpatient clinics of Kings County Hospital and Stony Brook Hospital.  
Finally, we are setting up a collaboration with the St Luke’s Roosevelt hospital PEER program in Manhattan, a 
dedicated first episode and prodromal psychosis outpatient program that just received 2-year structural funding 
from the van Ammeringen Foundation. Furthermore, we are in contact with the psychiatry department at SUNY 
Downstate. St. Luke’s Roosevelt and, potentially SYNU Downstate, will become sites for this study and will 
need to obtain their own IRB approval. The other mental health clinics will be utilized as referral sources. Thus, 
while presentations and outreach will take place, patients will not be assessed and treated at these centers; 
treatment will reside at the treatment sites, namely Zucker Hillside Hospital, St. Luke’s Medical Center and, 
possibly SUNY Downstate. 
 
Medication Schedule. Randomization codes to either aripiprazole or fluoxetine will be provided by the NSLIJ 
biostatistics group. To increase homogeneity and assure treatment with a clinically effective dose, patients will 
undergo a fixed titration phase during the first three  weeks, with the option to slow or halt the titration or  
 
 
Table 1. 
 
Wk 0/Wk 1 
 
Wk 1/2 
 
Wk 2/3 
 
Week 4-Week 24 
 
Titration 
Fixed  
 
Fixed  
 
Fixed  
 
Flexible Dosing, Range 
 
Fluoxetine 
 
 10 mg 
 
10 mg 
20 mg 
 
10mg – 60mg 
 
Aripiprazole 
 
2 mg 
 
5 mg 
 
10 mg 
 
5mg – 30mg 
 
decrease the target dose if intolerability develops (Table 1). After 3 weeks, dosing will be flexible and left up to 
clinical choice and need. 
 
Adjunctive Therapies. Based on our previous experience with administration of fluoxetine and aripiprazole in 
prodromal patients, we expect the need for rescue medication to be relatively infrequent.  However, adjunctive 
medication will be available to address clinically relevant, treatment emergent side effects. These include:  
benztropine (up to 2 mg bid) for extrapyramidal symptoms (EPS) in case dose reduction is ineffective or 
undesired; lorazepam (up to 1 mg bid) to treat restlessness, anxiety or agitation, or to improve sleep; and 
propranolol (up to 20 mg tid) for akathisia. Moreover, when a patient develops ≥7% weight gain, which triggers 
healthy lifestyle interventions involving simple education regarding diet and physical activity, and despite this 
exceeds 10% weight gain, metformimn (500-2000 mg) will be offered. After the patient is symptom free for at 
least two weeks a slow withdrawal of the adjunctive medication will be attempted. Patients will also receive 
supportive psychotherapy by during regular medication visits. Needs based individual psychotherapy will be 
provided for crisis situations and in a time limited fashion (i.e., six sessions). 
 
Assessments. Table 2 summarizes the proposed diagnostic, efficacy and safety assessments throughout the 
24-week study. Subjects can still be assessed +/- 7 days of their propsed assessment date in the event that 
there are unable to come in at the proposed time.  
 
The ACISR Trials Operation Unit maintains a cadre of trained raters and assessors with experience in the  
majority of measures utilized, the Clinical Assessment Strategies Unit has been instrumental in the 
development of individual assessment measures of patient function, and the Adverse Event Unit provides 
expertise in the assessment and management of drug-induced adverse events, of particular importance in this 
population who may be more sensitive to drug side effects, and which may predict non-adherence.  
 
Patients who discontinue the assigned medication or who initiate treatment with a medication that is not 
allowed as per the protocol will have an unscheduled study termination visit, but patients will be assessed at 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    6  
 
the predetermined time points independent of whether they are compliant with the study protocol to allow for 
an ITT analysis. The primary outcome variable for this project will be discontinuation of medication or addition, 
as verified by prescription, of another psychotropic medication to the daily treatment regimen of the subject 
(excluding prn medications).  Patients that are not compliant at least 80% of the time will be subject to an 
unscheduled study termination.   
Optional Genetic Test Component 
Once during the study period, each subject will be asked to provide an additional 16 ml blood sample 
(approximately 1 tablespoon) for DNA collection and genotyping. The collected blood samples will be stored in 
locked freezers. Blood samples will be transferred to the Feinstein Institute for Medical Research (Dr. 
Gregersen’s lab) Human Genetics Program core facility for lymphocyte extraction. From this lymphocyte 
extraction, 50% will be used for direct DNA extraction and 50% will be utilized to establish Epstein-Barr virus-
transformed cell lines. We will store the DNA for future exploratory analyses comparing patients with conversion 
to psychosis or worsening of prepsychotic symptomatology to those patients who did not worsen or convert. 
These exploratory analyses will target potentionally relevant genomic regions involved in schizophrenia and 
genomic regions involved in conversion to psychosis potentially identified by then in other prodromal research 
cohorts.  
 
 
Analytic Plan 
General Considerations. All analyses will be conducted in an ITT sample using all randomized patients who 
received at least one dose of medication. Although the analytic methods to be described below (i.e. survival 
analysis, mixed models, RMANOVA, etc.) are fairly routine, missing data can cause problems in the statistical 
analyses. Thus, if the necessary, we will consider the use of multiple imputation techniques (i.e., PROC MI and 
PROC MIANALYZE), using the assumption of data being “missing at random” (MAR). In this case, we will 
transform non-monotone missing data patterns to monotone patterns, which are easier to analyze. 
 
Specific Primary Aim 1. To compare fluoxetine and aripiprazole on time to all-cause-discontinuation/need to 
add another psychotropic agent, prodromal symptom change and adverse effects in prodromal individuals. 
Binary outcomes, such as the primary composite outcome variable and the dichotomized presence of specific 
side effects (i.e., present=moderate severity or higher) or non-adherence, will be analyzed using chi squared 
test or Fischer’s Exact test, as necessary. Standard methods of survival analysis (Kaplan-Meier product-limit 
method, logrank test, Cox proportional hazards regression) will be applied to the secondary, time dependent 
variable “time until all-cause-discontinuation/need to add another psychotropic”. If during the trial a subject is 
lost to follow up, that subject’s data will be “censored” at the week of dropout. Cox proportional hazards 
regression model will be used to determine which factors (if any) are predictive of all cause discontinuation.  In 
addition to the ITT analyses, we will also conduct a sensitivity analysis using only data from subjects as long as 
they remained on the assigned treatment, censoring data at the week of treatment discontinuation.  
Repeated measures analysis of variance (RMANOVA) using a mixed models approach (SAS PROC MIXED, 
SAS Institute, Cary, NC) will be used to examine the longitudinal and between-drug patterns in continuous 
outcomes, such as psychopathology rating scores and severity of side effects. In case of relevant missing 
data, PROC MIXED will be able to model the data despite the missing values. RMANOVA using the mixed 
models approach will be utilized to analyze changes in weight, BMI and HOMA-IR (using the log ratio 
transformation).  The method of generalized estimating equations (GEE) will be used to analyze ordinal data, 
such as Barnes and Simpson-Angus scores.  
 
Specific Secondary Aim. To compare the effect of fluoxetine and aripiprazole on social and role functioning and 
subjective well-being in individuals at risk for schizophrenia. As for primary aim 1, repeated measures analysis 
of variance (RMANOVA) using a mixed models approach (SAS PROC MIXED, SAS Institute, Cary, NC) will be 
used to examine the longitudinal and between-drug patterns in these continuous outcomes. In addition, the 
correlation between social and role functioning scale score changes and changes in attenuated positive and 
negative symptoms scores will be analyzed using the Bland and Altman methodology. Likewise, correlations 
between changes in subjective well being and psychopathology scores as well as side effect change scores 
will be analyzed using that same methodology. 
 
 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    7  
 
Table 2: Assessment Timetable 
Weeks/ Months 
Pre-
screen 
Screen Wk 
0 
Wk  
1 
Wk  
2 
Wk  
3 
Wk  
4 
Wk  
6 
Wk  
8 
Wk  
12 
Wk 
16 
Wk 
20 
Wk
24 
Assessments 
 
 
 
 
 
 
 
  
 
 
 
  
 
MD 
 
 
 
 
 
 
 
  
 
 
 
  
 
Physical Examination 
 
+ 
 
 
 
 
 
  
 
 
 
  
 
SAFTEE (side effects) 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Psychometrician 
 
 
 
 
 
 
 
  
 
 
 
  
 
Kid-SCID 
 
+ 
 
 
 
 
 
  
 
 
 
  
 
Premorbid Adjustment 
 
+ 
 
 
 
 
 
  
 
 
 
  
 
IQ Test 
 
+ 
 
 
 
 
 
  
 
 
 
  
 
SIPS/SOPS 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
BPRS, SANSS 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
CGI 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Hamilton Scale for Depression 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Young Mania Rating Scale 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Drug Attitude Inventory 
 
 
+ 
 
 
 
+ 
 
+ 
+ 
+ 
 
+ 
Social Functioning and Role 
Functioning Scale  
 
 
+ 
 
 
 
 
  
 
+ 
 
  
+ 
Subjective Wellbeing Scale (SWN-K, 
Naber 1995) 
 
 
+ 
 
 
 
 
  
 
+ 
 
  
+ 
Research Technician 
 
 
 
 
 
 
 
  
 
 
 
  
 
Simpson-Angus (EPS) 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Barnes Akathisia 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
AIMS (Dyskinesia) 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Vital signs/Weight 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Fasting blood tests (CBC, 
comprehensive metabolic panel, 
glucose, insulin, lipid profile, TSH, 
LFTs) and urine analysis 
 
+ a  
+ 
 
 
 
+ 
  
+ 
+ 
 
  
+ 
Study medication level 
 
 
 
 
 
 
+ 
 
+ 
+ 
 
 
+ 
Pregnancy test (urined or serum) 
 
+ 
+ 
 
 
 
+ 
 
+ 
+ 
 
 
+ 
Urine toxicology 
 
+ 
+ 
 
 
 
+ 
 
+ 
+ 
 
 
+ 
DNA blood draw & storage (optional)  
 
 
+b 
 
 
 
 
 
 
 
 
 
 
Brain Derived Neurotrophic Factor 
 
+ 
+ 
 
 
 
+ 
 
+ 
+ 
 
 
+ 
a can be non-fasting, no insulin and lipid level required;  b can be obtained at any time during the study if 
needed; C SIPS can be used from Pre-screen if screening done within 2 days. 
d when subject outpatient, urine test will be used, when inpatient then we will use serum pregnancy test already 
for in unit. 
 
 
 
Exploratory Aim. To compare the effect of fluoxetine and aripiprazole on BDNF levels to determine potentially 
beneficial neurotrophic effects that mediate symptomatic and/or functional benefits. Similar statistical methods 
as for the continuous outcomes in aim 1 and aim2 will be used. 
 
Power Calculations and Sample Size. This is a pilot study with the aim to assess the feasibility of this design for 
a larger trial and to obtain preliminary data that would guide future power and effect size analyses. For the 
purposes of this trial, we used an estimate of a 40% difference between the two treatments on the combined 
primary outcome of all-cause-discontinuation and need for addition of another major psychiatric medication. 
Based on preliminary data, we estimated the rates to be 65% with antipsychotics and 25% with antidepressants. 
With 24 subjects in each treatment arm, we will have 82% power to find a statistical difference in the primary 
composite outcome in a two tailed t-tests with alpha <.05 (online calculator used for this power/sample size 
calculation: http://www.stat.ubc.ca/~rollin/stats/ssize/b2.html). This is a conservative estimate, as repeated 


Principal Investigator/Program Director (Last, First, Middle): 
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Version: 12.28.1831 
Page    8  
 
measures ANOVA will yield greater power, compensating for any drop outs prior to the first post-baseline 
assessment. 
 
 
HUMAN SUBJECTS 
This human subjects research meets the definition for clinical research. 
 
Protection of Human Subjects 
 
1. Risks to the Subjects 
 
Fluoxetine is approved by the Food and Drug Administration (FDA) for the treatment of depression, obsessive-
compulsive disorder (OCD), and panic disorder in adults and for depression, anxiety and OCD in children and 
adolescents. Aripiprazole is approved by the FDA for the treatment of schizophrenia and bipolar didorder in 
adults and in children and adolescents age 10-17 (bipolar disorder) and age 13-17 (schizophrenia). Neither 
medication is specifically indicated in adolescents for the symptoms for which they are prescribed in this trial. 
However, both medications are widely used for a range of disorders in children and adolescents, and both 
have been used successfully in the RAP Program. This study includes detailed procedures for safety 
monitoring.  
 
These procedures are outlined below. 
 
There are a number of common, non-serious side effects associated with use of fluoxetine: nausea, diarrhea, 
intestinal discomfort, headache, insomnia, sexual side effects, dry mouth, fatigue/drowsiness and dizziness.  
 
Recently, the Food and Drug Administration (FDA) issued a public health advisory concerning a possible link 
between worsening depression and emergence of suicidal ideation or behavior in patients treated with certain 
antidepressant medications, including but not limited to sertraline. The FDA has not concluded that these drugs 
cause worsening depression or suicidality: worsening of symptoms could be due to the underlying problem or 
might be a result of drug therapy. As a result, we will carefully monitor patients in this trial for possible 
worsening of depression or suicidality, especially at the beginning of therapy or when the dose either increases 
or decreases.  
 
We will ask study participants to let us know immediately if they feel worse in any way, at any time during 
treatment.  If suicidal thoughts begin or worsen, associated with taking medication, they will be urged to call the 
study doctor immediately.  It is very important that participants do not abruptly stop taking the medication 
without first discussing this with the study doctor as suddenly stopping these medications may be followed by 
withdrawal symptoms or by a return of the depressive feelings.  
 
Common, non-serious side effects for aripiprazole are extra-pyramidal symptoms (including tremor, stiffness, 
and restlessness), sedation, dizziness, either weight loss or weight gain, hyperglycemia (high blood sugar), 
nausea, dry mouth, headache and sexual side effects.  
 
Two potentially serious but infrequent side effects have been associated with aripiprazole:  
 
Tardive dyskinesia (TD), which includes abnormal movements of the mouth, face, tongue, arms or legs. For 
some people, the movements continue even if the medication is stopped. The extent to which risperidone 
causes TD has not yet been determined, but there is evidence that it is as low as 1% per year of treatment. 
This rate is as low as or lower than the TD rates for other FDA-approved medications in the same class. 
 
Neuroleptic malignant syndrome (NMS), a very rare, but potentially serious disorder characterized by 
neurological changes, fever and other symptoms, has been reported with risperidone. If NMS develops, it 
typically does so shortly after medication is started. NMS is easily treatable and is readily detected by clinical 
evaluation that includes vital signs, the testing of muscle tone and blood tests if indicated. These evaluations 
will be performed at each psychiatric visit.  


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Version: 12.28.1831 
Page    9  
 
 
2. Adequacy of Protection Against Risks 
 
a. Recruitment and informed consent 
For each potentially eligible patient, a parent (or guardian) will be contacted by the treating physician to obtain 
permission to be contacted for participation in a research study. Following this permission, the treating 
physician, Co-I, or clinical psychologist affiliated with the study will discuss the study with the caregiver and the 
patient.   Each parent will receive a complete explanation of the purposes, duration, procedures, and potential 
risks and benefits of this study.  A similar explanation will be given to the child, commensurate with his/her age 
and ability to comprehend.  Any questions that the family may have will be answered. If the family agrees to 
participate, written informed consent will be obtained from the parents and written assent from the child.  A 
copy of the signed consent form will be placed in the child’s medical record.  Parents will be informed that both 
aripiprazole and fluoxetine are currently marketed medications, which can be prescribed by their physician for 
their child without study participation. The right of the family to withdraw the child from the study at any time will 
be made clear. Typically, several meetings with patients and family members will be devoted to the consent 
process.   Because the study involves pharmacological interventions, a child and adolescent psychiatrist will 
always be involved in obtaining consent.   
 
b. Protection against risk 
The proposed medications are not experimental agents, but are being used widely in children and adolescents 
in general clinical practice. Participation in the proposed study will mean that patients will undergo regular, 
frequent careful assessments of adverse effect and of efficacy as outlined in table 2. This is a more rigorous 
assessment of risks and benefits than usually provided as part of general psychiatric community care. 
Moreover, the study will use predefined exit rules, such as a CGI-I score of much or very much worse or a 20% 
worsening on the BPRS scale, further protecting against risk from not benefiting from study participation.  
To screen for and guard against suicidal ideation and suicidal behavior, the suicidality item in the HAM-D will 
be used as a screening tool. If any symptoms are rated greater than zero, this will be followed by a formal 
assessment with the Columbia-Suicide Severity Rating Scale (Mundt et al.  2010), and appropriate clinical 
steps will be initiated as needed. Additionally, for patients in whom weight gain of ≥7% is detected throughout 
the trial, healthy lifestyle interventions involving simple education regarding diet and physical activity will be 
implemented. If weight gain continues and exceeds 10% over baseline body weight, the subject may be 
withdrawn from the study or metformin can be offered as per clinical need while continuing in the study. 
3. Potential of Benefits of the Proposed Research to the Subjects and Others 
The patients who will be selected for inclusion in this study will be adolescents and young adults with 
symptoms and signs that fulfill criteria for the psychosis prodrome.  No benefit can be promised to the study 
participant, him/herself, although the medication treatment in each arm can be expected to alleviate oftern 
imparing and/or distressing symptoms and signs consistent with a psychosis prodrome. Moreover, patienrts 
will benefit from close observation during the study.  The blind for each study subject will be broken after all 
study data has been collected for that individual.  The information about the response of the subject may be 
helpful for treatment planning.   
 
4. Participant Compensation 
Participants will be paid $30 for each of the 6 longer visits, ie, at screening and weeks 0, 4, 8, 12 and 24 
($180), and $20 for each of the 6 short visits at weeks, 1, 2, 3, 6, 16, and 20 ($120). Thus, total maximum 
compensation for complete participation in all 12 visits of this randomized controlled study will be $300 per 
participating family. If a participant withdraws before the study is completed, they will be paid for their 
participation up to that time. Compensation will be provided as check or cash after each reimbursable study 
visit with instructions that it is intended to support the entire family’s expenses associated with the assessment. 
In addition, parking or public transportation costs will be reimbursed or transportation may be provided. Light, 
healthy meals or meal vouchers will be provided after fasting labs are obtained. 
 
5.  Importance of the Knowledge to be Gained 


Principal Investigator/Program Director (Last, First, Middle): 
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Version: 12.28.1831 
Page    10  
 
 
 
There are very few data to guide clinicians treating in young people with symptoms and signs that are consistent 
with the schizophrenia prodrome. It is critical that the efficacy and safety of non-antipsychotic drugs be studied 
specifically in this vulnerable patient population to improve the risk benefit ratio of available and commonly used 
second-generation antipsychotics in the treatment of the schizophrenia prodrome, both in clinical practice and 
in research settings.  
 
 
6. Data Safety Monitoring Plan 
The Data Safety Monitoring Board (DSMB) for this study will be affiliated with our ACISR (through which this 
study is funded). The DSMB will have access to all relevant clinical data necessary to assess the adequacy of 
human subjects protections provided throughout the study. Serious Adverse Events will be reported to DSMB 
members at the same time that they are reported to each IRB. In addition, summary reports of dropouts, 
adverse events, and other important events will be provided to the Board prior to their conference calls, which 
will occur twice yearly.  
 
 
Handling of Serious Adverse Events 
Bristol Myers Squibb will receive SAE reports immediately at the address below: 
  
Bristol-Myers Squibb Company 
                                                Global Pharmacovigilance  
                                                Email: WorldWide.Safety@bms.com  
  
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
•     results in death 
•     is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it were more severe) 
•     requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below) 
•     results in persistent or significant disability/incapacity 
•     is a congenital anomaly/birth defect  
•     is an important medical event (defined as a medical event(s) that may not be immediately life-threatening 
or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization.)  Potential drug induced liver injury (DILI) is also considered an important 
medical event.   
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, pathogenic or 
non-pathogenic) via the study drug is an SAE. 
 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not always serious by 
regulatory definition, these events must be handled as SAEs.   
 
Inclusion of Women 
The study population will include representation of both genders and gender will not play a role in patient 
recruitment. Based on data collected in our open label study (Cornblatt et al. 2007), we expect approximately 
40% of the sample to consist of females and 60% of the sample to consist of males (see target enrollment 
table).  If we find that the patient female/male recruitment ration is significantly unbalanced, we will make 
special efforts to target a gender-specific population. 
 
Inclusion of Minorities 
Based on the results of our open label study (Cornblatt et al. 2007), we expect approximately 12% of patients 
to be of Hispanic or Latino ethnicity and 88% to be of ethnicities other than Hispanic or Latino. We also expect 


Principal Investigator/Program Director (Last, First, Middle): 
Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    11  
 
approximately 6% of the patient sample will be Asian, 15% African-American, and 79% Caucasian. If we find 
that the patient sample is not representative of the patient population that we are recruiting from in terms of 
race or ethnicity we will make special efforts to target the under-represented groups.   
 
 
 


Principal Investigator/Program Director (Last, First, Middle): 
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Version: 12.28.1831 
Page    12  
 
 
 
Inclusion of Children 
This study focuses on children ages 12 to 17, as well as on adults ages 18-25.  Since minor subjects will be 
involved in this study, the following procedures have been put into place to ensure their safety.  All subjects will 
require written informed consent of a guardian in order to participate in the study, and will likewise be required 
to provide written informed assent for study participation, unless they are decisionally impaired, in which case 
minor assent will not be required.  
 
Vertebrate Animals – N/A 
 
Select Agent Research --N/A 
 
 
Targeted/Planned Enrollment Table 
This report format should NOT be used for data collection from study participants. 
Study Title: The Role of Antidepressant in the Schizophrenia Prodrome 
Total Planned 
Enrollment:
48 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
3 
5 
Not Hispanic or Latino 
115 
24 
35 
Ethnic Category: Total of All Subjects * 
17 
27 
48 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
2 
5 
7 
White 
14 
21 
35 
Racial Categories: Total of All Subjects * 
17 
27 
48 
 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All Subjects.” 


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Christoph U. Correll, M.D. 
Version: 12.28.1831 
Page    13  
 
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Buckley PF, Pillai A, Howell KR. Brain-derived neurotrophic factor: findings in schizophrenia. Curr Opin 
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Buckley PF, Mahadik S, Pillai A, Terry A Jr. Neurotrophins and schizophrenia. Schizophr Res. 2007 Aug;94(1-
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Calabrese F, Molteni R, Maj PF, Cattaneo A, Gennarelli M, Racagni G, Riva MA. Chronic duloxetine treatment 
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messenger RNA levels of the neuroprotective enzyme superoxide dismutase (SOD1). J Psychiatry 
Neurosci. 2000 Jan;25(1):43-7. 
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psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry. 2005 
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A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A. Randomized, double-blind trial of 
olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006 
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Psychiatry Suppl. 2002 Sep;43:s78-84.  
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Baltimore, Maryland 
Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, Yung AR, Bullmore ET, Brewer W, 
Soulsby B, Desmond P, McGuire PK. Neuroanatomical abnormalities before and after onset of psychosis: 
a cross-sectional and longitudinal MRI comparison. Lancet. 2003 Jan 25;361(9354):281-8.  
Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and 
outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005 
Oct;162(10):1785-804. 
Pillai A. Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of 
schizophrenia. Neurosignals. 2008;16(2-3):183-93. 
Pirildar S, Gönül AS, Taneli F, Akdeniz F. Low serum levels of brain-derived neurotrophic factor in patients with 
schizophrenia do not elevate after antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatry. 
2004 Jul;28(4):709-13. 
Rantamäki T, Hendolin P, Kankaanpää A, Mijatovic J, Piepponen P, Domenici E, Chao MV, Männistö PT, 
Castrén E. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor 
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Neuropsychopharmacology. 2007 Oct;32(10):2152-62. 
Ruhrmann S, Bechdolf A, Kühn KU, Wagner M, Schultze-Lutter F, Janssen B, Maurer K, Häfner H, Gaebel W, 
Möller HJ, Maier W, Klosterkötter J; LIPS study group. Acute effects of treatment for prodromal symptoms 
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Sanchez V, Camarero J, Esteban B, Peter MJ, Green AR, Colado MI. The mechanisms involved in the long-
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Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol 
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Yung AR, Nelson B, Stanford C, Simmons MB, Cosgrave EM, Killackey E, Phillips  LJ, Bechdolf A, Buckby J, 
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follow-up. Schizophr Res. 2008 Oct;105(1-3):10-7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
Version date: 09/02/16 
Subject consent 
IRB: 11-199 
 
 
Page 1 of 15 
   
 
 
COVER PAGE 
 
STUDY TITLE: 
 
THE ROLE OF ANTIDEPRESSANTS OR ANTIPSYCHOTICS IN PREVENTING PSYCHOSIS: 
FLUOXETINE VS ARIPIPRAZOLE COMPARATIVE TRIAL (FACT) 
 
CLINICALTRIALS.GOV PRS RECORD - NCT02357849 
 
VERSION DATE: 03/09/16 


 
Version date: 09/02/16 
Subject consent 
IRB: 11-199 
 
 
Page 2 of 15 
   
 
THE ZUCKER HILLSIDE HOSPITAL 
A DIVISION OF NORTHWELL HEALTH  
 
INFORMED CONSENT FOR RESEARCH 
 
Title:  The Role of Antidepressants or Antipsychotics in Preventing Psychosis: 
Fluoxetine vs Aripiprazole Comparative Trial (FACT) 
 
Principal Investigator: 
Christoph U. Correll, M.D. 
 
Sponsor: National Institute of Mental Health (NIMH) 
 
Please read this document carefully before signing. 
 
NOTE:  This consent form is written from the point of view of a research subject.  If consent will be 
obtained from the parent/legal guardian of a minor, the words "you" and "your" should be read as "your 
child". 
 
What you should know about this study: 
• You are being asked to join a research study. 
• This consent form explains the research study and your part in the study.   
• Please read it carefully and take as much time as you need.  
• Please ask questions at any time about anything you do not understand.   
• You are a volunteer.  If you join the study, you can change your mind later. You can decide not to 
take part or you can quit at any time. There will be no penalty or loss of benefits if you decide to 
quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to be in the study. 
• Ask your study doctor or the study team to explain any words or information in this informed 
consent that you do not understand. 
• You will be told of any new findings that may change your decision to participate. 
• Neither medication is specifically indicated in adolescents for the symptoms for which they are 
prescribed in this study. However, both medications are widely used for a range of disorders in 
children and adolescents, and both have been used successfully in other studies at the Zucker 
Hillside Hospital, including in adolescents with the same conditions as you have and that are the 
focus of this project.  
 
Financial Disclosure  
Sometimes a study doctor has a financial interest that could be affected by the results of the study. Dr. 
Correll, one of the doctors involved in this study, receives financial support from Alkermes, Intracellular 
Therapies, Janssen/Johnson & Johnson, Lundbeck, Takeda Pfizer, Sunovion and Otsuka. Aripiprazole, one 
of the medications that is involved in this study is made/marketed by Otsuka and Lundbeck. The money this 
study doctor receives from these companies is for work as a consultant, lecturer and/or advisor. This is 
separate from the sponsor’s support of this study. 
 
Why is this research being done?     
The purpose of this study is to compare the usefulness and effects (good and bad) of two medications, 
aripiprazole and fluoxetine, in the treatment of levels of suspiciousness, unusual thoughts and sensory 
experiences, odd behavior, social isolation, and poor school/work functioning in children, adolescents and 
young adults.  You are being asked to participate in this study because you have at least one of these 


 
Version date: 09/02/16 
Subject consent 
IRB: 11-199 
 
 
Page 3 of 15 
   
 
symptoms at a moderate level of severity, but you do not have a major psychotic disorder diagnosis. No 
single medication has been demonstrated to be best for this group of symptoms.  
 
How many people will be in this study?   
We are planning to enroll 48 participants in this study. 
 
How long will you be in this study? 
If you choose to participate, you will be in this study for approximately 25 weeks (about 6 months).  
 
What will happen if I join this study? 
This study consists of two parts.   
• Part one is the screening evaluation (1 visit) 
• Part two is the study treatment and evaluation phase (24 weeks long – 11 visits)  
 
Screening Phase (1 visit)  
If you agree to take part in the study, you will first receive a screening evaluation to see if you are eligible to 
participate in the medication treatment part of the study. This visit will take approximately 3 hours. During 
the screening visit, you will be interviewed with questions about thoughts and feelings to see which 
diagnoses you and the level of some of the symptoms you are experiencing. At the same time your parent or 
legal will also be asked similar questions.  
 
You will undergo a physical exam, including measurement of your height, weight, and vital signs to see if 
you have any health problems. A urine sample will be collected to test for amphetamines, cannabis and 
cocaine.  If you are a female is of childbearing age, your urine sample will also be used to test for pregnancy. 
Approximately 1 tablespoon (15mls) of blood will be drawn for laboratory testing. 
 
Females of childbearing age are required to take a pregnancy test to determine if they are pregnant. If you are 
pregnant, you will not be able to participate in the study.  In general, a urine pregnancy test will be 
performed, unless you are unable to provide urine.  If this is the case, a blood sample will be obtained to test 
for pregnancy.  
 
Your treatment history will be carefully evaluated by the study doctor to determine if you are eligible for the 
study. 
 
Treatment & Evaluation Phase (11 office visits over 24 weeks) 
After the screening visit, participants who are eligible will continue with the second part of the study.  
During this 24-week period, there will be 11 office visits.  These consist of 5 visits (baseline, 4, 8, 12 and 24) 
which will last approximately 2 hours and 6 shorter visits (1, 2, 3, 6, 16, and 20) that will last approximately 
1 hour. 
  
At the baseline visit, participants will be randomized into one of two groups.  This means that you will be 
assigned to a group by chance (like flipping a coin or drawing numbers from a hat).  The two groups are –  
 
• Treatment with Fluoxetine 
• Treatment with Aripiprazole 
 
You and the study doctor will not know which group you have been randomly assigned to. 
 
In order to know whether the study treatments are effective in improving health, it is important to compare 
them without knowing which medication you are taking. At the baseline visit and at each visit thereafter, you 


 
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Subject consent 
IRB: 11-199 
 
 
Page 4 of 15 
   
 
will be given either Fluoxetine or Aripiprazole in identically looking capsules. Every participant will receive 
an active medication (Fluoxetine or Aripiprazole) 
   
At each office visit, we will record your weight and vital signs, and the study doctor will ask about your 
symptoms and any side effects.  The study doctor will evaluate you and decide if the dose of your medication 
should be changed and whether adjustments should be made to other medications that you had been taking.   
Some participants will require additional medications in order to manage side effects. For example, certain 
medications may be prescribed to treat sleeplessness (insomnia), restlessness or anxiety, should these 
symptoms arise. You will be given a medication supply to last until the next office visit. 
 
A urine drug test and pregnancy test for females of child bearing age will be completed at baseline and every 
4 weeks for the first 3 months, and then at the end of the study.  
 
Medications 
Fluoxetine is approved by the Food and Drug Administration (FDA) for the treatment of depression, 
obsessive-compulsive disorder (OCD), panic disorder in adults; and depression, anxiety and OCD in children 
and adolescents.   
 
Aripiprazole is approved by the FDA for the treatment of schizophrenia, bipolar disorder and major 
depressive disorder in adults; and in children and adolescents with schizophrenia (ages 13-17), bipolar 
disorder (ages 10-17), and for the treatment of irritability associated with autistic disorder (ages 6-17).   
 
Neither medication is specifically approved in adolescents for the symptoms for which they are being 
used in this study.  Thus, in this study the drugs are considered investigational.  
 
Birth Control 
The drugs in this study may affect a baby, before or after the baby is born.  As a result, women should not be 
in this study if they are: 
• Pregnant 
• Breast-feeding, or  
• Trying to become pregnant 
 
If you are a female of childbearing age, you should use abstain from sex or use birth control for the entire 
time you are in the study.  Hormonal methods (birth control pill, etc.), double-barrier methods (condoms 
with spermicidal, sponge with spermicidal, or diaphragm with spermicidal), or not having sex may be used.  
Your doctor will discuss these with you. 
 
As per NYS law, the results of your pregnancy test will not be shared with your parents without your 
permission. 
 


 
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Schedule of Study Visits 
 
 
 
  
 
 
 
 
 
 
 
 
Medication Schedule  
 
 
 
 
Week 0/1 
Week 1/2 
Week 2/3 
Week 4-
Week 24 
Visit number Baseline Visit #1 Visit #2 
Visits 3-10 
 
Fixed 
Fixed  
Fixed 
Flexible Dosing 
Fluoxetine 
10mg* 
10 mg* 
20 mg* 
10 mg – 60 mg* 
Aripiprazole 
2 mg* 
5 mg* 
 10 mg* 
5 mg – 30 mg* 
*Indicates daily dose 
 
After your participation in the study is complete, you will resume medical care with your original physician. 
Your personal doctor will receive a letter that will include the details of your study medication dose, study 
length, benefits, side effects and results of laboratory work. This letter will help with the transition of your 
care from the research unit to the personal clinician’s office.  Therefore, continuation of any of the study 
medications provided during the study will be decided by you, your parent/legal guardian (if applicable), and 
your personal doctor/clinician. 
 
Optional Collection, Research and Storage of Genetic Material 
You are eligible to participate in the optional genetic research study, since you are in the main study. In an 
effort to find out the reasons people have good and bad effects from the medications that you are taking in 
this study and to better understand the underlying illness that prompted the use of these medications, we are 
requesting that you allow us to obtain two blood samples of your blood (16ml each either at the baseline visit 
or at any other visit throughout the study) to look at your genes and DNA.   
 
Screening 
Week 0 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Diagnostic interview and SOPS rating 
√ 
 
 
 
 
 
 
 
 
 
 
 
Study doctor visit 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Symptom ratings 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood draws 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
 
 
√ 
Pregnancy test (urine) (females) 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicology test (urine) 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
 
 
√ 


 
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There is no direct benefit to you for participating in the optional genetic research study.  However, this study 
may help us learn where a certain gene within DNA is located, identify changes in this gene that may help us 
learn more about it and may give us information about the disease(s) linked to this.  This may lead to better 
treatment and management of the disease.  There may also be other benefits to society that we do not yet 
know. 
In order to protect your confidentiality, we will not share the results of the genetic testing with you, your 
family members, or any their party.  This includes insurance companies and your employer. 
We ask for your permission to collect two blood samples of 16 ml each for genetic analysis. You do not have 
to consent to the genetic portion of this research study in order to participate in the main study.  
 
 
Please indicate your decision for this optional portion of the study -  
 
 
_____  I agree to provide one blood sample used to obtain DNA (genetic material). 
 
_____  I do not agree to provide one blood sample used to obtain DNA (genetic material). 
 
Your samples will only be used for research about medication related effects and the illnesses prompting 
their use. The samples collected will be stored in locked freezers. The samples will be inventoried and stored 
by codes defined by the researchers involved in this project. Samples will be stored for the period of this 
study and for an additional 10 years, unless you give us permission to use the de-identified samples 
indefinitely (see below) to be able to answer future research questions. Other researchers may be interested 
in using your samples to pursue their own individual research projects.  
 
Since you have control over the use of your samples, we ask your permission in considering their use in 
other studies. You do not have to consent to the future use of your samples in order to participate in the main 
study. 
 
I give my permission to use my sample in future studies under the following conditions (to be initialed by 
subject): 
 
_____  Future studies can be completed without contacting me if all identifying information is removed so 
that the sample cannot be identified as mine. 
 
_____  I wish to be re-contacted if future studies with this sample are considered. After the project has been 
explained to me, I will then decide if I want my sample to be included in the project. 
 
_____  Under no circumstances shall the sample be used for future studies. 
 
What are the risks or discomforts of the study?   
Risks or discomforts associated with participation in this study may include –  
 
Risks associated with the medications used in the study  
 
Likely Medication A: drowsiness or trouble sleeping, dizziness when standing up, blurred vision, 
constipation or upset stomach, increased appetite, weight gain, headache, dry mouth, rash, 
cough, runny nose, nervousness, and easier sun burning. 


 
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Medication B: headache, stomach upset, increased energy and activity, less sexual interest, 
sleeping too much or too little. 
Less 
Likely 
Medication A: stiffness, shaking, twitching, restlessness, sore throat, problems breathing or 
swallowing 
Medication B: nausea, diarrhea, lack of appetite or weight gain, restlessness. 
Very 
Rare 
Medication A: elevated blood sugars, diabetes, tardive dyskinesia (involuntary twitching 
of muscles, tongue, limbs, etc. – that can be irreversible), neuroleptic malignant syndrome 
(high fever >102° F without clear infection, unstable blood pressure or pulse, inability to 
pass urine, unusual confusion, seizure/convulsions, body temperature regulation problems, 
impairment of thinking or movements, agitation and, very rarely, death), heart and blood 
vessel disease, joint disease, potential for increased suicidal thinking and behavior. 
Medication B: increased suicidal thinking and behavior. 
 
 
Potential for worsening of psychiatric symptoms: Signs and symptoms of worsening psychiatric status 
might include new or worsening difficulties with –  
o sleep,  
o attention or concentration,  
o restlessness,  
o feeling or acting aggressive, dangerously or strange, 
o feeling overly happy without any reason,  
o feeling depressed for no apparent reason,  
o feeling hopeless or suicidal,  
o wanting to hurt oneself or wanting to hurt someone else,  
o feeling distrustful of others,  
o seeing, hearing, feeling, smelling or tasting things that are unusual or that others can’t 
recognize.   
 
To minimize the potential risk of worsening psychiatric symptoms, you will be carefully monitored by the 
study doctor.   
 
If your symptoms worsen, you may be withdrawn from the study to ensure appropriate medical care. Since 
clinical worsening may be related to issues beyond antipsychotic and antidepressant treatment (for example, 
recent stress or trauma, development of a new psychiatric condition, or failure to take medications), a decline 
in functioning will not necessarily lead to discontinuation of the study medication or withdrawal from the 
study, but will lead to a thorough clinical review of the case by the study team. The study team will then 
decide if you should continue in the study or possibly change your clinical treatment (for example, you will 
be seen more frequently) (Note: as these are clinically indicated visits (and not research visits), you will not 
receive extra reimbursement for them). The Principal Investigator has the ability to withdraw you from the 
study for any reasons felt appropriate.   
 
Note for Adult Participants and Parents/Legal Guardians: If psychiatric symptoms worsen, you will  
o need to report this immediately to the study doctor, and/or 
o seek medical assessment as soon as symptoms are noted (if applicable) rather than waiting for 
the next scheduled visit. 
 


 
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Blood draw:  There are no major risks of having blood drawn.  Risks of a blood draw include pain at the site 
of the need.  Bruising can sometimes occur. In rare cases, fainting or infection can occur.  These risks will be 
reduced by carefully cleaning your skin before introducing the needle, by using the smallest possible needle 
to take the blood, and by applying pressure to the site after the blood has been taken.  
 
Self-Reports:  When answering questions or completing questionnaires, you may get tired, bored, or 
anxious.    If you feel tired or anxious, you can take a break from answering the questions or choose not to 
answer the question.  You do not have to complete any question that you do not want to answer.  All of these 
uncomfortable experiences are expected to be mild and last only for brief period of time. 
 
Risks of discomfort associated with identifying suspected abuse or neglect or danger to self or others: 
Any information about suspected abuse or neglect that is revealed during the course of assessment or 
treatment will be reported to child protective services according to mandatory reporting guidelines. If your 
safety or that of those around you is in question you may be hospitalized involuntarily.  
 
Unknown Side Effects 
As with any drug, there might be side effects that are unknown at this time.  You will be monitored for side 
effects.  You should report any unusual events to the study staff. 
 
Risks to Women of Childbearing Potential and Pregnant Women  
We do not know the effects of the study medication on fertility or a fetus.  For this reason, if you believe you 
are pregnant or have a chance of becoming pregnant, you should not participate in this study.  A urine 
pregnancy test will be performed prior to the start of study procedures.  If you are unable to provide a urine 
sample, a blood sample will be collected to test for pregnancy.  Pregnancy tests will be performed at week 0, 
4, 8, 12 and 24 of the study.  If you are pregnant, you will not be allowed to participate in the study. 
 
If you do participate in this study, you must either abstain from sexual activity or use a medically recognized 
form of birth control for one month before entering the study, while participating in the study, and for at least 
one cycle after stopping the study.  If you become pregnant during the study, you will be immediately 
withdrawn from the study and followed through the outcome of your pregnancy. 
 
The side effects of this of this experimental procedure on newborns are also not known; therefore, if you are 
currently breastfeeding, you cannot participate in this study. 
 
Your parent/legal guardian will not be given the results of your pregnancy test without your persmission. 
 
Are there benefits to being in the study? 
The possible benefits you may experience from the procedures described in this study include possible 
benefits from either of the study medications on the symptoms that are the target of the interventions. 
Additional benefits include access to intensive monitoring of efficacy and side effects (beyond what can be 
achieved in a standard clinical setting) and medication treatment. Data obtained from the intensive 
monitoring will improve both the caregiver and treatment provider’s ability to assess ongoing risks and 
benefits associated with continued treatment. The results of this study may help others in the future.  
 
If you do not want to take part in this research study, what are your other choices? 
You do not need to participate in this study to receive treatment with antipsychotic or antidepressant 
medication for your condition. You may decide to not participate in the study and receive standard clinical 
care. You can receive fluoxetine or aripiprazole without participating in this study.   
 
Are there any costs for being in this research study? 


 
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You will not be billed for study related procedures and treatments. The costs for aripiprazole and fluoxetine 
will be covered by the study sponsor. The cost for all other medications you might be taking will continue to 
be covered by your insurance company. 
 
Will you receive any payments for participating in this research study? 
You may receive up to $300 in reimbursement for compensation of your time and effort. 
 
You will be paid $30 for the screening visit and visits on weeks 0, 4, 8, 12, and 24 for a total of $180; and 
$20 for visits on weeks 1, 2, 3, 6, 16, and 20 for a total of $120. 
 
If you stop the study before the last study visit or miss reimbursable study visits, you will only be reimbursed 
for the study visits that you attended. If you withdraw before the study is completed, you will be paid for 
your participation up to that time.  
 
Compensation will be provided as check or cash after each reimbursable study visit with instructions that it is 
intended to support the entire family’s expenses associated with the study visit. Additionally, participants 
will be provided with a voucher at each scheduled visit to cover the cost of parking and/or public transit. 
After your blood draws, a light, healthy meal or meal voucher will be given to you. If you are given a meal 
voucher, you will be guided to the cafeteria where you will be able to pay at the cashier with the voucher 
instead of using money. 
 
If the total payment you receive from Northwell Health, during this year, is equal to $600 or more, the 
payment is required to be reported to IRS.  Although this study does not pay $600, if you participate in other 
Northwell Health studies, it is possible your payment could end up totaling $600.  If this occurs, the payment 
you receive on this study will be reported to the IRS.   In this case, you will be issued a 1099 form and be 
required to provide your social security number at that time for reporting purposes.  You will also be 
responsible for reporting this income while filing your tax return. 
 
If the research produces marketable products, will you receive any payment? 
If this research produces a marketable product, there are no plans for you to receive any money. 
 
What happens if you am injured while participating in this study? 
If you are hurt from being in the study, you will receive medical care and treatment as needed from the 
Northwell Health.  However, you will be responsible for the costs of such medical treatment, directly or 
through your medical insurance and/or other forms of medical coverage.  No money will be given to you. 
 
What are your rights as a research participant? 
Your participation in this project is voluntary. The quality of your medical care will be the same, whether 
you join, refuse to join, or decide to leave the study. 
 
If you do not join the study you will not be penalized or lose benefits to which you are entitled. If you join 
the study you may withdraw at any time without prejudice to your future care at the NorthwellHealth. 
Follow-up examinations may be needed to assure your well-being.   
 
Could you be taken off the study before it is over? 
It is also possible that your participation in this study may end without your consent.  This decision may be 
made by an investigator, study sponsor or the IRB.   
 Reasons for withdrawal may include:   
• failure to follow instructions,  


 
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• failure to show up for study visits,  
• it is not in your best interest to continue on this study, or  
•  the study is stopped.   
 
If you withdraw from this study or if you are withdrawn from the study, any data already collected will 
continue to be used.  However, no new information will be collected.  Any remaining samples you have 
contributed will be discarded at the point of your withdrawal.  
 
If you leave the study early, the Zucker Hillside Hospital may use your health information that it already has 
if the information is needed for this study or any follow-up activities. Your data will be treated 
confidentially in the same way if you complete the study or discontinue early. In addition, gradual 
withdrawal may be required for safety considerations by a 50% reduction in dosage for aripiprazole and 
fluoxetine. 
 
How will your privacy and confidentiality be protected? 
If you agree to be in this study, we will collect health information that identifies you. We may collect the 
results of tests, questionnaires and interviews. We may also collect information from your medical record 
and ask other health care providers to give us information about your health status and healthcare.  You will 
be asked to give us a list of other health care providers that you use. We will only collect information that is 
needed for the research. This information has been described in this consent form. If you sign this consent 
form, you are giving us permission to collect, use and share your health information. This permission is 
called authorization.  If you do not want to provide authorization, then you cannot participate in this research 
study. 
 
Study records that identify you will be kept private. You will not be identified in study records or 
publications disclosed outside of the Northwell Health, except as detailed below.  
 
Investigators will share the results of your study tests and procedures with: 
• study sponsor, which is the National Institute of Mental Health or its agents, 
• data safety monitoring board, 
• clinical staff not involved in the study who may be involved in your treatment, health insurers or 
payers  
 
In addition, your records may be reviewed in order to meet federal or state research regulations. Reviewers 
may include representatives from government agencies, i.e. [the Food and Drug Administration, NIH 
(National Institutes of Health), NIMH (National Institute of Mental Health, etc.], and the NS-LIJHS 
Institutional Review Board (IRB – the committee that reviews research at this institution). If your research 
record is reviewed by any of these groups, they may also need to see your entire medical record. 
Please be aware that once private information is disclosed, it is subject to re-disclosure by the recipient and 
can no longer be considered protected by the federal law. 
 
If your research records are used for decisions related to your clinical care, then you have the right to review 
this information and request changes.  This is limited to information about your treatment, and does not 
include information related to procedures or tests that are for research purposes only. You may access this 
information only after the study analysis is complete. You have the right to know who has and who will see 
your records.  To request this information, or for any questions related to your health information, you may 
contact the Research Privacy Officer at 516-321-2100. 
 


 
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If you change your mind about being in the study, you may withdraw at any time. If you want us to stop 
collecting your health information, you need to send a letter to the researcher at the following address: 
 
 
 
Christoph U. Correll, M.D. 
The Zucker Hillside Hospital, 
Department of Psychiatry Research 
75-59 263rd Street 
Glen Oaks, NY 11004 
 
Your letter needs to say that you have changed your mind and do not want the researcher to collect and share 
your health information.  We may still use the information we have already collected. We need to know what 
happens to everyone who starts a research study, not just those people who stay in it. 
 
The information that is collected for research will be analyzed for many years and it is not possible to know 
how long this analysis and follow-up will take. Therefore, you are allowing access to this information 
indefinitely. 
 
Data from this research may be used in medical publications or presentations.  The information will be de-
identified so that individual subjects cannot be recognized and the information will no longer be considered 
Protected Health Information (PHI). 
 
 
What if there is a Certificate of Confidentiality for this study?  
To help us protect your privacy, we have applied for a Certificate of Confidentiality from the US Department 
of Health and Human Services (DHHS). The Certificate of Confidentiality will mean that the researchers 
cannot be forced to identify you, even under a court subpoena. The Certificate does not mean the Secretary 
of DHHS approves or disapproves of the project. It adds special protection for the research information about 
you.  You should know, however, that researchers may provide information to appropriate individuals or 
agencies if harm to you, harm to others, or child abuse becomes a concern.  In addition the federal agency 
funding this research may see your information if it audits us. 
 
A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily releasing 
information about yourself or your involvement in this research.  However, if an insurer, employer, or other 
person learns about your participation and obtains your consent to receive research information, then the 
researchers may not use the Certificate to withhold that information. 
 
Who do you contact if you have questions or concerns? 
If you have any questions regarding the project, side effects or research-related injury call Dr. Christoph 
Correll at 718-470-4812. If you need emergency care, you may call the Emergency Department at 718-470-
7500 or dial 911. For questions regarding your rights as a research subject, you may call the Office of the 
Institutional Review Board (the committee that oversees research at this Institution) at (516) 321-2100. A 
copy of this signed consent form will be given to you. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
 


 
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RESEARCH REVIEW QUESTIONNAIRE TO FOLLOW 
 
 
 
 
 
 
RESEARCH REVIEW QUESTIONNAIRE 
 
Please answer the following questions after reviewing the consent form for this study. The researchers doing 
this study want to be sure that you know what is involved in being in this research study. This questionnaire 
will help them make that decision. You may ask questions of the researcher and review the consent form 
again at any time. 
I am being asked to be in a research study. 
This study involves the use of a drug not approved by the FDA for 
adolescents to treat the symptoms for which they are prescribed in this 
study. 
I have to participate in this research study to receive care. 
I and my doctor will know which study medication I am taking 
I can withdraw from participating in this study at any time. 
There are no risks to me from participation in this study. 
I am guaranteed to feel better from being in this study. 
True      False 
True      False 
True      False 
True      False 
True      False 
True      False  
True      False 
 
 
__________________________________________ 
Printed Name of Subject 
 
__________________________________________ _____________________ 
Signature of Subject/LAR/ Date  


 
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_________________________________________ _____________________ 
Investigator's Signature                                  
      Date 
 
 
 
 
THE REMAINDER OF THIS PAGE IS LEFT BLANK INTENTIONALLY 
 
 
 
 
 
 
 
 
 
 
Summation of Signatures 
 
You have read the above description of the research study. You have been told of the risks and benefits 
involved and all your questions have been answered to your satisfaction.  A member of the research team 
will answer any questions you may have. You voluntarily agree to join this study and know that you can 
withdraw from the study at any time without penalty. By signing this form, you have not given up any of 
your legal rights. 
 
If you are consenting for yourself (≥ 18 years old) 
 
________________________________     _______________________________   __________ 
Subject’s Printed Name 
 
          Subject’s Signature 
                             Date 
 
________________________________     _______________________________   __________ 
Witness’s Printed Name 
 
          Witness’s Signature 
 
        
   Date 
(Preferably someone not connected with the study) 
 __________________________________________________________ 
OR 
 
If you are consenting as the Parent or Legal Guardian of a minor: 
 
_______________________________________________________________________________         
Subject’s name                                                     
 
________________________________     _______________________________   __________ 
Parent’s/Legal Guardian’s Printed Name     Parent’s/Legal Guardian’s Signature     Date             
      
________________________________     _______________________________   __________ 
Witness’s Printed Name 
 
          Witness’s Signature 
 
        
   Date 
(Preferably someone not connected with the study) 


 
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 __________________________________________________________ 
 
 
Physician’s Statement 
In addition to advising the above subject or the subject’s parent/legal guardian of other forms of treatment 
and therapy which are appropriate, I have offered an opportunity for further explanation of the risks and 
discomforts which are, or may be associated with this study, and to answer any further questions related to it. 
 
 
________________________________     _______________________________   __________ 
Physician’s Printed Name 
 
          Physician’s Signature                            Date 
 
 
ASSENT BY MINOR SUBJECTS LESS THAN EIGHTEEN YEARS OF AGE 
 
I have been asked to join this research study. I have the right to find out what will or might happen to me if I 
am in the study. I have the right to tell my parent(s)/guardian and the doctor whether I do or do not want to 
be in this study. 
My parent(s)/guardian will also be asked to give permission for me to be in this study. 
________________________   and my parent(s)/guardian have explained what I will have to do in the study. 
_________________________ and my parent(s)/guardian have also explained any discomforts, risks and 
inconveniences I may experience if I am in the study. 
 
I have been told that I will be given at least five urine drug tests. If the drug test is positive, then one of the 
study doctors will meet with my parents and tell us the results. 
I agree that I need to avoid using any alcohol, including beer and wine, while in this study, as it could make 
me sick and cause serious side effects. 
If I am female, I have been told that I will be asked to discuss sexual activity and birth control in private and 
my parents will only be involved in the discussion if I want them to be there. 
If I am a female, I have been told that I will have pregnancy testing if I am able to have a child and the 
results will be kept private and not shared with my parents without my permission. I have been told that I 
need to remain pregnancy free throughout the study. 
 
I have asked any questions I had, and all my questions have been answered (to be initialed by subject): 
 
______ I agree to be in this study. 
______ I do not want to be in this study. 
 
_______________ 
Subject’s age 
 
________________________________     _______________________________   __________ 


 
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Subject’s Printed Name 
 
          Subject’s Signature 
                           Date 
 
 
________________________________     _______________________________   __________ 
Witness’s Printed Name 
 
          Witness’s Signature 
 
        
   Date 
(Preferably someone not connected with the study) 
 
All procedures, risks and discomforts have been explained to the subject. 
 
________________________________     _______________________________   __________ 
Physician’s Printed Name  
 
 
Physician’s Signature                           Date