DECIFER: Depression and Citalopram In First Episode Recovery

We propose to conduct a 12-month, placebo-controlled, double-blind, parallel-group trial of
citalopram added to treatment with any oral or injectable second-generation antipsychotic
plus standardized psychoeducation. Subjects will be 100 patients ages 16-40 with first
episode schizophrenia or schizophreniform disorder with onset before age 35 who have received
at least 4 weeks and fewer than 16 cumulative weeks of antipsychotic medication, have not
been treated with an SSRI within four weeks and do not meet criteria for major depression or
significant suicidal ideation. This study will be conducted by the Schizophrenia Program of
the NYU Langone Medical Center and at the Psychiatry Outpatient Clinic of Bellevue Hospital
located in New York, NY

Upon signing consent, patients will undergo screening procedures to assess eligibility. A
diagnosis of schizophrenia or schizophreniform disorder will be determined by the Structured
Clinical Interview for DSM IV (SCID) completed by a research clinician using all available
clinical data and will be confirmed by consensus diagnosis. A comprehensive medical history
and physical exam, including measurement of vital signs, will be performed. A psychiatric
history, including diagnosis, treatment history, current medications, and substance use will
also be performed. At screening only, a fasting blood sample will be obtained to perform
routine laboratory tests including electrolytes, BUN, creatinine, liver function tests,
fasting glucose, calcium, phosphate, magnesium, albumin and CBC with differential. Urinalysis
will be performed to identify unstable medical illness. A urine toxicology screen will be
performed and a urine pregnancy test will be done for women of child bearing potential. A
research assistant will complete the demographics and administer the Calgary Depression Scale
for Schizophrenia (CDSS), Scale for the Assessment of Negative Symptoms (SANS) and InterSePT
Scale for Suicidal Thinking (ISST) to determine whether inclusion criteria are met.

Subjects who meet study eligibility criteria will complete the baseline assessment which will
include the following assessments: Brief Psychiatric Rating Scale (BPRS), SANS, CDSS, ISST,
Clinical Global Impression for Severity of Suicidality (CGI-SS), Clinical Global Impression
(CGI), Heinrich Quality of Life Scale (QLS), WHO Quality of Life Scale (WHO-QOL), Scale for
the Assessment of Positive Symptoms-Delusions (SAPS-D),Birchwood Insight Scale (IS), Brief
Time Use Survey (BTUS), MIRECC Global Assessment of Functioning (MIRECC GAF), Beck Depression
Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI),MacArthur Perceived Coercion
Scale (PCS), Basis-24, Subject Well-being under Neuroleptic Scale (SWN-S),Subjective Scale to
Investigate Cognition in Schizophrenia (SSTICS), Brief Adherence Rating Scale (BARS),
Medication Adherence Rating Scale (MARS), Social Behavior Scale (SBS), WHO Alcohol Smoking
and Substance Involvement Screening Test (WHO ASSIST), and a Drug Use Survey. In addition,
side effects will be rated using the Systematic Assessment for Treatment Emergent Events
(SAFTEE), Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale (BAS) and the
Simpson Angus Scale for Extrapyramidal Symptoms (SAS). Assessment of cognitive functioning
will be measured by the MATRICS battery.

Subjects will undergo 4 high-resolution MP-RAGE scans: once each at Baseline, 2 months, 6
months and 12 months. Scheduled Participants will be randomized 1:1 to citalopram or placebo.
We will follow a standard approach to flexible dosing with citalopram as recommended by the
manufacturer, initiating treatment with a dose of 20 mg (two capsules) daily. Clinicians may
increase or decrease the dose by one capsule every two weeks to a maximum of 4 capsules and a
minimum of one capsule daily.

Beginning at Week 1, participants will receive 16 sessions of weekly, individual
psychoeducation and relapse prevention planning followed by 8 monthly sessions. Participants
who score 3 (moderate suicidality) on the CGI-SS or > 7 on the CDSS will be treated with a
standard 12 session CBT approach to depression that includes elements targeting suicidality
when appropriate. Clinical judgment will be used to determine whether to offer the CBT for
depression sessions once or twice weekly.

The CDSS, ISST, and CGI-SS will be administered at baseline and then weekly up to week 8,
then monthly. The SANS, BPRS, and BARS will be administered at baseline, then monthly for the
duration of the study. The Heinrich's QOL and WHO QOL will be administered at baseline, and
then monthly until study completion, excepting week 28, week 36, week 44, and week 48. The
SAPS-D,IS, BTUS, MIRECC GAF, CGI, STAI, PCS, Basis-24, SWN-S, SSTICS, MARS, and SBS will be
administered at baseline, week 24, and week 52. The BDI-II will be administered at screening,
baseline, weeks 1-16, then monthly. The WHO-ASSIST will be administered at baseline, week 12,
week 24, and week 52. The drug use survey will be administered at baseline, week 4, week 8,
week 12, week 16, week 20, week 24, and week 52.

A fasting blood sample will be drawn at Baseline, weeks 4 and 8 and every 8 weeks thereafter
for BDNF assay. Blood samples collected at Baseline, week 24, and week 52 will be assayed for
prolactin and inflammation markers. Blood samples collected at baseline, week 8, week 24, and
week 52 will be assayed for C-Reactive Protein. Additionally, a blood sample for DNA will be
collected at week 4. Saliva will be collected with tongue swabs at Baseline, Week 4, Week 8,
Week 16, Week 24, Week 36, and Week 52 for cortisol analyses.

Participants who choose to discontinue study drug will be asked if they are willing to
continue their scheduled assessments. These subjects will continue to be followed for the
entire course of the study but will not receive any study medication. Final study visit will
be conducted 1 year post randomization.

The primary outcome measure is change in depression symptoms as measured by the Calgary
Depression Scale total score. Secondary outcome measures include a measure of changes in
negative symptoms (SANS), relapse rates (BPRS), suicidal ideation (ISST), and quality of life
(QOL), measured at various time points during the 12-month trial.

Inclusion Criteria:

- Male or female

- Ages 16-40 years

- Schizophrenia, any subtype or Schizophreniform disorder

- Treated with any of the following second generation antipsychotics for at least 4
weeks and fewer than 16 weeks: risperidone, olanzapine, quetiapine, aripiprazole,
ziprasidone, or paliperidone)

- Willing to participate in psychoeducation

- Sufficient proficiency in English to complete assessments

Exclusion Criteria:

- Major depression by DSM-IV criteria

- Clinical Global Assessment of Severity of Suicidality of 3 (moderate) or greater.

- Calgary Depression Scale for Schizophrenia (CDRS) score of 7 or greater

- Serious suicide attempt within three years or ANY suicide attempt for subjects age
16-25.

- Current treatment with an MAOI or pimozide

- Active alcohol or other substance abuse or dependence within three months

- Unstable medical illness

- History of SSRI intolerance

- Pregnant or nursing

- QTc ≥ 500 msec