DECIFER: Depression and Citalopram In First Episode Recovery

Study Overview
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Brief Summary
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This study seeks to examine the effectiveness of citalopram added to treatment with any oral or injectable second-generation antipsychotic plus standardized psychoeducation in first episode schizophrenia patients. Because depressive symptoms are common in first episode patients, we will test the hypothesis that adding the SSRI citalopram to a pre-established medication regimen will improve quality of life and decrease relapse and suicidality over the course of a 12-month trial.

Detailed Description
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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.

Official Title
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Citalopram in First Episode Schizophrenia

Conditions
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Schizophrenia, Schizophreniform Disorder

Intervention / Treatment
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* Drug: Citalopram
* Drug: Placebo
* Behavioral: Psychoeducation
* Behavioral: Cognitive Behavioral Therapy (CBT)
* Radiation: Functional Magnetic Resonance Imaging (fMRI)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Citalopram<br>Participants will receive a daily dose of citalopram, with flexible dosing as determined by clinician, for 12 months. | Drug: Citalopram<br>* 40 mg by mouth daily for 12 months. Dosing will start at 20mg daily and may be increased after a minimum of one week to the target dose of 40 mg daily. Dose decreases will be made in the presence of side effects. Allowed dose range will be 10 mg daily to 40 mg daily.<br>* Other names: Cipramil;|
| Placebo Comparator: Placebo<br>Participants will receive a daily dose of placebo for 12 months. | Drug: Placebo<br>* Placebo by mouth daily for 12 months.<br>* Other names: Sugar pill;Behavioral: Psychoeducation<br>* 16 sessions of weekly, individual psychoeducation and relapse prevention planning followed by 8 monthly sessions<br>* Other names: Therapy;Behavioral: Cognitive Behavioral Therapy (CBT)<br>* Participants who exhibit symptoms of moderate suicidality at any point during the trial will be treated with 12 sessions of CBT, either once or twice weekly based on clinical judgment. Participants who continue to exceed suicidality criteria after 4 weeks of CBT will be dropped from double-blind treatment and may be prescribed openly an SSRI<br>* Other names: Therapy;Radiation: Functional Magnetic Resonance Imaging (fMRI)<br>* 3 1-hour sessions of fMRI brain scanning, assessed at baseline, and weeks 24 and 52<br>* Other names: Neuroimaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calgary Depression Scale for Schizophrenia (CDSS) | The Calgary Depression Scale for Schizophrenia (CDSS) is a rater-administered assessment that measures depression in schizophrenia. The scale consists of 9 questions each rated 0 to 3. 0 corresponds with absent and 3 corresponds with severe. The total score for all items is provided for each time point. The minimum score is 0 and the maximum score is 27. A higher score indicates increased depressive symptoms. | Screening, Baseline, Weeks 1-8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Scale for the Assessment of Negative Symptoms (SANS) | The Scale for the Assessment of Negative Symptoms (SANS) is a 25-item rater-administered scale to assess negative symptoms in schizophrenia. Each item is rated from 0 to 5 where 0 is none and 5 is severe. The SANS consists of five subscales: affective flattening/blunting, alogia, avolition/apathy, ahnedonia/asociality, and attention. Each subscale contains a global rating item which assesses the overall severity of symptoms within the subscale. The total score consists of a sum of all items except the global ratings and items 10, 23, 24, and 25. The total score is reported for each time point. The minimum total score is 0 and the maximum total score is 85. A higher score indicates increased severity of negative symptoms. | Screening, Baseline, Weeks 4, 8, 12, 16, 20, 24, 28,32, 36, 40, 44, 48, 52 | 
| Brief Psychiatric Rating Scale (BPRS) | The Brief Psychiatric Rating Scale (BPRS) is a 24-item rater-administered scale assessing overall psychiatric and psychotic symptoms. Items 1-14 are assessed through self-report and items 15-24 are assessed on the basis of observed behavior. Each item is rated from 1 to 7 where 1 is not present and 7 is extremely severe. A score of 0 indicates not assessed. The total score is a sum of all items and is reported for each time point. The minimum score is 24 and the maximum score is 168, and higher values indicate increased symptom severity. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 
| InterSePT Scale for Suicidal Thinking (ISST) | IntraSePT Scale for Suicidal Thinking (ISST) consists of 12 questions rated from 0 to 2 with increasing intensity (i.e. none, weak, moderate to stron). It quantifies the current conscious and overtly expressed suicidal thinking in schizophrenic patients by canvassing various suicidal thoughts and wishes during a 20- to 30-min semi-structured interview. The total score is computed by adding the 12 individual item scores and ranges from 0 to 24. A score of zero indicates low suicidal ideation and a score of 24 indicates high suicidal ideation. | Screening, Baseline, Weeks 1-8 | 
| Heinrich Quality of Life Scale (QOL) | The Quality of Life Scale (QOL) is a 21-item scale based on a semi-structured interview to assess functional deficits in schizophrenia. Each item is rated on a 7-point scale where 0 indicates a normal level of functioning, or no deficit, and 6 corresponds to more severe deficit. The total score is a sum of all items. The minimum total score is 0 and the maximum total score is 126, higher scores indicate increased impairment in functioning. | Baseline, Week 4, 8, 12, 16, 20, 24, 32, 40, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Citalopram, First episode, fMRI, Cognitive behavioral therapy, Psychoeducation