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Study Description

This pharmacogenomic study focused on the response of patients with MDD to an 8-week course of treatment with citalopram or escitalopram.

Briefly, clinical assessments and research assessments were performed at each study visit as summarized in Table 1. Many patients continued on antidepressant medication after the 8 week study.

Table 1: Study timeline and patient contacts.

Week Consent/Med Hx Write Rx SI Qx SCID HRS-D17 QIDSC16 CGI-I
0 SC RC RC SC SC SC
4 RC RC SC SC RC
8 RC RC SC SC RC

HRS-D17=Hamilton Rating Scale for Depression, QIDS-C16=Quick Inventory of Depressive Symptomatology, CGI-I=Clinical Global Impression-Improvement, SCID=Structured Clinical Interview for DSM-IV, SC=Study Coordinator, RC=Research Clinician.

Enrollment and baseline assessment. Upon initial intake, the Study Coordinator (SC) obtained informed consent as well as clinical and demographic information, including history of bone marrow or liver transplant or blood transfusion within the previous 6 weeks, and prior history of treatment during the current major depressive episode. The SC completed the Structured Clinical Interview for DSM-IV (SCID), the HRS-D17 (17-item Hamilton Rating Scale for Depression) and the QIDS-C16 (Quick Inventory of Depressive Symptomatology) and reviewed the inclusion/exclusion criteria. After review with the Research Clinician (RC) and when appropriate, after a negative pregnancy test, the SC invited the subject to participate in the study if entry criteria were met. If the subject agreed, he/she received treatment according to the study protocol.

Treatment schedule. Participants selected for inclusion in the study were seen at weeks 0, 4, and 8. The appropriate treatment antidepressant (citalopram or escitalopram) was determined following discussion between the patient and RC concerning medical, financial, and insurance considerations. The study medication citalopram was given in tablet or liquid form, depending on the patient's need. A fixed-flexible dose schedule was employed with the possibility of a dose escalation. In particular, the initial dose of citalopram was 20 mg and escitalopram was 10 mg. This dose was increased to 40 mg and 20 mg, respectively, after 4 weeks if the subject had a score of >/= 6 on the QIDS-C16 and the RC concluded that the subject could tolerate the increase. If necessary, dose was reduced at the discretion of the RC. The importance of medication compliance was discussed with the subject, and subjects were asked to bring in the medication at each visit for the purpose of counting remaining pills to assess compliance.

Participants may have had an abbreviated course of therapy if they were clearly intolerant of the drug or failed to respond to a 40 mg dose of citalopram or a 20 mg dose of escitalopram. They then received standard treatment from a primary physician or psychiatrist with different medications and/or therapeutic modalities (e.g. psychotherapy). Special attention was given to subjects with suicidal ideation. Those subjects were offered additional appointments as needed to ensure their safety. Participants were also contacted by telephone at week 1 and week 2 by the Clinical Nurse Specialist (CNS) or other study personnel to ensure medication compliance and patient safety. The CNS was supervised by the study psychiatrist and principal investigator and deferred to the physician's judgment as needed. The SC was trained to notify the RC at the time of the clinical visits or the phone interviews if the subject endorsed any suicidal ideation or plans. For those subjects who were unable to attend the follow-up visits as scheduled, the patient was contacted by phone to complete the HRS-D17/QIDS-C16. The participant was also asked to return to the clinic to complete a final blood draw for the study.

Adjunctive and concurrent medications. Adjunctive treatments were those used to manage transient associated symptoms (e.g., insomnia) or transient or longer-term medication side effects (e.g., sexual dysfunction). Adjunctive treatments that were not used to treat depression were allowed during the study. However, drugs in the exclusion criteria for this study were not used as adjunctive therapies. Subjects were allowed to participate in the study while receiving concurrent medications for general medical conditions as long as there was no contraindication to use while taking citalopram or escitalopram.

Drug efficacy phenotype evaluation. The change in QIDS-C16 score and change in HRS-D17 score were used as the major research outcome measures to assess drug response. At each clinical research visit, the RC also completed the Clinician Global Impression of Improvement (CGI-I) scale. For the primary genome-wide association analyses, dichotomous outcome variables, remission and response, were defined based on the QIDS-C16 last visit score. Remission was defined as a QIDS-C16 score of 5 or less, while response was defined as at least a 50% reduction in the QIDS-C16 score from baseline.

Specimen collection. Specimen collections were obtained by the General Clinical Research Center (GCRC) at St. Mary's Hospital (SMH). Subjects had blood drawn on an outpatient basis at GCRC-SMH on three separate occasions - baseline (0), week 4 and week 8 visits. Prior to sample collection, date and time of last dose of study medication was gathered at the 4 and 8 week visits. For those patients who were unable to complete the regularly scheduled visits, a dismissal blood draw was requested. GCRC then shipped samples to Mayo Clinic's Biospecimens Accessioning and Processing Lab.

Genotyping and biomarker assays. DNA from 529 patients was genotyped by the RIKEN Center for Genomic Medicine (Yokohama, Japan) using Illumina Human610-Quad BeadChips (Illumina, San Diego, CA). The study also included the determination of plasma drug levels at weeks 4 and 8, and metabolite levels at baseline and weeks 4 and 8 for a subset of subjects.

The primary genome-wide association study based on these data, which includes a summary of the protocol, subject description, selection of subjects for genetic analyses, and definitions of clinical outcomes, was published in the Pharmacogenomics Journal (Ji et al., 2012).

  • Study Type: Prospective
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 529

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

PARTICIPANTS

Inclusion Criteria:

Male and female participants were included who met the following criteria:

  1. Outpatients or inpatients with nonpsychotic MDD for whom antidepressant treatment is deemed appropriate by the treating clinician.
  2. A baseline score of >/= 14 on the HRS-D17.
  3. Age 18-85 years.

Exclusion Criteria:

  1. Subjects with medical contraindications that precluded citalopram or escitalopram treatment and those who previously failed to respond to citalopram or escitalopram were excluded.
  2. Patients with schizophrenia, schizoaffective disorder, or who have Bipolar I disorder were excluded.
  3. Subjects who were on antidepressant medication with subtherapeutic results in terms of depression management underwent a medication taper and discontinuation prior to initiation of citalopram or escitalopram treatment. The subjects were closely monitored by the primary physican or psychiatrist during the medication taper and discontinuation phase. The medication taper was determined by the treating physician or psychiatrist. Study subjects who could not be safely tapered from their medication or experienced adverse effects during the taper were excluded from the study.
  4. Subjects using the antidepressant medication for management of nicotine dependence, chronic pain, migraine prophylaxis or other diagnoses were not eligible for the study.
  5. Study subjects who were on antipsychotic medications (e.g., typical and atypical antipsychotic drugs) and mood stabilizing agents (e.g., lithium, carbamazepine, valproate, lamotrigine, gabapentin, or other anticonvulsants) were not eligible for the study with the exception of those starting quetiapine after baseline. Trazadone, Melatonin, and Diphenhydramine were allowed for use as rescue medications for insomnia. Benzodiazepines were allowed for treatment of anxiety and atomoxetine for the treatment of attention deficit disorder.
  6. Subjects unable to give informed consent were excluded.
  7. Pregnant subjects were excluded.
Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Illumina Human610_Quadv1_B 601273 1048904
Study History

The first subject was recruited on May 4, 2005. The last subject was enrolled on October 8, 2012. The primary genome-wide association study based on the first 529 subjects, which includes a summary of the protocol, subject description, and definitions of clinical outcomes, was published in the Pharmacogenomics Journal in 2012 (Ji et al., 2012).

Selected publications
Diseases/Traits Related to Study (MESH terms)
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