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Design and Rationale for a Randomized, Controlled Trial of Interpersonal Psychotherapy and Citalopram for Depression in Coronary Artery Disease (CREATE)

From the Department of Psychiatry, McGill University, Montreal Canada (N.F.-S., F.L.); Department of Psychiatry, University of Montreal, Montreal, Canada (N.F.-S., M.-A.L., F.L.); Department of Psychiatry, University of Ottawa, Ottawa, Canada (D.K., J.R.S.); Department of Psychiatry, University of Toronto, Toronto, Canada (B.B.); Department of Psychiatry, Queen’s University, Kingston, Canada (T.v.Z.); Montreal Heart Institute Research Center, Canada (N.F.-S., M.-A.L., G.G., F.L.); Center Hospitalier de l’Université de Montreal Research Center, Montreal, Canada (N.F.-S., F.L.); School of Nursing, McGill University, Montreal, Canada (N.F.-S.); Institute of Mental Health Research, Royal Ottawa Hospital, Ottawa, Canada (D.K., J.R.S.); University of Ottawa Heart Institute, Ottawa, Canada (J.R.S.); Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, Canada (B.L.A.); and Department of Social and Preventive Medicine, University of Montreal, Montreal, Canada (J.L.).

Address correspondence and reprint requests to Nancy Frasure-Smith, PhD, Montreal Heart Institute Research Center, 5000 Bélanger, Montreal, Quebec H1T 1C8, Canada. E-mail: nancy.frasure-Smith{at}mcgill.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 
Objective: Recognition that depression is associated with increased morbidity and mortality in coronary artery disease (CAD) patients has augmented the need for evidence-based treatment guidelines. This article presents the design of a multisite, Canadian trial of the efficacy, safety, and tolerability of interpersonal psychotherapy (IPT), an empirically supported, depression-focused therapy, and the selective serotonin reuptake inhibitor citalopram, alone or in combination, in the treatment of major depression in CAD patients.

Methods: Two hundred eighty stable CAD patients with a current major depressive episode of at least 4 weeks’ duration, based on the Structured Clinical Interview for Depression (SCID), and who have a baseline score >19 on a centralized, telephone-administered, 24-item Hamilton Depression Rating Scale (HAM-D) will be randomly assigned to receive 12 weekly IPT sessions or 12 weekly sessions of standardized clinical management (CM). Patients are also randomly assigned to receive 20 to 40 mg per day of citalopram or pill-placebo. This results in a 2-by-2 factorial design with four groups: IPT plus pill-placebo, IPT plus citalopram, CM plus pill-placebo, and CM plus citalopram. This permits the evaluation of both IPT and citalopram. Blinded, centralized, 24-item, HAM-D telephone ratings constitute the primary outcome variable. The self-report Beck Depression Inventory-II is the secondary outcome. Analyses will involve the intent-to-treat principle with last observation carried forward for incomplete assessments.

Results: Not applicable.

Conclusions: The results of this trial will contribute to the development of evidence-based clinical guidelines for managing depression in the context of CAD.

Key Words: psychotherapy • selective serotonin reuptake inhibitor • 2-by-2 factorial • telephone assessment • clinical trial • coronary artery disease

Abbreviations: CREATE = Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy; IPT = interpersonal psychotherapy; CAD = coronary artery disease; SCID = Structured Clinical Interview for Depression; HAM-D = Hamilton Depression Rating Scale; CM = clinical management; SADHART = Sertraline Antidepressant Heart Attack Randomized Trial; ENRICHD = Enhancing Recovery in Coronary Heart Disease; SSRI = selective serotonin reuptake inhibitor; ECG = electrocardiogram; NIMH = National Institute of Mental Health; TDCRP = Treatment of Depression Collaborative Research Program; MMSE = Mini-mental Status Exam; STAR*D = Sequenced Treatment Alternatives to Relieve Depression; IDS = Inventory for Depressive Symptomatology; BDI-II = Beck Depression Inventory-II; IPRI = Interpersonal Relationship Inventory; FPI = Functional Performance Inventory; SAE = serious adverse event; LOCF = last observation carried forward; DSMB = data safety monitoring board.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 
The recognition of the prognostic importance of depression in patients with coronary artery disease (CAD) (1) has increased the need for treatment guidelines based on well-designed clinical trials. Current treatment recommendations for moderate to severe major depression in the nonmedically ill include prescription of antidepressant medications (usually selective serotonin reuptake inhibitors [SSRIs] or other new antidepressants) and/or participation in one of two types of brief, specific psychotherapy (cognitive behavioral therapy [CBT] or interpersonal psychotherapy [IPT]) (2,3). There are considerable data showing the efficacy, safety, and tolerability of each of these treatments in depressed patients who are otherwise healthy (3,4) but very few in patients with physical illness. Although many thousands of subjects have been involved in randomized clinical trials of antidepressants (5), physical comorbidity has usually been an exclusion criterion (6). Therefore, the choice of treatment for depressed patients with CAD is based largely on clinician preference and experience with various antidepressants, as well as the availability of suitably trained psychotherapists. Apart from the fact that, because of the potential for conduction disturbances and postural hypotension, most would agree that the tricyclic antidepressants are not the first choice in treating depression among patients with cardiac disease (7), there is little evidence base to help guide clinicians. To date, the results of only two major randomized trials of depression treatment in CAD patients have been published, SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) (8) and ENRICHD (Enhancing Recovery in Coronary Heart Disease) (9).

SADHART was a double-blind efficacy/safety study of 24 weeks of sertraline for the treatment of major depression in 369 patients who had recently experienced an acute MI or episode of unstable angina. Results demonstrated that sertraline was safe in terms of changes in left ventricular ejection fraction, heart rate, blood pressure, electrocardiographic measures, 24-hour heart rate variability, and standard laboratory parameters, including blood counts. While apparently safe, sertraline was not significantly better than placebo in reducing symptoms of depression in the overall sample. However, in two preplanned subgroups, patients experiencing a recurrent depression, and those with an initial 17-item Hamilton Depression Rating Scale (HAM-D) 18 (10) who also had at least two previous depression episodes, sertraline was significantly better than placebo.

ENRICHD was a National Heart Lung and Blood Institute–funded survival trial comparing 6-months of individual CBT supplemented with sertraline at 5 weeks, if needed, with usual care in 2,481 depressed or socially isolated patients who were randomized approximately 1 month after an acute MI. Physicians of patients in the usual care group were informed of their patients’ depression or social isolation status, and all patients in both groups received standard written educational material. Changes on the HAM-D and on a measure of social support were statistically significant. However, there was no impact on the primary endpoint of combined all-cause mortality or nonfatal, recurrent MI over a mean follow-up period of 29 months.

Designed and funded before the completion of these trials, the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) study is a 2-by-2 factorial, placebo-controlled trial of two other treatments with demonstrated efficacy for relieving depression symptoms in patients without comorbid CAD: IPT and citalopram. IPT is a short-term, structured psychotherapy dealing with interpersonal problems common in depressed CAD patients. Citalopram is a highly selective SSRI, with a very low risk of drug interactions. CREATE is an investigator-initiated and -designed trial funded by the Canadian Institutes of Health Research (CIHR) clinical trials program. The primary aim of CREATE is to determine whether 12 weeks of treatment with IPT or citalopram are more effective than their respective control conditions in reducing depressive symptoms in stable CAD patients. The secondary aim is to examine the tolerability and the safety of each treatment in comparison to the control condition.

Rationale for IPT
IPT is a brief, manualized psychotherapy that was developed in the early 1970s by Klerman et al. (11) as a research intervention for adult outpatients with major depressive disorder. It emphasizes the current social and interpersonal context associated with the onset and persistence of depressive symptoms but recognizes the etiological contribution of genetic, biochemical, developmental, and personality factors. IPT is based on the premise that psychosocial stressors affect mood and that depression itself has adverse effects on interpersonal functioning. For each patient, therapy focuses on one or, at most, two interpersonal problem areas derived from extensive research on the role of environmental influences on mood. These areas are characterized as unresolved grief following the death of a loved one, role transition (difficulty adjusting to changed life circumstances), interpersonal role disputes (conflicts with a significant other), and interpersonal deficits (impoverished social networks and social isolation). The primary goal of IPT is to treat the depressive episode by helping patients link their disturbed mood to current psychosocial stresses and facilitating resolution of these stresses.

Several clinical trials have documented the efficacy of IPT for major depression (12,13). IPT has also been shown to be efficacious in relieving depression when used alone or in combination with medication in geriatric patients (14). Although there is similar evidence for CBT (15), there are a number of reasons why we selected IPT in the context of treatment for depression in CAD patients. In a trial of IPT adapted for patients with HIV infection, Markowitz et al. (16) found that IPT was as good as imipramine and better than CBT in alleviating symptoms of depression. The authors commented that, unlike CBT, in which patients are encouraged not to exaggerate cognitive and emotional reactions to their situation, IPT acknowledges the reality of the distress associated with comorbid medical conditions and then helps patients to pragmatically and optimistically move on and make the best of their future. In addition, IPT addresses the problem of social isolation that has been linked to increased mortality and morbidity in some studies of CAD patients (9). In fact, a secondary analysis of post-MI data collected in Montreal showed that among the depressed patients who survived the first year, those with better baseline support were more likely to experience improvements in depression symptoms than the depressed with lower support (17). However, overall rates of depression at 1 year remained high, indicating a need for appropriate intervention strategies beyond naturally occurring support for many patients. Thus, we believe that IPT may prove to be particularly useful.

Rationale for Citalopram
Citalopram’s favorable side-effect profile, its lack of significant cardiovascular side effects, and relative lack of toxicity in overdose, combined with its lack of potential for drug-drug interactions, makes it one of the most attractive antidepressants for use in CAD patients who usually take multiple cardiac and other medications. The antidepressant efficacy of citalopram has been demonstrated in medically healthy, depressed patients in 8 placebo-controlled studies addressing short-term efficacy and in 2 placebo-controlled studies of long-term (6 months) treatment (18). Most patients respond to 20 mg daily. However, there is some evidence that more severely depressed patients respond to doses of up to 40 mg daily. Citalopram’s side effects are similar to other SSRIs and include nausea, diarrhea, headache, and sexual dysfunction. The placebo-adjusted rate for most side effects is less than 15%, comparable to or better than other SSRIs (18).

Although data suggest equivalent efficacy for all SSRIs (2), the choice of citalopram was based on its favorable drug interaction profile. It is a weak inhibitor of the cytochrome isoenzyme 2D6, has minimal or no effects on CYP1A2, CYP3A4, or CYP2C19, and has the least potential of all SSRIs for drug-drug interactions (19,20). Although preclinical toxicology studies reported unexpected QT-interval prolongations with high doses of citalopram in beagle dogs, this was found to be due to high levels of didemethylcitalopram, a major metabolite of citalopram in beagle dogs, but a minor one in humans. Furthermore, the Rasmussen et al. (21) extensive review of the available cardiac safety data from all clinical trials of citalopram carried out between 1978 and 1996 strongly suggests that therapeutic doses of citalopram have no effect on cardiac conduction and repolarization in humans during either short- or long-term treatment. Analyses of electrocardiograms (ECGs) from three trials (n = 1,460) showed no differences between active treatment and placebo groups in the mean QRS and QTc intervals.

Rationale for Using Placebo
SADHART and ENRICHD had not been published in June of 2001, when CREATE received funding. However, their results, discussed earlier, have not changed the fact that there is no established reference treatment for depression in patients with CAD. The comparison "standard" still needs to be established in the trial itself. This can only be done by demonstrating that the efficacy and tolerability of citalopram and/or IPT are superior to treatment with a pill-placebo and/or psychotherapy control condition.

The CREATE protocol has several built-in safeguards to assure the well-being of patients in all arms of the trial. No patients at serious risk of suicide or who are known to be intolerant or nonresponsive to citalopram or to two other SSRIs will be included. For those in the trial, weekly contact with therapists (see following section) assures that signs of significant worsening of depression or cardiac status are noted early so that appropriate action can be taken.

Rationale for Clinical Management (CM)
To our knowledge, CM is the best standard control condition for testing the efficacy of psychotherapy (22). CM is a manualized intervention that involves structured, standardized provision of what a psychopharmacologist would do during 15- to 20-minute weekly sessions in order to evaluate the course of depressive symptoms and monitor medication side effects. Because we are dealing with patients with comorbid cardiac disease, the CM session also included structured questions about cardiac symptoms. Therapists are taught to carry out CM avoiding psychotherapeutic interventions such as giving suggestions about approaches to handling day-to-day problems and making interpretations of patient behavior. The guidelines used for training clinical managers were developed for the National Institute of Mental Health (NIMH)-TDCRP (Treatment of Depression Collaborative Research Program) study (23) and modified at the University of Pittsburgh (24).

	METHODS

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 
Overview
CREATE is a 2-by-2 factorial trial with patients randomly assigned to receive 12 weekly IPT sessions or 12 weekly sessions of standardized CM. Patients are also randomly assigned to receive 20 to 40 mg per day of citalopram or pill-placebo. This results in four treatment groups: (1) IPT plus pill-placebo; (2) IPT plus citalopram; (3) CM plus pill-placebo; and (4) CM plus citalopram.

Selection Criteria
Inclusion Criteria

1. Diagnostic and Statistical Manual-IV diagnosis of current major depressive episode based on the Structured Clinical Interview for Depression (SCID) (25) with at least 4 weeks’ duration;
   
2. Baseline score >19 on the centralized, telephone-administered, 24-item HAM-D (10);
   
3. Evidence of CAD based on hospital chart evidence of a previous hospitalization for acute myocardial infarction, or coronary angiographic evidence of 50% blockage in at least one major coronary artery, or previous revascularization;
   
4. Stable CAD based on physician’s clinical judgment;
   
5. Provision of informed consent.
   

Exclusion Criteria

1. <18 years of age;
   
2. Coronary bypass surgery planned during the next 4 months;
   
3. Canadian Cardiovascular Society Angina Class (CCS) = 4 (26);
   
4. SCID (25) documented bipolar disorder, major depression with psychotic features, or evidence of substance abuse or dependency during the previous 12 months;
   
5. Serious suicide risk based on clinical judgment;
   
6. Use of antidepressants, lithium, or anticonvulsants for mood disorder;
   
7. Currently undergoing any form of psychotherapy;
   
8. Absence of response to a previous adequate trial of citalopram or IPT;
   
9. Two previous unsuccessful trials of treatment for depression for the index episode;
   
10. Lifetime history of early termination (<8 weeks) of citalopram because of adverse events or side effects;
    
11. Lifetime history of early termination (<8 weeks) of two other SSRI antidepressants (paroxetine, fluoxetine, fluvoxamine, sertraline) because of adverse events or side effects;
    
12. Significant cognitive problems (Mini-mental Status Exam; MMSE (27) <24);
    
13. Depression due to a general medical condition based on clinical judgment;
    
14. Participation in other trials;
    
15. Inability to speak English or French;
    
16. Investigator’s judgment that a patient is unable or unwilling to comply with the study regimen.
    

Recruitment
CREATE is a multisite trial with recruitment originally planned in Montreal, Kingston, Ottawa, and Toronto. Because of slower-than-expected accrual, sites in Halifax and Calgary were added. Ethics approval was obtained from each hospital before beginning at each site, with the first patient randomized on May 1, 2002, in Montreal.

Recruitment methods are site specific and involve a combination of systematic screening; targeted advertisements in outpatient cardiac clinics, rehabilitation centers, and hospital wards; media advertisements; and referral from cardiologists, internists, psychiatrists, or general practitioners. Although sample generalizability is important, according to the NIMH (28), it is a secondary question that should be considered in very large inclusive trials, only after the initial questions of efficacy and tolerability are answered.

Assessment and Randomization Procedures
Eligibility Assessments and Baseline Measures
To confirm study eligibility, following provision of informed consent, the SCID for Axis I Disorders module (25) and the MMSE (27) are administered by a trained clinician at the eligibility assessment. The baseline interview also includes an assessment of sociodemographic and medical history variables, current medications, and cardiac risk factors. Height, weight, and supine systolic and diastolic blood pressures are measured. Patients have a 12-lead ECG and a blood test for thyroid function. Following these assessments, patients complete a telephone-administered interview in which the 24-item HAM-D is administered. If patients score >19 on the centralized rating, they are eligible for study participation and are given an appointment for their first therapy session, at which time randomization takes place.

Randomization
Following the completion of the first CM session with each patient, therapists telephone the coordination center to determine the patient’s study group assignment. Eligibility criteria are verified by telephone and fax before randomization. Randomization is stratified by therapist and involves two separate randomizations: one to CM and IPT versus IPT only and the other to Citalopram versus pill placebo. The pill placebo is matched in size and appearance to Citalopram, and this portion of the trial is completed in a double-blind fashion, with therapists, patients, telephone raters, and personnel at the coordinating center blind to patients’ group assignment. Specially prepared code-break cards are provided to the pharmacies at each participating site for the rare cases in which the randomization code of the medication must be broken before the end of the trial to assure adequate care. As a partial check on the preservation of the blind, at the end of the trial patients and therapists are independently asked to guess whether the patient received active medication or placebo.

Efficacy Measures
Recent reports have questioned the design of antidepressant studies in which treating clinicians, supposedly blind to treatment group, are responsible for rating the improvement of their patients (29). This is an even greater problem in a psychotherapy trial in which clinicians cannot be blind. Therefore, the primary efficacy measure in CREATE, the 24-item HAM-D, is administered centrally by telephone at baseline, 6, and 12 weeks by a trained clinical psychologist blind to treatment group. The rating calls are audiotaped for monitoring purposes. We based our approach on that adopted for the large NIMH-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial (30), and our raters participated in a workshop led by the STAR*D Rating Center Coordinator. For exploratory purposes, the Inventory for Depressive Symtomatology (IDS) (31) is also rated during the centralized assessments. The secondary efficacy measure, the self-report Beck Depression Inventory-II (BDI-II) (32), is administered at baseline, 6, and 12 weeks, along with measures of social support (the Interpersonal Relationship Inventory (IPRI) (33) and network items from the RAND health studies (34)) and functioning in daily activities (the Functional Performance Inventory [FPI] (35)). The Montgomery-Åsberg Depression Rating Scale (MADRS) (36) is completed weekly by IPT/CM therapists as part of CM to allow for close monitoring of depression severity but is not intended as a primary or secondary outcome.

Therapy Process Measures
All CM and IPT therapy sessions are audiotaped for quality control, with separate recordings for the CM and IPT sessions for the IPT patients. After patients have competed all study measures, three CM tapes for both IPT and CM therapist-patient dyads and three IPT tapes for the IPT patients are randomly selected from an early (sessions 1–4), middle (sessions 5–9), and late (sessions 10–12) session and reviewed by an independent, blind rater. The integrity of treatment is rated with 15 items assessing IPT, CM, and general therapy characteristics selected from the Collaborative Study Psychotherapy Rating Scale developed for the NIMH-TDCRP study (13). Following the third session of CM or IPT, patients complete the California Psychotherapeutic Alliance Scale (CALPAS) (37) in order to assess aspects of therapeutic alliance. Finally, at the end of IPT sessions 3 and 12, therapists are asked to identify the primary (and secondary, if appropriate) IPT problem focus.

Treatment Procedures
Drug Administration
Patients take study medication (citalopram or pill-placebo) once daily or in divided doses if necessary. Medication is provided as tablets of 20 mg or 40 mg of citalopram or pill-placebo. All patients start on a half dose of 10 mg, and, if there are no clinically significant side effects, the dose is increased to 20 mg after 1 week. If the centralized HAM-D at 6 weeks is not 8, the dose is increased to 40 mg for the duration of the study.

Concomitant Psychotropic Medication
Because changes in use of benzodiazepines could influence symptoms of depression, every attempt is made to avoid new prescriptions of benzodiazepines. Patients already on stable doses of benzodiazepines are maintained on the same dose in order to avoid withdrawal difficulties. Diphenhydramine or zopiclone is allowed for major sleep difficulties.

IPT and CM
Both IPT and CM patients take part in weekly, individual CM sessions involving a brief structured review of side effects and progress that lasts 15 to 20 minutes. These sessions are administered by the IPT therapists, who have been trained to evaluate side effects and cardiac symptoms, and are supervised by the site principal investigators.

IPT is administered over 40 to 60 minutes on a weekly basis by a certified IPT therapist who follows the treatment manual developed by Klerman et al. (11) and Weissman et al. (38). The intervention was slightly adapted to meet the needs of depressed CAD patients (39), including a 12-week duration of therapy instead of the usual 16 weeks to decrease the time maintaining patients on a placebo and also to decrease the study burden on patients in order to maximize the rate of treatment completion. IPT sessions immediately follow structured CM. To facilitate participation in the intended 12 IPT sessions, up to four sessions may be conducted by telephone if needed.

Certification and training of all therapists, and blind rating of IPT tapes (see below) is carried out by the Therapist Training and Rating Center at the University of Ottawa. Because of their isolation from other team members, therapists from all sites participate in monthly conference calls with each other and PIs trained in IPT.

Termination
In the next few days after the 12-week visit, all patients have a follow-up appointment with a psychiatrist for continued treatment. To assure optimal care, the code of the study medication is broken by the coordinating center and the information provided to the psychiatrist before the follow-up visit. However, because the outcome assessment is done centrally and before the poststudy visit, the risk of contamination from breaking the blind is minimal. Psychiatrists are requested not to divulge the group assignment to therapists or other study personnel, and all study personnel are cautioned not to discuss any patient data with raters.

Protocol Compliance
All efforts are made to maintain noncompliant patients in their assigned groups, including having a flexible visit schedule in case of worsening of the cardiac condition or other constraints. If necessary, patients are allowed to continue with either medication (citalopram/placebo) only, or just IPT/CM. If a patient refuses to continue to participate with either of these treatments (CM/IPT or citalopram/placebo) or is discontinued from the trial for any other reason, we make every attempt to perform the 6- and 12-week telephone assessments as planned. All patients who do not complete the 12-week trial are referred for continued treatment of their depression, if they so desire.

Tolerability and Safety
Nonserious and serious adverse events (SAEs) are systematically screened at all visits. The term adverse event covers any unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the study. SAEs include any change in medical condition that leads to death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/incapacity, or is judged to be medically important, including significant worsening of depression or suicide attempts or ideation requiring any revision of antidepressants. An event committee, blind to treatment allocation, verifies the classification of SAEs. The safety of citalopram and IPT will be assessed by comparing them with their respective control conditions in terms of rates of SAEs over the study period. The tolerability of citalopram and IPT will be assessed by comparing them with their control conditions in terms of rates of nonSAEs.

Platelet Substudy
Evidence is mounting that depression and CAD share many pathophysiological mechanisms, including inflammation, endothelial dysfunction, and platelet activation. It has been suggested that SSRIs may modulate these processes (40). The platelet substudy will assess the effects of citalopram, IPT, and placebo on levels of P-selectin, ß-thromboglobulin, soluble intercellular adhesion molecule (sICAM-1), and nitric oxide synthase in 60 CREATE patients recruited from sites in Montreal, Kingston, and Calgary. Patients involved in the platelet substudy are asked to sign a separate informed consent for participation.

Sample Size and Data Analysis
Sample Size
The aim is to reject the null hypothesis and to conclude that patients in each active treatment, i.e., citalopram and IPT, have a significantly greater improvement in depressive symptoms than patients in their respective control condition. According to Cohen (41), a unique benefit of 2-by-2 factorial designs is that because both the main effects and interaction each have 1 degree of freedom, a study that is powered to detect a given main effect size will also have the same power to detect an interaction of the same effect size. It does not, however, assure the same power to compare the subgroups involved in the interaction. This would require a significantly larger number of subjects, and 2-by-2 studies that specifically seek to test interaction effects need to be powered to make these comparisons. However, we do not expect that there will be a clinically significant interaction between the treatments, i.e., no mitigating or multiplying effects when combined. That is, we expect that IPT and citalopram will have some additive effects (as recently observed for nefazodone and the "cognitive- behavioral-analysis system of psychotherapy" in the treatment of chronic depression (42)).

Power calculations involve the following additional assumptions: (1) experiment-wise = 0.05; (2) two-sided tests; (3) ability to detect medium effect sizes for main effects of treatments and their interaction; (4) analyses based on intent-to-treat principle with all randomized patients included and every attempt made to obtain 12-week assessments on patients not completing the full 12-weeks of treatment; (5) adjustment for loss of final assessment of not more than 10% (n/0.90); (6) adjustment for noncompletion of 12 weeks of treatment of not more than 15% in each group (n/((1–0.15)²) (43); and (7) adjustment for multiple outcomes (44).

Studies available at the time of study design in 2001 suggested that standard deviations on the clinician-administered versions of the 17- and 24-item HAM-D in intent-to-treat analyses of clinical trials involving antidepressants and psychotherapy are in the range of 4 to 8 (13,16). Data from the available open-label treatment studies of depressed post-MI and heart failure samples were similar (45,46). Therefore, an effect size of 0.5 (medium effect size) in changes between treatment and control would be equivalent to detecting a difference of between 2 and 3 points on the scale. We reasoned that a difference smaller than this would not likely be of sufficient clinical significance to justify the additional treatment burden for patients already taking a multitude of other medications. Although SADHART recently reported a smaller effect size than this with sertraline treatment in CAD patients (less than 1 point on the HAM-D) (8), the recently published National Institute for Clinical Excellence guidelines for management of depression in the United Kingdom (47) concluded that changes smaller than 2 to 3 points on the HAM-D are of questionable clinical significance.

Because the HAM-D is the primary study outcome variable, supplemented with the secondary outcome of the BDI-II, we considered the impact of multiple outcomes on sample size. Both indices are intercorrelated measures of depression severity. It has been suggested that a simple Bonferroni correction for the number of outcomes is overly conservative, particularly in situations in which there is fairly high correlation among the different measures (48). Therefore, we have used the approach suggested by Davis (44). In order to assure a studywise error rate <0.05, we need to test the primary outcome (HAM-D) at p .033 and the secondary outcome (BDI-II) at p .017.

Based on program SamplePower (49), combining these adjustments with a correction for a 10% loss of final assessment and a 15% rate of noncompletion means that randomizing 70 patients per cell (total n = 280) will assure a power of at least 0.87 for detecting medium effect sizes for both IPT and citalopram, as well as their interaction, in the primary outcome at p .033. This number of patients will also assure a power of at least 0.80 for detecting medium effect sizes on the secondary outcome at p .017.

Analyses
Our primary efficacy analysis will compare treatment conditions on the mean difference between baseline and 12-week scores on the 24-item HAM-D. Because of the telephone rating system, we expect few missing final assessments on the primary outcome. Nonetheless, we will compare the baseline characteristics for patients lost to follow-up with those of the patients who complete assessments to help assure that loss to follow-up has not biased study results. For missing 12-week measures, we will adopt the traditional last observation carried forward (LOCF) approach and use the 6-week assessment as the final measure. The secondary efficacy measure will be the BDI-II, again using LOCF. Each outcome will first be assessed using a 2-by-2 analysis of covariance to evaluate the main effects and interaction of IPT and citalopram on 12-week scores after controlling for baseline measures. If, as expected, the interaction is not significant, the interaction terms will be dropped from the analyses.

Several additional exploratory analyses will be carried out, including (1) assessment of efficacy using baseline, 6-, and 12-week changes on the IDS; (2) analysis of data at 6 weeks for all randomized patients (if results differ from those at 12 weeks, there will be additional investigation of time effects); (3) comparison between each active treatment and its respective control group in terms of the percentage of asymptomatic patients at the end of treatment; (4) multiple linear and logistic regression approaches will be used to explore the moderating or mediating impact of the following factors on continuous measures of treatment response: previous depression, comorbid anxiety disorders, global cognitive functioning as measured by the MMSE (27), social support measured by the IPRI (33), and functional performance (FPI) (35). Although not included in the original protocol, because of evidence of sex differences in the efficacy of therapy in ENRICHD (50), we will explore the potential moderating role of patient sex.

Study Structure
The organizational structure of the trial (see appendix) includes a steering committee, whose members participate in monthly conference calls, an event committee, and a data safety monitoring board (DSMB). Although the chair of the DSMB was chosen by the steering committee, the chair selected the members of the DSMB without the input of the committee, and the DSMB has the mandate to function independently to recommend stopping the trial early if it is judged appropriate to do so. The DSMB will monitor study progress and safety data after the completion of 50 and 140 patients or at any other time deemed appropriate by the DSMB.

	CONCLUSION

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 
Despite the high prevalence of CAD and of depression in CAD patients, as well as the clearly harmful consequences of the combination of the two conditions, depressed CAD patients’ access to mental health resources is limited. Many depressed CAD patients are never diagnosed, and even when diagnosed, treatment options are unclear. We believe that by demonstrating the effectiveness of citalopram, IPT, or both as tolerable and safe treatments for depression, a major milestone will have been reached in assuring proper care of depressed CAD patients.

	Appendix: Create Investigators and Clinical Centers

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 
Study Chair and Cochair

François Lespérance, MD (Chair), and Nancy Frasure-Smith, PhD (Cochair)

Steering Committee Members

François Lespérance, MD; Nancy Frasure-Smith, PhD; Diana Koszycki, PhD; Marc-André Laliberté, MD; Louis T. van Zyl, MD; Brian Baker, MBChB; Susan Abbey, MD; John Robert Swenson, MD; Kayhan Ghatavi, MD; Jean Leblanc, MD; Beth L. Abramson, MD

Coordinating Center (Montreal Heart Institute)

Ginette Gravel, MSc (coordinator); Johanne Lalancette; Martine Habra, PhD

Therapist Training and Rating Center (University of Ottawa)

Diana Koszycki, PhD (director); Manon Bertrand;

Centralized Depression Raters

Lana Pratt, PhD; Wendy Smith, PhD; Manon Bertrand; Jennifer Ellison; Marie-Pierre Leduc, MSc

Centralized ECG Rating (St. Michael’s Hospital, Toronto)

Beth L. Abramson, MD

Events Committee

Paul Dorian, MD; François Lespérance, MD

Study Biostatisticians (Montreal Heart Institute)

Jean Lambert, PhD; Marie-Claude Guertin, PhD

Data Safety Monitoring Board (University of Florida, Gainesville)

David S. Sheps, MD, MSPH (Chair); Pierre Blier, MD; Sue McGorray, MD

Citalopram/Placebo Coordination (Lundbeck, Canada)

Jean Proulx

Consultants

Charles F. Reynolds, III, MD (University of Pittsburgh); Melanie M. Biggs, PhD (University of Texas Southwestern Medical Center, Dallas)

Clinical Centers

Montreal Heart Institute (Montreal): Marc-André Laliberté, MD (PI); François Lespérance, MD; Marie-Pierre Leduc, MSc; Aline Masson, MSc; Elaine Kennedy, MPs; Sylvie Bouchard, PhD; Sacré-Cur Hospital (Montreal): Jean Leblanc, MD (PI), Jocelyne Julien, MPs; Line Roy; Kingston General Hospital: Louis T. van Zyl, MD (PI), Joan Bowie; Pilsu-qua Lloyd; Hotel-Dieu Hospital (Kingston): Susan Finch, MD; Joan Bowie; Paul Kasurak, MSW; Pilsu-qua Lloyd; Bethmarie Michalska, MA; Eleanor Rosenzweig, MSW, MTS; Paul Kasurak, MSW; St. Michael’s Hospital (Toronto): Beth L Abramson, MD; Shree Bhalerao, MD; Paul Dorian, MD; Laurie Gillies, PhD; Edward McAnanama BMR(OT), MEd, MSc; Lara Ross; Brigitta Zile; Ottawa Heart Institute: John Robert Swenson, MD (PI); Rebecca Cohen, PhD; Élyse Sévigny; J. David Smith, PhD; Calgary Health Region: Margaret Oakander, MD (PI); Maureen Milligan, PhD; MSW; Bette Moxham; Linda Seyler; Queen Elizabeth II Health Science Center (Halifax): Kayhan Ghatavi, MD (PI); Gordon Butler, PhD; Bonnie Moore; University Health Network (Toronto): Brian Baker MBChB (PI); Susan Abbey, MD.

Platelet Substudy

Louis van Zyl, MD (PI); François Lespérance, MD; Victor Serebruany, MD

	NOTES

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 

Received for publication May 10, 2005; revision received August 2, 2005.

DOI:10.1097/01.psy.0000195833.68482.27

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS CONCLUSION Appendix: Create Investigators... NOTES REFERENCES

 

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