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Considerations on the Stigma of Mental Illness
Julio Arboleda-Flórez
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Stigma and the Daily News: Evaluation of a Newspaper Intervention
Heather Stuart
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Interventions to Reduce the Stigma Associated With Severe Mental Illness: Experiences From the Open the Doors Program in Germany
Wolfgang Gaebel, Anja E Baumann
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Determinants of the Public’s Preference for Social Distance From People With Schizophrenia
Matthias C Angermeyer, Michael Beck, Herbert Matschinger
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Addiction: A Disease of Volition Caused by a Cognitive Impairment
William G Campbell
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Defining Anxious Depression: Going Beyond Comorbidity
Peter H Silverstone, Erica von Studnitz
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Psychiatric Distress Among Road Rage Victims and Perpetrators
Reginald G Smart, Mark Asbridge, Robert E Mann, Edward M Adlaf
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Risk of Weight Gain Associated with Antipsychotic Treatment: Results From the Canadian National Outcomes Measurement Study in Schizophrenia
Roger S McIntyre, Kostas Trakas, Daryl Lin, Robert Balshaw, Pieway Hwang, Kimberly Robinson, Andrew Eggleston
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An Open-Label Study of Nefazodone Treatment of Major Depression in Patients With Congestive Heart Failure
François Lespérance, Nancy Frasure-Smith, Marc-André Laliberté, Michel White, Sylvain Lafontaine, Angelino Calderone, Mario Talajic, Jean-L Rouleau
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Subtypes of Schizophrenia: A Cluster Analytic Approach
Edward Helmes, Jhan Landmark
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Counselling Problem Gamblers: A Self-Regulation Manual for Individual and Family Therapy.
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Bongs, a Method of Using Cannabis Linked to Dependence

Obsessive–Compulsive Symptoms in Schizophrenia Induced by Risperidone and Responding to Fluoxetine

Lengthy Period of Incarceration as Personal Treatment Goal

Autoamputation in Psychosis: Diagnostic Issues

A Preliminary Report on Substance Use Patterns in an Adolescent Psychiatric Population

Facialis Palsy Attributable to Depot Antipsychotic Therapy

Recognizing Complicated Grief in Clinical Practice

Original Research

An Open-Label Study of Nefazodone Treatment of Major Depression in Patients With Congestive Heart Failure

François Lespérance, MD¹, Nancy Frasure-Smith, PhD², Marc-André Laliberté, MD³, Michel White, MD⁴, Sylvain Lafontaine, MD⁵, Angelino Calderone, PhD⁶, Mario Talajic, MD⁷, Jean-L Rouleau, MD⁸

Depression is associated with worse cardiac prognosis following hospitalization for myocardial infarction (MI) (1–3), unstable angina (4), cardiac catheterization (5), bypass surgery (6), and congestive heart failure (CHF) (7). It is increasingly clear that we need to know more about appropriate treatments for depression in patients with coronary artery disease (CAD). Because most clinicians agree that tricyclic antidepressants should be used with great caution in patients with heart disease (8), investigators have started to evaluate newer antidepressants. Small, open-label trials (9,10) followed by larger, randomized trials (11–13) with selective serotonin reuptake inhibitors (SSRIs) have been conducted in patients with CAD. The study results suggest sufficient tolerability, safety, and efficacy to proceed with larger, randomized, placebo-controlled trials to document the impact of these medications on cardiac prognosis.

However, to justify such a mortality trial, some prior documentation of a beneficial impact of antidepressants on at least one of the presumed underlying mechanisms linking depression with cardiac mortality (such as increased sympathetic nervous system activity) is essential. Also, for a study to be feasible with a reasonable sample size, it is crucial to demonstrate the potential benefits of the medication in a subgroup at greatest risk for mortality, such as CHF patients.

Among the mechanisms hypothesized to explain the impact of depression on cardiac mortality, increased activity of the sympathetic nervous system is of particular interest. Increased noradrenergic outflow is associated with worse prognosis in post-MI patients (14) and in patients with CHF (15,16). In patients without known cardiac disease, major depression is associated with elevations in basic heart rate (17), plasma norepinephrine, and norepinephrine metabolites (18), and also with increased norepinephrine secretion (17), relative to control subjects without depression. Although increased plasma norepinephrine levels have not yet been confirmed among CAD patients with depression, there is evidence of an increased resting heart rate and decreased heart rate variability (HRV) (19), suggesting at least some dysregulation of the sympathetic nervous system.

Nefazodone is one of the new generation of antidepressants synthesized and marketed to replace the older tricyclics. However, its chemical structure is unrelated to the SSRIs. It acts primarily as a 5-HT2 receptor antagonist. Because another 5-HT2 receptor antagonist, ketanserin, has been reported to lower blood pressure and to reduce sympathetic activation during exercise (20,21), we hypothesized that nefazodone might share some of the pharmacologic properties of ketanserin and be particularly beneficial for CHF patients suffering from depression.

In this context, we undertook an open-label pilot study to evaluate the feasibility of screening and recruiting patients with CHF who meet DSM-IV criteria for current major depression. We aimed to obtain preliminary data on the safety and efficacy of nefazodone treatment of patients with CHF who suffer from depression. We also aimed to explore nefazodone’s impact on catecholamine levels and HRV in patients with CHF.

Methods

The SErzone Antidepressant Remedy in Congestive Heart Failure (SEARCH) trial was an investigator-controlled and initiated, peer-reviewed, open-label study of 12 weeks of nefazadone treatment. The study was approved by the Ethics Board of the Montreal Heart Institute on July 9, 1997.

Selection Criteria
Subjects were eligible if they were aged 18 years or over; currently under treatment for CHF with a Class II or III functional capacity according to the New York Heart Association (NYHA) classification; had a left ventricular ejection fraction of 40% or less documented within the previous 6 months; had a current episode of major depression confirmed by the Structured Clinical Interview for DSM-IV (SCID) (22); and had a baseline score of 15 or more on the 17-item Hamilton Depression Rating Scale (HDRS) (23). Patients were excluded if they had experienced an acute MI, coronary angioplasty, or bypass surgery within 2 months of study entry, unless the CHF predated the MI or the procedure. They were also excluded if they were likely to receive a cardiac transplant in the next 3 months or if they had any of the following symptoms: orthostatic hypotension (defined as a symptomatic or greater than 20 mm Hg drop in systolic blood pressure, with supine systolic pressure less than 90 mm Hg); uncontrolled hypertension (defined as systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 100 mm Hg); a resting heart rate of 50 bpm or less; a serum creatinine level greater than 250 µmol/L; digoxin levels of 1.5 nmol/L or higher; uncorrected hypo- or hyperthyroidism; or clinically significant hepatic disease. They were also not eligible if they were currently under antidepressant or lithium treatment; were at serious risk for suicide; had a DSM-IV diagnosis of bipolar I disorder, substance abuse, or substance dependence, either currently or within the past 6 months; were currently involved in another medication trial; or had any other medical condition likely to reduce their survival to less than 6 months.

Recruitment Procedures
Potential patients were recruited from 2 sources: CHF patients hospitalized at the Montreal Heart Institute and patients treated in the outpatient clinic between August 1997 and May 1999. Hospitalized CHF patients with ejection fractions of 40% or less and not meeting any exclusion criteria were asked to provide informed consent for screening of depression with the self-report Beck Depression Inventory (BDI) (24). We asked patients with a BDI score of 10 or higher (indicating possible depression) to come back after discharge for further evaluation by one of the study psychiatrists. Other potentially eligible CHF patients were identified through chart searches of patients seen at the outpatient clinic and were contacted by telephone with the consent of their treating cardiologists. After we explained the project, we asked them to participate in a short telephone screening interview, the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire (25). We asked those who screened positively for depression to come to an outpatient appointment to learn more about the study and to be more completely evaluated. At the outpatient appointment, we asked those subjects meeting SCID-based DSM-IV criteria for major depression and all other study criteria to sign a consent form to participate in the baseline assessment and to start the medication.

Drug Administration
Nefazodone was provided as commercial tablets of 100 mg. The starting dosage of 50 mg daily was increased to 100 mg after 4 days; it was then increased gradually to 400 mg (200 mg twice daily) by the 4-week visit, regardless of the clinical response at a lower dosage. However, in the event of nefazodone dosage-related side effects, we allowed down titration. When response was insufficient, and if tolerated, the dosage was increased to a maximum of 600 mg daily. At each visit, we recorded all medications taken by the patient and assessed compliance by a pill count.

Concomitant Medications
CHF patients usually take many medications. Although nefazodone is a potent inhibitor of the CYP450 IIIA3/4 enzyme responsible for the metabolism of calcium channel blockers and most statins (26), we allowed concomitant use of these medications, provided that patients were closely monitored. Terfenadine, astemizole, cisapride, and ketoconazole were prohibited. We assessed international normalized ratios (INR) at baseline and at each follow-up visit for monitoring patients on coumadin, an anticoagulant. Patients on digoxin had their serum levels monitored at each visit following an increase in dosage of either nefazodone or digoxin. Increases or new prescriptions of benzodiazepines were not allowed.

Assessment Procedures
In addition to completing baseline assessments, we asked patients to come for follow-up visits at weeks 1, 2, 4, and 8 and to participate in the final evaluation at 12 weeks. The efficacy measures at baseline and at each follow-up visit included the 17-item HDRS (23) and the Clinical Global Impression Scale (CGI), rated by one of the study psychiatrists, along with the self-report BDI (24), completed before seeing the psychiatrist. Two other self-report measures of efficacy, the State version of Spielberger’s State-Trait Anxiety Inventory (S-STAI) (27) and the Minnesota Living with Heart Failure Questionnaire (LIhFE) (28) were completed at baseline and at the last visit. Other baseline measures included sociodemographic and medical history data, a physical exam, a 12-lead ECG, and a symptom checklist to identify emerging adverse events. Patients had a 24-hour Holter recording, and a fasting blood test was taken for standard biochemical analyses and plasma norepinephrine levels. The physical exam, 12-lead ECG, blood tests, and Holter were repeated at the final visit.

Medical personnel carefully monitored patients for adverse events at each visit. Patients were discontinued from the study at any time if their depression worsened significantly, if they experienced adverse events of such severity that the therapeutic benefit of continued treatment with nefazadone was outweighed, if they deviated from the protocol concerning concomitant medication or compliance, or if they wanted to discontinue for any reason.

Fasting blood samples were taken in the morning at baseline and at follow-up. Prior to blood sampling, patients rested comfortably, lying down for 30 minutes in a quiet, darkened room. Plasma levels of norepinephrine were measured using standard technique (29). Plasma was frozen to –80EC until it was measured by means of an isocratic HPLC system (Gibson, Middleton, US). An experienced cardiologist analyzed all ECGs. Many patients had atrial fibrillation or pacemakers, and we therefore calculated heart rate, QT, QTc, and QRS separately, rather than using measures automatically generated with the ECG printout.

We installed 2-channel Holter monitors, using 5 leads and the standard technique. We analyzed tapes using a Marquette Holter Analysis System; a technician screened and corrected this automated analysis. Records with excessive ectopy (more than 30%) were discarded, as were recordings of less than 18 hours. We analyzed time-domain measures of HRV on the resulting normal RR intervals, using successive 5-minute segments of data.

Statistical Analysis The primary efficacy measure was the HDRS score at week 12 or the last observation, if it occurred before then. We carried out efficacy analyses on those patients who had at least 4 weeks of medication. We used paired t-tests to assess mean changes between baseline and final assessment in all continuous outcome measures.

Results

Sample
A total of 443 CHF patients were screened for depression with either the BDI during hospitalization or the PRIME-MD by telephone. Of these, 103 had positive screening scores and were evaluated using the SCID. Of these, 62 had a confirmed diagnosis of major depression; 28 met other study criteria and began study medication. The most frequent reasons for nonparticipation were left ejection fraction greater than 40% (n = 11), alcoholism (n = 3), and refusal to participate in the treatment phase (n = 11). Diverse reasons led to the exclusion of the other 10 patients.

The final sample included 20 men and 8 women, with a mean age of 59.6 years (range 37 to 77). On average, patients had completed 10 years of schooling; 64% (n = 18) were married or living with someone. The mean left ventricular ejection fraction was 29.3% (range 13% to 40%). The study cardiologist classified 18 patients as Class II and 10 as Class III, according to the NYHA classification. All but 3 patients had ischemic heart disease as the primary cause of their CHF.

Most patients (n = 19) were experiencing their first episode of major depression; 4 had a current diagnosis of comorbid panic disorder, and 2 had generalized anxiety disorder. Some 32% (n = 9) smoked daily.

All but 1 patient were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers, 22 were on diuretics, 16 on statins, 12 on beta blockers, 11 on amiodarone, 7 on long-lasting nitrates, 11 on potassium supplements, 9 on warfarin, and 6 on calcium channel blockers. On entering the study, 16 patients were taking benzo- diazepines. On average, patients were taking 10 different medications daily.

Dropouts and Adverse Events
Of the 28 subjects who began the study medication, 5 dropped out before week 4: 1 for noncompliance; 1 for dizziness and impotence; 1 for dizziness, nausea, and headaches; 1 for sedation and blurred vision; and 1 who had to be hospitalized for worsening of CHF. (This last patient was on the waiting list for heart transplantation at the time of the baseline assessment, but he was not expected to receive a transplant within the following 3 months. However, he did receive a transplant during that hospitalization, and he was eventually discharged. The worsening of his CHF was not attributed to study medication.) Thus, 23 patients completed the predetermined minimum 4 weeks’ treatment required for inclusion in the efficacy end point analyses. However, 4 more patients dropped out before completing 12 weeks of treatment: 1 because of noncompliance; 1 because of nightmares; 1 because of CHF overload due to a probable interaction with amlodipine; and 1 because of dizziness, fatigue, and diarrhea. A total of 19 subjects had final measures taken after 4 weeks on medication and were included in the safety analysis (Table 1).

There were no deaths during the study period, although 1 patient had to be hospitalized for bacterial bronchopneumonia. Because this adverse event was not thought to be secondary to nefazodone treatment, the patient continued in the study. Among the 23 patients who completed at least 4 weeks of treatment, the mean dosage of nefazodone was 276 mg daily, with a median dosage of 300 mg daily (range 50 mg to 600 mg).

Efficacy
For those who completed at least 4 weeks of treatment, the baseline and end-of-follow-up mean scores for the HDRS, CGI, BDI, STAI, and LihFE scales appear in Table 2 (last observation carried forward, n = 22 for self-reports and n = 23 for clinician ratings). There was significant improvement on all depression scales, as well as on the quality-of-life measure, but there was no change in the measure of anxiety. Some 74% of the patients who completed treatment were responders (that is, their HDRS scores declined by 50% or more), and 21.7 % were partial responders (that is, their HDRS scores declined by 25% to 49%). Finally, at the end of treatment, 52% were in remission with a final HDRS score of less than 7.

Vital Signs and Cardiovascular Measures
Table 1 includes the baseline and final values of the cardio- vascular measures for the 12-week completers. The 19 subjects who completed the trial and were on nefazodone at the time of the 12-week ECG showed a small decrease in heart rate and a small increase in QT and QRS, but not in QTc, intervals. The observed reduced heart rate may explain these increases. To further explore this important issue, we obtained the first available ECG for these 19 subjects after they were withdrawn from nefazodone. We found that the mean heart rate, QT, and QRS intervals returned to their baseline value, indicating that the observed increase in QT and decrease in heart rate were likely due to exposure to nefazodone.

HRV measures based on 24-hour Holter recording at baseline and the last visit were available for 16/19 patients who completed 12 weeks of treatment. Two of the completing patients did not have Holter data because they had pacemakers, and 1 because of atrial fibrillation. Unlike the ECG data, the Holter recordings showed no evidence of significant changes in any of the frequency domain measures of HRV.

Interestingly, we found a trend toward reduced norepine- phrine levels for the 19 completers.

Discussion

We planned this small, 12-week, open-label trial to collect preliminary efficacy, tolerability, and safety data on nefazodone treatment of major depression in patients with CHF and to explore nefazodone’s impact on plasma norepinephrine levels and HRV.

Although anticipated, we found that, to enrol 28 subjects, we had to screen a large number of CHF patients. Only about 6% of patients with CHF had a major depressive episode, were otherwise medically eligible, and agreed to participate. Screening procedures to enrol subjects in clinical trials are notoriously labour-intensive, and antidepressant trials among patients with comorbid heart conditions make the process even more difficult. For example, researchers in the largest randomized trial on post-MI depression, the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial (30), had to screen 32 246 patients who met study criteria for MI to randomize 1834 subjects with depression to cognitive- behavioural therapy or usual care. Similarly, the Sertraline AntiDepressant Heart Attack Random Trial (SADHART) screened 3355 post-MI or unstable angina patients to randomize 369 patients (13). This represents 6% to 10% of eligible patients, whereas rates of depression in this population are estimated to be around 15% to 20% (2,4,7). Therefore, although feasible, clinical trials targeting the depression- related increase in mortality among patients with CHF would be very expensive.

To evaluate the potential benefit of antidepressants among patients with heart disease, we deliberately selected patients with a severe medical condition: these patients have the greatest potential to demonstrate a decrease in depression-related cardiac mortality. However, only 19 patients (67%) completed the 12-week trial. Although this is not very different from the 71% reported by Glassman and colleagues in their SADHART trial involving post-MI and unstable angina patients with less severe cardiac conditions treated with sertraline (13), it is somewhat lower than the 90% reported by Roose and others for stable CAD patients treated with paroxetine (12). However, Roose and others’ study was only 6 weeks long, with enrolled patients having a mean left ventricular ejection fraction of 58%, whereas the mean in our sample was 29%. Therefore, given the differences in disease severity between the samples, it seems likely that nefazodone had tolerance rates similar to those of the SSRIs.

Keeping in mind the limitations of our open-label design, nefazodone was associated with a significant improvement in depressive symptoms: the response rate was 74%, with 52% of patients experiencing remission after 12 weeks of treatment. These rates are similar to Roose and others’ 68% response rate according to the HDRS, with 61% in remission at the end of 6 weeks (12). Similarly, a 67% response rate according to the CGI and a mean drop of 8.4 points on the HDRS was reported in the SADHART trial for patients randomized to sertraline (13). In comparison, patients randomized to placebo experienced a 53% response rate on the CGI and a mean drop of 7.6 points on the HDRS—a difference with unclear clinical significance. Clearly, placebo-controlled trials are not only ethically justified but also scientifically necessary to establish efficacy. Until a larger, placebo-controlled trial of nefazodone is published, sertraline remains the antidepressant with the most convincing cardiovascular safety data.

One of our objectives was to explore the impact of nefazodone treatment on some of the cardiovascular parameters thought to link depression to cardiac mortality; that is, reduced HRV and increased plasma norepinephrine. However, our small sample size precludes statements about the lack of nefazodone’s impact on these indices, owing to the risk of type-2 error. Nevertheless, we found a trend toward reduced plasma norepinephrine levels in association with a reduced heart rate. If confirmed in other studies, this reduction might result in clinically significant cardiovascular benefits: a small reduction of plasma norepinephrine level has been associated with better prognosis in CHF patients (31).

Finally, we found that nefazodone may have induced an increase in QT intervals, but not in QTc intervals—probably because it also seems to have reduced the heart rate. To our knowledge, nefazodone has not been previously reported to increase either QT or QTc intervals, nor has intoxication or overdose with nefazodone been found to cause Torsades de Pointes or other ventricular arrhythmias. Experienced cardiologists carefully analyzed all ECGs, and no subject had an increase in QTc that was thought to be of clinical significance.

In a sample of patients with class II and III CHF, nefazodone treatment was associated with a promising clinical improvement in depressive severity. It had an acceptable tolerability profile and may have had a clinically meaningful impact in reducing sympathetic nervous system activity. These results need to be confirmed with an appropriately designed and powered study.

Funding and Support

This study was supported by the Medical Research Council of Canada (MRC); by an unrestricted grant from Bristol Myers Squibb, through the MRC–Industry program (PA-14543); by the Montreal Heart Institute Research Fund; and by the Pierre David Fund.

Acknowledgements

We acknowledge the work of the research assistants who made this project possible: Ginette Gravel, Aline Masson, Johanne Marquis, and Melanie Richard.

References

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Author(s)

Manuscript received August 2002, revised, and accepted April 2003.

Previously presented in part at the American Psychiatric Association 146th Annual Meeting; 1999; Washington (DC). Previously presented in part at the Heart Failure Society of America Annual Meeting; 1999; San Francisco (CA). Previously presented in part at the American Psychosomatic Society Annual Meeting; 2001; Monterey (CA).

1. Associate Professor, Department of Psychiatry, University of Montreal, Montreal, Quebec; Psychiatrist, Centre Hospitalier de l’Université de Montréal and Montreal Heart Institute, Montreal, Quebec.

2. Professor, Department of Psychiatry and School of Nursing, and Associate Member, Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec; Associated Professor, Department of Psychiatry, University of Montreal, Montreal, Quebec; Senior Research Associate Montreal Heart Institute, Montreal, Quebec; Associate Researcher, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec.

3. Lecturer, Department of Psychiatry, University of Montreal, Montreal, Quebec; Chair, Department of Psychosomatic Medicine, Montreal Heart Institute, Montreal, Quebec.

4. Associate Professor, Department of Medicine, University of Montreal, Montreal, Quebec; Cardiologist and Director, Heart Failure Program, Montreal Heart Institute, Montreal, Quebec.

5. Lecturer, Department of Psychiatry, University of Montreal, Montreal, Quebec; Psychiatrist, Hôpital Louis-H Lafontaine, Montreal, Quebec.

6. Associate Professor of Research, Department of Physiology, University of Montreal, and Montreal Heart Institute, Montreal, Quebec.

7. Associate professor, Departement of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec; Chair, Department of Medicine, Montreal Heart Institute, Montreal, Quebec.

8. Dean and Professor of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec; Cardiologist, Montreal Heart Institute, Montreal, Quebec.

Address for correspondance: Dr F Lespérance, Department of Psychiatry, Centre Hospitalier de l’Université de Montréal, 3850 St-Urbain, Montreal, QC H2W 1T8

e-mail: francois.lesperance@umontreal.ca

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