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Objective: Major depressive disorder is associated with increased cardiac mortality. A decrease in vagal modulation related to reduced heart rate variability might contribute to increased mortality among many other factors. We sought to examine the hypothesis that nortriptyline treatment will be associated with a decrease in heart rate variability and coupling between heart rate and respiration compared to treatment with S-citalopram., Methods: Fifty-two patients suffering from major depression were included. Patients were examined unmedicated in the acute stage and after 5weeks of treatment. Twenty-six were reinvestigated after they received S-citalopram and 26, after nortriptyline. We used non-linear measures of heart rate variability and also a novel measure to examine cardio-respiratory coupling to assess cardiac vagal modulation., Results: There were significant decreases of non-linear measures of heart rate variability in the nortriptyline group in addition to reduced cardio-respiratory coupling in comparison to the group of patients that received S-citalopram. We observed a significant association between the severity of the disease and vagal withdrawal prior to treatment., Conclusions: These findings indicate that S-citalopram influences autonomic modulation on different regulatory levels to a lesser extent than nortriptyline. Our results have implications for treatment of patients with depression as some of them may already have a higher risk for cardiovascular mortality. In addition, it underlines the beneficial use of SSRIs in patients with cardiac diseases., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: It has been proposed that a history of suicide attempts could be a correlate of severe depressive disorder and that suicide attempters (SA) could represent a particular subtype of subjects suffering from major depressive disorder. We investigated clinical and demographic characteristics associated with SA and tested the hypothesis that a history of suicide attempts predicts poor response to antidepressants., Methods: One-hundred-and-forty-one SA and 670 non-SA subjects with major depressive disorder (MDD) were treated for twelve weeks with escitalopram or nortriptyline in GENDEP, a part-randomized multi-center clinical and pharmacogenetic study. Baseline characteristics were compared using linear and logistic regression. Linear mixed models were used to analyse continuous outcomes during the twelve weeks of follow-up., Results: At baseline, SA subjects suffered from more severe depression (mean Montgomery-Asberg Depression Rating Scale: 30.29 (7.61) vs 28.43 (6.54), p=0.0002), reported higher level of suicidal ideation (1.21 (0.82) vs 0.73 (0.48), p<0.0001), had a younger age of onset and experienced more depressive episodes, had higher harm avoidance scores and poorer socio-demographic environment than non-SA individuals. However, during the twelve weeks of treatment and after adjustment for baseline severity of depression there was no difference in treatment response between SA and non-SA., Limitations: Due to its retrospective design, it is possible that more severely depressed subjects might report more suicide attempts than less depressed individuals., Conclusions: While SA differed from non-SA in several clinical and demographic characteristics, the antidepressants were similarly effective in SA as in comparably severely depressed subjects without a history of suicide attempts., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender., Methods: Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models., Results: Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants., Limitations: As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution., Conclusions: Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.

Background: Late-life depression studies have found that comorbid anxiety, as a symptom or comorbid disorder, is associated with poorer treatment response and increased likelihood of dropout. This study evaluated the impact of comorbid anxiety on response, dropouts, and side effects, in elderly subjects treated for depression., Methods: We analyzed data from a 12-week trial comparing nortriptyline and paroxetine in 116 patients aged 60 and older with depression. Subjects classified as having anxious depression were compared to those with nonanxious depression in terms of treatment response rate, time to response, dropout rate, and early side effects. The analysis was replicated with another study, in which 125 subjects aged 69 and older were treated openly with paroxetine and interpersonal psychotherapy., Results: Anxious and nonanxious groups did not differ in terms of response rates, time to response, dropout rates, or time to dropout. Side effects declined more quickly and more significantly in the anxious group than in the nonanxious group., Limitations: Subjects were treated in a specialty mental health setting, and the findings may not apply in other settings., Conclusions: We found no association between comorbid anxiety and a poorer prognosis during acute treatment of late-life depression. For elderly patients with anxious depression, standardized treatment in the mental health sector is associated with a good response.

The goal of the study was to describe with prospective methodology the therapeutic response to nortriptyline in the respiratory panic disorder (PD) subtype versus the non-respiratory subtype. A total of 118 PD outpatients (DSM-IV) were previously divided into respiratory (n=77) and non-respiratory (n=41) subtypes and then treated with nortriptyline for 1 year. Demographic and clinical features were compared in the two groups. Anxiety scales were administered before and during the treatment by raters who were blind to the subtype diagnosis. The principal instruments used to evaluate response were the Clinical Global Impression, the Sheehan Panic and Anticipatory Anxiety Scale, and the Panic Disorder Severity Scale. In the first 8 weeks of treatment (acute phase), the respiratory subtype had a significantly faster response on all the major scales. At the end of the study (week 52), there was no difference in the scale scores, and the reduction in panic attacks from baseline to end-point did not differ significantly between the two groups. In the respiratory subtype, the disorder had a later onset, was associated with a high familial history of mental disorder, and significantly more often required treatment with more than an occasional benzodiazepine. The non-respiratory subtype had significantly more previous depressive episodes. In conclusion, the respiratory PD subtype had a faster response to treatment with nortriptyline at 8 weeks than did the non-respiratory subtype, and an equivalent response after 1 year of treatment.

Background: The literature on acoustic measures of voice in depression is reviewed. Authors have separated results derived from studies of automatic speech, such as counting or reading, from free speech. Free speech requires cognitive activity such as word finding and discourse planning in addition to the motor activity of automatic speech. Also, results have been less ambiguous if homogeneous groups of agitated or retarded depressed patients were examined., Methods: These distinctions are applied to the results of a 12-week double-blind treatment trial that compared response to nortriptyline (25-100 mg/day) with sertraline (50-150 mg/day). Twelve male and ten female elderly depressed patients and an age-matched normal control group (n=19) were studied. Patients were divided into retarded or agitated groups on the basis of ratings. Results from measures of fluency (speech productivity and pausing) and prosody (emphasis and inflection) are described., Results: Depressed patients showed less prosody than the normal subjects. Improvement in the retarded group was reflected in briefer pauses but not longer utterances. There was a trend in the agitated group for improvement to be reflected in the utterance but not the pause measure., Conclusions: Clinical impressions are substantially related to acoustic parameters. Temporal changes associated with depression appear to reflect the depressed state whereas prosodic features seem to reflect a depressed trait. Acoustic measures of the patient's speech may provide objective procedures to aid in the evaluation of depression. Limitations of the study are discussed.

The Major Depression Rating Scale (MDS) has been derived from the Hamilton Depression Scale and the Melancholia Scale. The MDS contains the nine DSM-IV items for major depression which all have anchoring scores from 0 to 4; hence, the theoretical score range is up to 36. The Major Depression Rating Scale has in this study been psychometrically analysed in randomized moclobemide trials. The results showed that the MDS had higher internal validity than the Hamilton Depression Scale. Thus, the homogeneity of the items was higher; factor analysis identified only one general depression factor (after 4 weeks of treatment explaining more than 50% of the variance). The inter-rater reliability of the two scales was of the same high level. The ability to measure changes (external validity) was tested in randomized clinical trials with moclobemide versus tricyclics (clomipramine and notriptyline) performed in Denmark in the psychiatric setting as well as in the general practice. The results showed that in the psychiatric setting tricyclics were superior to moclobemide with effect sizes ranging between 0.43 and 0.53. The highest effect size was obtained with the Melancholia Scale and the Major Depression Rating Scale, while the Hamilton Depression Scale was below 0.50. In the general practice setting no difference was found between moclobemide and clomipramine. In conclusion, the Major Depression Rating Scale has been found to have a more homogeneous factor structure than the Hamilton Depression Scale, but still with the same level of reliability and external validity. However, studies are needed to standardize the scale, especially in the general practice setting.

This study evaluated the outcome of elderly depressed patients who were refractory to, or intolerant of, an initial trial of nortriptyline and who then underwent systematic treatment with other antidepressant therapies. 101 patients entered the study and 61% responded to nortriptyline, 64% of patients who did not improve with nortriptyline eventually responded to other antidepressant treatments. Response to second-line treatment (phenelzine) was significantly slower than response to the tricyclic antidepressant. Treatment nonresponders were more likely to have a longer episode length at index assessment and higher baseline anxiety scores compared with responders. This study demonstrates the importance of persisting with systematic antidepressant therapy in elderly patients who do not respond to the first trial of treatment.

The specific aim of this study was to contrast effects of recruitment method (solicited, referred) on demographic, psychosocial, medical, and treatment outcome measures in an ongoing clinical trial of maintenance therapies in late-life depression. Data from 125 elderly patients (56 solicited via media campaign, 69 clinically referred) with recurrent, unipolar major depression were available for analysis. Several statistical contrast procedures, including group t tests, chi 2 tests, survival analysis, and logistic regression, were used to assess differences in patient profiles related to method of recruitment. Referred patients included a higher proportion of African Americans and had a lower level of education, fewer economic resources, and higher chronic medical burden. Solicited patients had been in the index episode longer than the referred patients at the time of protocol entry and were 3.4 times more likely to have experienced a "provoking agent" (severe life event or chronic difficulty) during the 6 months that preceded the onset of depressive symptoms. In contrast to these demographic and illness history differences, there were no differences in treatment response rates or time to response related to recruitment method. Solicited patients had an overall treatment response rate of 71% versus 62% in the referred group. Median time to response was 14.3 weeks in the solicited group and 13.6 weeks in the referred group. These results suggest that the inclusion of solicited patients in geriatric depression clinical trials does not bias short-term treatment outcome.

Moclobemide and nortriptyline were compared with placebo in a double-blind randomized multinational (Canada, Denmark and UK) trial comprising 109 patients of > 60 years of age with major depression (DSM-III-R). Patients were randomized to 7 weeks of treatment with doses of 400 mg/day moclobemide, 75 mg/day nortriptyline or placebo. It was necessary to adjust nortriptyline dosage in < 20% of patients to maintain serum levels within the postulated therapeutic window of 50-170 ng/ml. At end of treatment, the remission rates were 23% for moclobemide, 33% for nortriptyline and 11% for placebo. Anticholinergic and orthostatic events occurred more often with patients on nortriptyline than either moclobemide or placebo.

Body weight and appetite were evaluated in 40 depressed outpatients from a private psychiatric practice who were receiving low-modest doses of tricyclic antidepressants. Amitriptyline (maximum of 150 mg/day), nortriptyline (maximum of 50 mg/day), and imipramine (maximum of 80 mg/day) were given for an average of 6 months of treatment. There was a mean weight increase of 1.3-2.9 lbs/month, which led to an average total weight gain of 3-16 lbs, depending on drug, dose and duration. These weight increases were linear over time and were accompanied by marked increases in the preference for sweets. Ultimately, excessive weight gain was the most common cause of discontinuation of treatment, occurring in one-half of the patients. Significant weight loss occurred upon discontinuation of drug. These findings show that chronic administration of low-modest doses of tricyclic antidepressants frequently cause considerable weight gain and can significantly interfere with the ability to provide long-term maintenance therapy.

Body weight change was monitored in 73 hospitalized depressed patients treated with one of four antidepressants for 1 month. After a 2-week medication-free period, patients were randomly assigned to treatment with amitriptyline, nortriptyline, desipramine, or zimelidine. By the end of 1 month, treatment with all three tricyclic compounds promoted weight gain, with the greatest increase observed during amitriptyline treatment; less weight was gained by patients treated with nortriptyline and desipramine. In contrast, most patients treated with zimelidine showed no weight gain and, in many cases, demonstrated weight loss. Weight change during treatment was not associated with age, sex, severity of depression, obesity, weight loss during depression, or clinical response.