Venlafaxine- and trazodone-induced serotonin syndrome.
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Cyclohexanols↗
Biomedical subjects
R E McCue
Publications and source records attributed to R E McCue.
Using tricyclic antidepressants in the elderly.
Only a few of the eight tricyclic antidepressants available today have been studied systematically in the elderly. Tertiary amine tricyclics such as amitriptyline and imipramine have been reported to be effective in depressed geriatric patients, but because of their potential for side effects, it is not advisable to use them in the elderly. Desipramine has a less toxic side effect profile, especially with respect to anticholinergic effects, but its efficacy has not been well studied. This does not mean, however, that it is not an effective drug for the elderly depressed. Nortriptyline is the tricyclic that has been the most studied. The results of those studies show that it should be recommended as an antidepressant for older patients. It is effective in both the acute and continuation treatment of depression in the elderly. As far as its use in maintenance treatment, the results are mixed but at this moment there is nothing with which to compare it. It has a favorable side effect profile: low anticholinergic activity; relatively few cardiac side effects, even in patients with preexisting cardiac disease; and relatively less orthostatic hypotension. Nortriptyline also has the virtue of an established therapeutic range for its steady-state plasma level. The role of its 10-hydroxy metabolite needs to be further explored, but when its contribution to efficacy and toxicity is better understood, it may be possible to use nortriptyline in a more precise and safe way in elderly patients. The bulk of evidence suggests, partly by default, that nortriptyline should probably the tricyclic-of-first-choice in treating an elderly patient with major depression.
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A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients.
Fifty-one elderly depressed outpatients who had responded to antidepressants and completed continuation therapy were observed under double-blind conditions for 1 year. Twenty-three had been switched to placebo, while 13 and 15 took nortriptyline hydrochloride and phenelzine sulfate, respectively. Patients administered phenelzine did significantly better with 13.3% recurrences than patients administered either nortriptyline (53.8% recurrences) or placebo (65.2% recurrences). In addition, patients who had higher Hamilton scores and who had an earlier age of onset of the first depressive episode were significantly more likely to have recurrences.
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Plasma levels of nortriptyline and 10-hydroxynortriptyline and treatment-related electrocardiographic changes in the elderly depressed.
Thirty-one elderly depressed patients were treated for seven weeks with nortriptyline with plasma levels kept between 50-180 ng/ml. Electrocardiograms were taken at the third and seventh weeks of treatment. There were significant increases in the PR interval, QTc interval, and heart rate from before and after treatment. However, there were no consistent correlations between electrocardiographic changes during treatment and plasma levels of nortriptyline, 10-hydroxynortriptyline and either of its two isomers (E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline). Increased QRS duration after seven weeks of treatment was correlated with daily dose of nortriptyline.
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Factors affecting the delay of antidepressant effect in responders to nortriptyline and phenelzine.
Seventy-six elderly depressed patients who had responded to either nortriptyline or phenelzine after a trial of up to 3 months were examined. The mean week of response was nearly 6 weeks. Patients who were more severely depressed took longer to respond. Patients with endogenous depression responded sooner on nortriptyline than did patients with nonendogenous depression. For patients on nortriptyline, lower plasma levels in the early weeks of treatment may delay response while differences in platelet monoamine oxidase inhibition in the early weeks of treatment do not appear to affect week of response for patients on phenelzine.
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The effects of mood changes and antidepressants on the cognitive capacity of elderly depressed patients.
Seventy-eight nondemented elderly depressed patients underwent an extensive battery of cognitive tests both before and after seven weeks of treatment with nortriptyline, phenelzine, or placebo. Clinical and cognitive evaluations of the patients were under double-blind conditions. Response to treatment did not appear to significantly affect cognitive capacity; neither did treatment with an active substance as compared to placebo. In addition, the baseline level of cognitive functioning did not appear related to whether a patient responded to treatment. The authors conclude that under optimal conditions neither antidepressant produces measurable changes in the cognitive capacity of nondemented elderly patients.
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10-Hydroxynortriptyline and treatment effects in elderly depressed patients.
Sixty-four elderly depressed outpatients were treated with nortriptyline for seven weeks. Plasma nortriptyline and its main metabolite, 10-hydroxynortriptyline, were measured weekly. No relationship was found between levels of 10-hydroxynortriptyline and clinical response. Plasma levels of the trans isomer, E-10-hydroxynortriptyline, were significantly lower when dizziness and symptoms of orthostatic hypotension were reported, although there was no significant correlation with actual orthostatic drop in systolic pressure. Plasma level of 10-hydroxynortriptyline was not significantly correlated with the other reported side effects.
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How effective and safe is continuation therapy in elderly depressed patients? Factors affecting relapse rate.
Sixty elderly depressed patients who had responded to either nortriptyline hydrochloride or phenelzine sulfate were followed up under double-blind conditions during four to eight months of continuation treatment. Over 70% of patients (43) remained well during this period, while 11 (18.3%) had relapses, three (5.0%) dropped out because of side effects, and three (5.0%) prematurely terminated in good clinical condition. There was no significant difference in the relapse rate between patients receiving nortriptyline (five [16.7%]) and those receiving phenelzine (six [20.0%]). Patients receiving phenelzine were more likely to require dose reductions, and all three patients who dropped out because of side effects were receiving phenelzine. Patients with chronic depression (greater than two years' duration) accounted for all of the relapses.
Age Factors↗
Clinical and treatment effects on 3H-clonidine and 3H-imipramine binding in elderly depressed patients.
3H-clonidine and 3H-imipramine binding were measured in depressed patients, 55 years and older. There was no significant difference in either 3H-clonidine or 3H-imipramine binding between depressed patients and age- and sex-matched controls. There was no significant correlation between 3H-clonidine or 3H-imipramine binding and severity of depression before treatment. There was a significant negative correlation between the KD of 3H-imipramine binding sites and Hamilton score over seven weeks of antidepressant treatment. There was no significant difference between receptor data of responders and nonresponders to antidepressant treatment.
Blood Platelets↗
Clinical predictors of response to antidepressants in elderly patients.
A group of 42 patients, ages 55 and above, suffering from major depression were examined in an attempt to isolate clinical variables that would predict response to antidepressants. These patients were part of a placebo-controlled, double-blind study and were given either nortriptyline or phenelzine for 5-7 weeks. There was no significant difference in response rates between patients subclassified as endogenous or nonendogenous by either RDC or Newcastle criteria. No difference in response rates was found between the DSM-III melancholic and nonmelancholic subtypes. Neither drug preferentially treated a subtype. None of the 21 variables representing symptoms, demographic traits, or characteristics of the depressive illness were found to be significant predictors of antidepressant response.
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Prediction of response to nortriptyline and phenelzine by platelet MAO activity.
Thirty-seven depressed patients over the age of 55 were treated for 5-7 weeks with either nortriptyline, a tricyclic antidepressant, or phenelzine, a monoamine oxidase (MAO) inhibitor. Patients' platelet MAO activity was measured following a drug washout period before treatment. Patients with higher MAO activity had a better response to treatment, regardless of which drug was used.
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Electrocardiographic effects of nortriptyline, phenelzine, and placebo under optimal treatment conditions.
The authors treated 44 outpatients 55 years old or older who were suffering from major depression with either nortriptyline, phenelzine, or placebo for 7 weeks. Plasma levels of nortriptyline were kept between 50 and 170 ng/ml, and platelet monoamine oxidase (MAO) inhibition in phenelzine-treated patients was kept between 70% and 80%. ECGs were compared before and after treatment. Nortriptyline produced statistically significant increases in both the heart rate and the PR interval, although none was outside the normal range. Phenelzine produced a significant decrease in the QT interval. None of the patients had pathological ECG changes under the closely monitored treatment conditions of this study.
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Response of depressive symptoms to nortriptyline, phenelzine and placebo.
The effects of nortriptyline, phenelzine, and placebo on 13 symptoms of depression were compared in 75 patients, aged 55 or over, who were suffering from major depression. Nortriptyline and phenelzine were more effective than placebo in treating depression mood, guilt feelings, suicidal ideation, agitation, anxiety, loss of energy, and a.m. diurnal variation of mood. Nortriptyline was better than phenelzine or placebo in improving middle/late insomnia. Most of the symptoms did not show significant improvement until the fourth week of treatment.
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A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients.
Seventy-five patients, 55 years or older, were treated for major depression with either nortriptyline, phenelzine, or placebo during a 7-week period. There was a significantly greater mean orthostatic fall in systolic pressure in patients treated with nortriptyline and phenelzine as compared to the placebo group, but no significant difference was evident between the nortriptyline and phenelzine groups. The orthostatic changes appeared during the first week of treatment and were not correlated with plasma level of nortriptyline, percent platelet monoamine oxidase inhibition, or pretreatment orthostatic changes.
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Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly.
This comprehensive study investigated both the role of antidepressant drugs in the treatment of affective disorders of later life and their safety with careful clinical and pharmacological monitoring. A 7-week double-blind comparison was made of the efficacy and safety of nortriptyline (a tricyclic), phenelzine (a monoamine oxidase inhibitor), and placebo. The results indicated a response rate of approximately 60% for both nortriptyline and phenelzine versus a 13% response rate for placebo. Anticholinergic side effects were more frequently reported in the nortriptyline group. Orthostatic symptoms were reported with similar frequency in both drug groups. Overall, both drugs were well tolerated.
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Relationship of platelet MAO activity to characteristics of major depressive illness.
Sixty-seven patients (greater than or equal to 55 years of age) with major depressive disorder had pretreatment assays of platelet monoamine oxidase (MAO) activity. As in previous studies, women had higher MAO activity than men, and MAO activity was positively correlated with age. Patients with melancholia (DSM-III) had significantly higher MAO activity than those without melancholia. This finding may reflect the higher MAO activity associated with the symptoms of anhedonia and mood autonomy. Anxiety also was correlated with higher MAO activity, as was a positive family history of depression. In addition, postdexamethasone cortisol levels were correlated with platelet MAO activity.
Age Factors↗
Dexamethasone suppression in dementia, depression, and normal aging.
Dexamethasone suppression tests (DSTs) were performed for 18 moderately demented elderly patients, 66 depressed elderly outpatients, and 25 age- and sex-matched healthy elderly control subjects. Seventeen percent of the demented patients and 4% of the normal subjects were DST nonsuppressors, compared to 38% of the total depressed group. The postdexamethasone plasma cortisol levels of the dementia group fell between those of the normal and the depressed subjects. In addition, demented patients had postdexamethasone cortisol levels significantly lower than those of depressed patients with high Hamilton depression scores. Older subjects in all diagnostic categories, including normal subjects, had higher postdexamethasone plasma cortisol levels.
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Benefits and limitations of major pharmacological treatment for depression.
An extensive amount of research in clinical psychiatry, psychopharmacology, and the neurosciences has led to effective pharmacological treatments for affective disorders. These impressive developments have suffered from several limitations. In the case of antidepressant drugs, the delayed onset of antidepressant effect, troublesome side effects, possible lethality after an overdose, and the 20 to 30 percent of depressed patients not responsive to them have made these drugs less than a panacea. In addition to the limitations of the drugs themselves, there is frequently inattention to pharmacotherapeutic principles by clinicians. There is definitely a need for further research in the field, especially regarding major unresolved issues such as the proper selection of patients for whom antidepressants are indicated, clinical and biological predictors of treatment response, and the development of new antidepressants with superior efficacy and safety as well as an earlier onset of action. Meanwhile, an empathic psychotherapeutic alliance coupled with careful clinical and pharmacological monitoring are the essential prerequisites for successful antidepressant treatment.
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