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Clinical activity and tolerability of trazodone, mianserin, and amitriptyline in elderly subjects with major depression: a controlled multicenter trial.

The aim of this multicenter study was to compare trazodone (TRA) with two reference drugs, amitriptyline (AMI) and mianserin (MIA), under double-blind conditions, in an elderly population, to ascertain age-related patterns for efficacy and tolerability. One hundred six elderly depressed inpatients, ranging in age from 60 to 83 years, diagnosed as having major depression according to DSM-III, were treated with 75 mg AMI (37 patients), 60 mg MIA (33 patients) or 150 mg TRA (36 patients) p.o.t.i.d. for 5 weeks. There were no differences in the clinical outcome among the three groups of patients at the end of the trial, with a significant amelioration (p less than 0.01) for the Hamilton Rating Scale for Depression (HRS-D) and the Geriatric Depression Scale (GDS). TRA showed a lower overall prevalence of side effects than AMI or MIA, particularly for anticholinergic (p = 0.03 vs. AMI) and cardiovascular (p = 0.05 vs. MIA) effects. For these data GDS seems to be most reliable in detecting changes in elderly depressive symptomatology; moreover a comparable therapeutic response (among the three drugs) but a better tolerance for atypical antidepressants, particularly TRA, make advisable the use of the latter drug in the elderly population.

Aged↗

A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression.

OBJECTIVE: To determine amitriptyline's (AMI) efficacy in the acute treatment of adolescent major depressive disorder (MDD). METHOD: Subjects aged 12 through 17 years meeting Research Diagnostic Criteria for MDD, diagnosed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS), participated in a 2-week placebo-washout followed by an 8-week, randomized, double-blind, parallel-design, placebo-controlled trial of AMI, 5 mg/kg per day. The K-SADS nine-item scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions rating scale were used as outcome measures. RESULTS: Thirty-one subjects were randomized (18 AMI, 13 placebo). Twenty-two subjects were study completers (12 AMI, 10 placebo). AMI's efficacy was suggested by the Clinical Global Impressions but not the K-SADS-derived data. Perhaps the primary limitation of the current study is its small sample size. CONCLUSION: No definitive recommendation can be made regarding the efficacy of tricyclic antidepressants in the treatment of adolescent MDD.

Adolescent↗

Randomized, controlled trial of amitriptyline versus placebo for adolescents with "treatment-resistant" major depression.

OBJECTIVE: To assess the response to a serotonergic/noradrenergic tricyclic antidepressant, amitriptyline (AMI), in a group of adolescents with treatment-resistant major depressive disorder (MDD). METHOD: Twenty-seven depressed adolescents admitted to a state hospital underwent a 10-week randomized, controlled trial with a flexible dose of AMI or placebo. RESULTS: There were no differences between patients taking AMI (n = 13) and placebo (n = 14). Both treatment groups showed approximately 70% to 80% improvement on the clinical outcome measurements, and 65% to 70% showed functional improvement. At the end of the protocol, 30% of patients still fulfilled criteria for MDD and had impaired functioning. Patients taking AMI experienced significantly more dry mouth and tachycardia. The final AMI dose was 173.1 mg/day +/- 56.3 mg/day; blood levels were 226.2 ng/mL +/- 80.8 ng/mL. CONCLUSIONS: No significant differences were found between AMI and placebo, in part because of the high placebo response rate. Although both treatment groups showed substantial response, at the end of treatment a substantial proportion of patients still had MDD of subsyndromal symptoms of depression. This and other studies of tricyclic antidepressants question the use of this medication as first-line treatment for youths with MDD.

Adolescent↗

Amitriptyline metabolism in elderly depressed patients and normal controls in relation to hypothalamic-pituitary-adrenal system function.

The pharmacokinetics of amitriptyline (AMI) have been extensively studied, and a large interindividual variability between oral dose and concentration of the drug in plasma has been documented. The aim of this study was twofold: first, to compare AMI kinetics in depressed patients with those of healthy controls and, second, to describe the relationship between AMI levels in plasma and hypothalamic-pituitary-adrenal (HPA) system changes during depression. Thirty-eight patients with a DSM-III-R diagnosis of major depression and 13 healthy control persons received 75 mg of AMI daily for 6 weeks. Levels of AMI and nortriptyline in plasma were determined, and neuroendocrine testing with the combined dexamethasone-suppression/CRH-stimulation test (DST) was done before AMI administration and after weeks 1, 3, and 6 of medication. AMI levels in plasma were significantly higher in the patient group compared with controls during the entire treatment period, whereas nortriptyline levels did not differ between the two groups. Drug levels correlated significantly with age, but gender had no effect on the concentration of the drug in plasma. Twenty-two patients remitted after treatment. There was no difference in drug levels between responders and nonresponders. Fifteen patients were DST nonsuppressors before treatment; 23 patients and all controls suppressed cortisol after dexamethasone. DST suppressors had significantly higher AMI levels in plasma at weeks 3, 5, and 6 compared with DST nonsuppressors. In comparison to patients with high AMI levels in plasma, those with low drug concentration had higher postdexamethasone cortisol and adrenocorticotropic hormone levels and an increased hormone release after additional CRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome.

In a multicenter, double-blind, parallel group trial, the efficacy of risperidone (RIS) was compared with a combination of haloperidol and amitriptyline (HAL/AMI) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder, depressive type, a major depression with psychotic features, or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria. A total of 123 patients (62 RIS; 61 HAL/AMI) were included; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI. Efficacy results for those 98 patients (47 RIS; 51 HAL/AMI) who completed at least 3 weeks of double-blind treatment revealed in both treatment groups large reductions in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale (RIS 37%; HAL/AMI 51%) and the Bech-Rafaelsen Melancholia Scale total scores (RIS 51%; HAL/AMI 70%). The reductions in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale scores in the total group were significantly larger in the HAL/AMI group than in the RIS group (p < 0.01), mostly because of significant differences in the subgroup of patients suffering from depression with psychotic features, whereas treatment differences in the other diagnostic subgroups were not significant. The incidence of extrapyramidal side effects as assessed by the Extrapyramidal Symptom Rating Scale was slightly higher under RIS (37%) than under HAL/AMI (31%). Adverse events were reported by 66% of RIS and 75% of HAL/AMI patients. The results of this trial suggest that the therapeutic effect of HAL/AMI is superior to RIS in the total group of patients with combined psychotic and depressive symptoms. However, subgroup differences have to be considered.

Adolescent↗

Intravenous versus oral administration of amitriptyline in patients with major depression.

Antidepressants can be administered by different routes. Advantages for either the oral or the intravenous administration have been suggested from pharmacokinetic as well as from clinical points of view. Controlled comparison studies of the two routes do not provide unequivocal recommendations. In this investigation, amitriptyline was studied over a 4-week period consisting of a 2-week, double-blind/double-dummy phase with either oral (150 mg/day), high-dose intravenous (150 mg/day), or medium-dose intravenous (100 mg/day) treatment and a 2-week phase of open oral treatment in 80 patients with major depression. A psychopathologic assessment was made using the Hamilton Rating Scale for Depression, the Clinical Global Impressions Scale, the von Zerssen's "Befindlichkeitsskala," an adjective checklist, and a Visual Analog Scale. No significant differences were found concerning the mean scores of the rating scales or time of onset of action in the physicians' ratings. In the patients' self-ratings, there was an earlier therapeutic effect in the high-dose intravenous group. The number of improvers after 7 days was significantly higher in the high-dose intravenous group compared with both other groups. After 14 days, no significant differences in the numbers of improvers and responders between groups were detected. The results of this study do not clearly favor one of the tested options. The main differences found in this study seem to be dose-related rather than differentiating between oral and intravenous routes of administration.

Administration, Oral↗

Changes in quantitatively assessed tremor during treatment of major depression with lithium augmented by paroxetine or amitriptyline.

Tremor is a relatively frequent side effect of lithium and of antidepressants with serotonergic properties. It can be expected that combinations of lithium (which is itself serotonergic) with such antidepressants will enhance not only efficacy, but also the incidence of side effects, including tremor. To quantitatively monitor the effect of antidepressant augmentation of ongoing lithium therapy on tremor, lithium-maintained patients with a breakthrough episode of major depression were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (N = 14) or amitriptyline 75 mg/day (N = 17). The initial dosages could be increased after 2 weeks to 40 mg/day and 150 mg/day, respectively, and the patients were treated for 6 weeks. Tremor activity was assessed weekly, quantitatively by accelerometry and qualitatively with the Dosage Record and Treatment Emergent Symptom Scale. Statistical analysis detected no significant difference between the treatment groups with respect to changes in mean tremor activity relative to baseline. However, analysis of the pooled data showed that tremor increased significantly during the course of combined lithium and antidepressant therapy, with the greatest increments occurring independent of dosage approximately 3 weeks after initiation of combination treatment. Although the mean tremor activity subsided toward the end of treatment, tremor activity on the whole was still significantly greater after 6 weeks of combined lithium and antidepressant treatment than at the start of combination therapy. Increased tremor was not associated with decreased medication compliance, and no patient discontinued treatment because of increased tremor. Tremor frequency was not affected by the study treatments.

Adult↗

Antidepressive treatment with amitriptyline and paroxetine: effects on saliva cortisol concentrations.

With regard to the course of basal human hypothalamus-pituitary-adrenal (HPA) system activity, there is a lack of data for comparing different classes of antidepressants. Ninety-four patients were included in a study comparing standardized treatment with paroxetine (PAROX) and amitriptyline (AMI) after a drug-free period of at least 6 days. Saliva for measurement of cortisol concentrations was obtained daily at 0800, 1600, and 2200 during the 6 days of drug-free washout and 35 days of active treatment. The course of HPA system activity and psychopathology, as assessed by the Hamilton Depression Scale, was compared by means of repeated-measurement analyses of variance (ANOVA-rm). Only AMI responders-not PAROX responders or nonresponders to either antidepressant-had a significant decline in saliva cortisol concentrations. In hypercortisolemically depressed patients, treatment with AMI may be preferable to PAROX in order to lower HPA system activity.

Amitriptyline↗

Amitriptyline pharmacokinetics and clinical response: II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin.

A subgroup of 16 out of 30 endogenous depressive inpatients (cf. part I), treated for 3 weeks with 150 mg amitriptyline (AT) daily, participated in a pharmacogenetic study: all were phenotyped with debrisoquine and 3 of them with mephenytoin. Four patients were found to be poor metabolizers (PMs) of debrisoquine and one of mephenytoin. Plasma levels of AT + NT (nortriptyline) were highest in the PMs of debrisoquine, but the ratio of hydroxylated metabolites to the parent compounds appeared to be lower in these subjects. From these data, it is speculated that, in the PM of mephenytoin, the demethylation of AT is impaired. In 12 patients, free plasma 10-hydroxy-AT (ATOH) and 10-hydroxy-NT (NTOH) were found to be bound to a similar extent to plasma proteins, but not so firmly as their parent compounds, by a factor of 6 and 4 respectively. While mean total plasma ATOH reached only 15% of the value of AT, total plasma NTOH was as high as NT. ATOH correlated significantly with its parent compound, but NTOH did not correlate with NT. No drug plasma levels/clinical relationship was found in this small group of patients, even when the hydroxylated metabolites were taken into account. Both poor and extensive metabolizers of debrisoquine responded to treatment. The debrisoquine-test appears to be a useful clinical tool for detecting in patients a genetic deficiency in the hydroxylation of AT-type drugs.

Adult↗

Prediction of the amitriptyline response: psychopathology versus neuroendocrinology.

In this prediction study 50 patients with DSM-III major depressive episode were assessed before treatment with respect to symptomatology (Newcastle and Hamilton features), diagnostic sub-types (according to the Newcastle scale and the DSM-III) and neuroendocrinology (DST and TRH-test). Subjects were given 150 mg of amitriptyline daily and the treatment response was determined on day 11 and 21. The duration of hospitalization served as a further criterion of outcome. The data suggest that neither diagnostic sub-typing nor neuroendocrinological variables were significantly related to outcome. Prediction, however, became possible using the following clinical parameters: DSM-III depressive psychotic features, DSM-III personality disorder and sudden onset of illness were significantly associated with poor treatment response and explained 34% of the outcome variance.

Adult↗

Rapidity of symptom reduction in depressions treated with amitriptyline.

A group of depressed women treated with amitriptyline was studied with particular attention to the speed of response in different symptoms of depression and in psychotic as compared to neurotic depressives. The findings showed rapid improvement in suicidal feelings, insomnia, and anorexia, but slower and more gradual improvement in impaired work and interests, retardation and pessimism and hopelessness. Psychotic depressives did not show substantial improvement until the third week of treatment whereas neurotic depressives improved markedly within the first week. It is suggested that the psychotic classification may be more useful as a predictor of speed of response than as a predictor of final treatment outcome.

Adjustment Disorders↗

The effects of amitriptyline and lithium on a patient with 48-hour recurrent depressions.

A 61-year-old man with a 5-year history of 48-hour mood swing cycles--1 day depressed, 1-day euthymic--was treated with medications in a double blind trial. Placebo had no effect on his cycles, amitriptyline lessened the amplitude of depression on "bad days" but did not effect the 48-hour periodicity, whereas lithium carbonate therapy terminated both affective symptoms and the cycle itself. After several months on lithium, the patient discontinued the drug, but neither symptoms nor cycles returned. Forty-eight-hour affective cycles are unusual, and this patient's response to lithium is particularly striking.

Amitriptyline↗

Effects of amitriptyline on left ventricular function in conscious dogs.

Amitriptyline (Am) is a frequently prescribed tricyclic antidepressant drug associated with an increased risk of sudden death that has been presumed to be arrhythmia related. Little has been known about the effects of Am on left ventricular function. We studied i.v. Am (0.5, 1.0, and 1.5 mg/kg) in 10 conscious, resting, chronically instrumented dogs. Heart rate (HR) increased up to 70%; this increase was only partially prevented by propranolol. Left ventricular end diastolic pressure (LVEDP) decreased without, but not with, propranolol. Mean arterial pressure (MAP) increased by 10-13% transiently. The maximum rate of rise of left ventricular pressure (dP/dtmax) decreased by 16-18% without propranolol and by 14-29% with propranolol, indicating a moderate decrease in myocardial contractility. Changes in stroke volume were similar to changes in dP/dt. Thus, i.v. Am, at levels similar to therapeutic blood levels, causes a moderate depression of myocardial contractility, which is accentuated by propranolol. Tricyclic antidepressants, therefore, could have adverse effects on cardiac performance in patients with underlying myocardial dysfunction.

Amitriptyline↗

Amitriptyline-associated seizures in a toddler with Munchausen-by-proxy.

We describe an unusual case of a toddler diagnosed with an idiopathic seizure disorder that later was proved to be caused by deliberate administration of amitriptyline by his custodian. In spite of seizures associated with widened electrocardiographic wave (QRS) and right axis deviation on the electrocardiogram (EKG), the correct diagnosis eluded clinicians through a series of hospital admissions. Unfortunately, clinicians are quite accustomed to the fact that patients previously diagnosed with epilepsy have seizures and may not investigate other causes of seizure. This allowed classic signs of cyclic antidepressant poisoning to go unrecognized.

Amitriptyline↗

Clinical trial of amitriptyline and fluphenazine in diabetic peripheral neuropathy.

Ten adult insulin-dependent diabetics with symptomatic peripheral neuropathy were treated with amitriptyline alone or in combination with fluphenazine hydrochloride. Nine of the subjects had a good result within 48 to 72 hours. Two patients reacted adversely to the medication. These medications appear effective in treating the discomfort associated with diabetic peripheral neuropathy.

Amitriptyline↗

Amitriptyline and chronic low-back pain. A randomized double-blind crossover study.

The effect of antidepressant medication on chronic low-back pain patients was studied in a randomized blind crossover study. Among those patients who completed the study, there was a 46% decrease in the use of analgesics while on amitriptyline when compared to placebo (P less than 0.005). There was also improvement in affect, but no measurable change in activity level. The MMPI profile of those patients who were unable to comply with the study protocol differed from that of patients who completed the study. The noncompliers demonstrated an elevation of the F, Pd, Pt (P less than 0.05) and Mf (P less than 0.01) scales. Although the interpretation of such a profile is left open to speculation, it may serve as an indicator of noncompliant individuals.

Activities of Daily Living↗

A sensitive gas chromatographic assay for amitriptyline and nortriptyline in plasma.

A method for the quantitative determination of the tricyclic antidepressant drug amitriptyline (AT) and its active major metabolite, nortriptyline (NT), in plasma is described. The method involves a three-step extraction procedure, no derivatization, and a rapid run on a gas--liquid chromatograph equipped with a nitrogen detector. The standard curves were linear in the range of 25-1,000 ng/ml. The lower detection limit was 2-5 ng/ml for both drugs. The method is specific for AT and NT, with a recovery of AT and NT of 68 and 71%, respectively. The precision of the method, expressed as the coefficient of variation, was 10.7% for AT and 12.9% for NT within 25--1,000 ng/ml. The method has proven to be suitable for monitoring plasma levels of AT and NT in patients, and in animals during experimental studies on pharmacokinetics after therapeutic and toxic doses of NT.

Amitriptyline↗