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PubMed1984

Neuroendocrine dysfunction and response to tricyclic antidepressants.

Patients with DSM-III unipolar major depression (N = 26) were treated with tricyclic antidepressants after 2 weeks of inpatient drug-free observation and neuroendocrine testing. Medication was prescribed with individualized dosages and was monitored with blood levels. Treatment response (greater than or equal to 50% decrease in Hamilton depression score after 4 weeks) was seen in 6 of 13 patients given desipramine and 7 of 13 given nortriptyline. Of the 13 nonresponders, 9 accepted treatment with another drug and/or ECT; 5 responded. Thus, 18 of the 26 patients responded to treatment. Abnormal pretreatment DST was correlated with increased responsiveness to treatment, although all patients had a high probability of response.

Antidepressive Agents, Tricyclic↗
PubMed1978

Determination of drugs in plasma by high-performance thin-layer chromatography.

High-performance thin-layer chromatography was used to determine chlorpromazine, amitriptyline, nortriptyline, imipramine, desipramine, phenobarbital, and phenytoin in plasma, to demonstrate the utility of this technique for routine analysis. We quantitated the separated components by use of ultraviolet reflectance spectrometry with detection limits as low as 1 microgram/liter. Regressions of psychoactive agents extracted from plasma were linear over the range of 0 to 300 microgram/liter. The anti-convulsant drugs, phenobarbital and phenytoin, were determined over a range of 0 to 50 mg/liter. Analyses were rapid, reproducible, and well-suited to large-scale programs. Separated components also can be identified in situ by ultraviolet spectrophotometry.

Amitriptyline↗
PubMed1982

Plasma concentrations of tricyclic antidepressants in clinical practice.

Plasma concentrations of four tricyclic antidepressant drugs were monitored in 180 patients. Plasma concentrations incongruent with dose suggested noncompliance at some time among 20% of the patients. Plasma concentrations correlated poorly with dose except with amitriptyline. Plasma concentration of drug and active metabolite, in the case of imipramine and amitriptyline, tended to be higher in ng/ml than the daily dose in mg; the converse was true for nortriptyline and desipramine. Most patients achieved "therapeutic"plasma concentrations at doses of 150 mg/day. However, "therapeutic" plasma concentrations did not correlate well with clinical response.

Amitriptyline↗
PubMed1981

Pharmacokinetics of amitriptyline in the elderly.

The pharmacokinetics of amitryptyline (AMI) have been evaluated in six healthy elderly volunteers (72-83 years of age) after a single dose of 125 mg of AMI-HCl. AMI was absorbed rather slowly (mean peak time 10.4 +/- 1.6 hrs) but very efficiently (F: 0.59-0.75). The rate of formation of nortriptyline (NT) as well as the appearance clearance values (0.18-0.45 l/h/kg) of AMI were significantly lower than those previously described for younger subjects. Reversible alterating ECG were observed in 5 cases concomitantly with AMI peak plasma concentrations. The results indicate the desirability of reduced and/or divided daily doses of AMI in the elderly.

Aged↗
PubMed1981

Liquid-chromatographic analysis for common tricyclic antidepressant drugs and their metabolites in serum or plasma with the technicon "FAST-LC" system.

We describe a single procedure for assay of seven tricyclic antidepressant drugs and metabolites in serum or plasma: protriptyline, nortriptyline, amitriptyline, desmethyldoxepin, doxepin, desipramine, and imipramine. With the Technicon "FAST-LC" system, samples are aspirated directly into the unit and pretreated via double extraction; the concentration of each drug is then determined by "high-performance" liquid chromatography. Final chromatograms are monitored at 205 nm, at analysis rates of 7.5 samples/h. Concentration and absorbance are linearly related for each drug from 0 to 1400 micrograms/L. Day-to-day CVs averaged 5 to 6% for each drug, and there is good correlation of FAST-LC values with those obtained by gas-chromatographic methods. Total sample volume is 750 microliters.

Amitriptyline↗
PubMed1980

Plasma concentrations of amitriptyline during single nightly and thrice daily administration. Cross-over study.

Plasma amitriptyline and nortriptyline concentrations were measured in ten depressed in-patients after administration of amitriptyline hydrochloride 75 mg in three divided doses or as a single nightly dose. Mean steady state plasma concentrations during the two dosage regimens were similar. Plasma level differences between dosage schedules at sampling times were small and not significant. It was concluded that the single nightly administration of amitriptyline is a helpful therapeutic schedule which can be used instead of the divided dose when the opportunity is given.

Amitriptyline↗
PubMed1980

Reliability of commercially available tricyclic antidepressant levels.

Recent studies show that there may be a relationship between plasma levels of tricyclic antidepressants and clinical response. A number of commercial laboratories have introduced methods for measuring these drugs in plasma for clinical practice, and each recommends a particular method by which plasma samples should be drawn, processed, and stored. In this pilot study we compare results from 4 laboratories, using identical plasma samples containing amitriptyline and nortriptyline, in order to assess interlaboratory reliability. While there is generally good agreement between our results and those of the commercial facilities, some large interlaboratory discrepancies are evident. Caution is advised when utilizing plasma tricyclic levels to monitor patient progress, and we suggest using a laboratory which is well established in this area.

Amitriptyline↗
PubMed1980

The prediction of tricyclic antidepressant plasma concentrations.

It is possible to predict steady-state plasma nortriptyline concentrations from pharmacokinetic data obtained after giving a single oral dose. The best pharmacokinetic predictor was found to be intrinsic clearance, although simpler kinetic criteria such as the 24, 48, or 72 hour plasma concentration were almost equally valuable. Use of such a tolerance test is a simple yet powerful way of obtaining advance information on individual differences in drug disposition. From such kowledge it should be possible to individualize drug dosage regimes so as to maximize antidepressant action, while at the same time minimizing the risk of toxicity. This test could be applied routinely in the psychiatric care of both inpatients and outpatients.

Depression↗
PubMed1980

An external quality-control scheme for tricyclic antidepressants.

Some hospital clinical pharmacology departments operate quality-control schemes to monitor the efficiency of their own and outside pharmacological laboratories in analysing specimens, to maintain or improve quality of performance and to compare the reliability of different methods. The Department of St. Bartholomew's Hospital, London, has been operating a quality-control scheme in which the results from some 18 or more laboratories in analysing the mixed tricyclic-antidepressant content of spiked sera were compared for reliability, six methods being used in all. The measures employed were the overall standard deviation and coefficient of variation, a small coefficient of variation indicating a good quality of performance. Sera contained either amitriptyline and nortriptyline, or imipramine and desipramine. The coefficients of variation were considerably smaller than those reported previously and were greater for external than internal laboratories, while laboratories where tricyclic antidepressants are assayed routinely had a low variation. The skill and experience of the analyst are therefore important. Although there is room for improvement in the scheme, it has already provided valuable objective measures of performance and emphasized the need for a self-critical approach.

Amitriptyline↗
PubMed1995

N-demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors.

Biotransformation of amitriptyline (AMI) to its demethylated product nortriptyline (NT) was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concentration was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 microM AMI. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 +/- 0.013 microM (+/- S.D.), whereas quinidine (up to 50 microM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 microM), a CYP1A2 inhibitor only at low concentrations, showed no effect. All selective serotonin reuptake inhibitors (SSRIs) tested had an inhibitory effect on the formation of NT, with mean Ki values of 4.37 (+/- 3.38) microM for sertraline, 5.46 (+/- 1.95) microM for desmethylsertraline, 9.22 (+/- 3.69) microM for fluvoxamine, 12.26 (+/- 5.67) microM for norfluoxetine, 15.76 (+/- 5.05) microM for paroxetine, and 43.55 (+/- 18.28) microM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein ratios varying from 1:1 to 10:1, inhibited N-demethylation of AMI to an asymptotic maximum of 60%. These results are consistent with several case reports describing impairment of AMI metabolism by SSRIs. Inhibition of AMI demethylation by low concentrations of ketoconazole and by anti-3A antibody supports an important role for CYP3A isoforms in mediating this reaction.

1-Naphthylamine↗
PubMed1994

A prospective study of lithium augmentation in antidepressant-resistant geriatric depression.

This open, prospective study investigated the efficacy of lithium augmentation in elderly patients who had failed to respond to a 6-week course of antidepressant medication. Twenty-one patients (age range, 64 to 88 years) with DSM-III-R unipolar, nonpsychotic major depression refractory to a 6-week course of nortriptyline, fluoxetine, or phenelzine underwent a minimum of 2 weeks of lithium augmentation. Five patients had a complete response, 3 had a partial response, and 13 did not respond. Half of the patients developed dose-limiting side effects, most commonly neuromuscular or neurologic. Patients developing side effects were significantly older (p = 0.05), and there was a tendency for side effects to occur more frequently in patients treated with fluoxetine. The rate of response to lithium augmentation in this elderly population was lower than that reported for most open and controlled studies in younger patients. Possible reasons for this are discussed.

Aged↗
PubMed1993

An animal model of postmortem amitriptyline redistribution.

An experimental rat model was developed to study postmortem changes of drug concentration after an acute overdose. Overnight fasted rats were fed 75 mg of amitriptyline (AMI). Two h after dosing, the rats were anaesthetized and blood samples were drawn from the femoral vein (peripheral blood--PB) and the heart (HB). The rats were sacrificed by CO2 and left at room temperature for either 0.1, 0.5, 1, 2, 5, 10, 24, 48, or 96 hours, when samples of heart blood, blood from the inferior vena cava (PB) and tissue samples from different liver lobes, heart, lungs, kidney, thigh muscle, and brain were taken. Samples were analyzed by high performance liquid chromatography. The AMI concentration in HB increased fairly rapidly within the first 2 h postmortem and from then the average ratio was 6.4 +/- 0.8 (mean +/- sem) (n = 31). In PB, the post/antemortem AMI concentration ratio followed an approximately exponential rise; at 2 h postmortem the ratio was 1.6 +/- 0.3 (n = 5), and at 96 h 55.1 +/- 23.8 (n = 4). For the main metabolite nortriptyline (NOR), the concentration changes followed the same pattern, but to a lesser extent. Among the tissues, the liver lobes had high, but variable drug concentrations; lobes lying closest to the stomach had the highest drug concentrations. The drug concentration in the lungs declined significantly. This animal model demonstrates postmortem drug concentration changes similar to those described in humans. Probable mechanisms include drug diffusion from the stomach and GI tract to the surrounding tissues and blood; and postmortem drug release from the lungs and possibly other drug-rich tissues into the blood.

Amitriptyline↗
PubMed1993

Preliminary observations of the effects of amitriptyline in decomposing tissues on the development of Parasarcophaga ruficornis (Diptera: Sarcophagidae) and implications of this effect to estimation of postmortem interval.

Larvae of Parasarcophaga ruficornis (Fabricius) (Diptera: Sarcophagidae) were reared on tissues from rabbits administered different dosages of amitriptyline to study the effects of this drug on the development of this insect species. The rabbits were given 300, 600, and 1000 mg of amitriptyline via ear vein infusion. No significant differences in rates of larval growth were observed among the colonies. Durations of the larval stage were significantly longer for larvae fed on tissues from rabbits receiving amitriptyline. Larval mortality was observed to be 5.5% for the control colony, but ranged from 40.5 to 57.5% for the test colonies. Durations of the puparial stage were significantly longer for the colonies fed on tissues from the rabbits receiving the 600 and 1000 mg dosages of amitriptyline than for the control and colony fed on tissues from the rabbit receiving the 300 mg dosage. Observed differences in the durations of the larval and pupal stages from the test colonies were sufficient to alter a postmortem interval estimate by up to 77 h, if based on normal developmental patterns for this species at 26 degrees C. Presence of amitriptyline and nortriptyline could be detected in larvae from all colonies fed on tissues from the rabbits receiving amitriptyline using high-performance liquid chromatography (HPLC).

Amitriptyline↗
PubMed1976

Structure-activity relationships among desmethyl derivatives of neuroleptics and antidepressants for substrate specificty to indolethylamine N-methyltransferase from rabbit lung.

Desmethylperazine (norperazine) and desmethylprochlorperazine (norprochlorperazine), like nor1- and nor2chlorpromazine, are excellent substrates for indolethylamine N-methyltransferase (NMT) and also inhibit the formation of dimethyltryptamine (DMT) from N-methyl-tryptamine (NMT). Nortriptyline and protriptyline, antidepressant compounds which like NMT contain a secondary amino group, also serve as substrates for INMT but lack in inhibitory effect on DMT formation.

Animals↗
PubMed1997

Possible markers for postmortem drug redistribution.

The possibility that postmortem biochemical changes in blood might parallel drug redistribution and thus serve as markers was explored in a detailed case study. Eighteen blood and 14 tissue and fluid samples were taken at autopsy 16 h after the death of a 34-year-old female from amitriptyline overdose. Ranges of drug concentrations in blood were amitriptyline 1.8 to 20.2 micrograms/mL, nortriptyline 0.6 to 7.3 micrograms/mL, levels were lowest in femoral vein and highest in pulmonary vein blood. Corresponding levels of 17 amino acids showed markedly different patterns of site-to-site variability. There was a strong positive correlation between individual amino acid and drug concentrations in pulmonary blood samples (n = 5), particularly for glycine, leucine, methionine, serine, and valine. In blood samples from the great veins and right heart (n = 10), the correlation was less strong (r = 0.6 to 0.7). Methionine showed a strong positive correlation in pulmonary samples (r = 0.93), and negative correlation in great veing samples (r = -0.68). Lactic acid showed a strong negative correlation in pulmonary samples (r = -0.93) but a positive correlation in great vein samples (r = 0.71). Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, and bilirubin had a weak positive correlation with drug levels in great vein samples but not pulmonary samples. The results suggest that hepatic enzymes are relatively poor markers for postmortem hepatic drug shifts but that amino acids, particularly methionine, may be useful markers for pulmonary drug shifts.

Adult↗
PubMed1977

Electrocardiographic findings in patients undergoing amitriptyline treatment.

Fifteen depressed patients were treated with amitriptyline in a dosage ranging from 75 mg to 200 mg/day for a minimum of three weeks, two of which were at a fixed dosage. Plasma samples were drawn 12 to 16 hours after the bedtime dose of medication for determination of amitriptyline and its metabolite nortriptyline. Electrocardiograms were taken prior to treatment and after three weeks of drug treatment. The only abnormality noted prior to treatment was bradycardia in one patient. After treatment, two patients exhibited nonspecific T-wave abnormalities. Otherwise, the electrocardiograms were unremarkable. A significant increase in heart rate (p less than 0.001) was noted. The mean increase in rate was sixteen beats per minute. Those patients having a rate change greater than sixteen beats per minute had significantly higher amitriptyline levels (p less than 0.05), and total tricyclic antidepressant levels (p less than 0.05), than those patients having a mean rate increase less than sixteen. While tricyclic antidepressants can produce multiple cardiac effects, the risk of cardiac morbidity and mortality is relatively low in patients undergoing tricyclic antidepressant treatment with moderate dosages.

Adolescent↗
PubMed1997

Treating depressed primary care patients improves their physical, mental, and social functioning.

BACKGROUND: This study describes the functioning of primary care patients with major depressive disorder, the relationship of medical comorbidity to functional status, and the effects of depression-specific treatment on functional status after 8 months. METHODS: Patients were randomized to a protocol intervention (nortriptyline hydrochloride or interpersonal psychotherapy) or to usual care with the patient's physician in a clinical trial of primary care treatments of depression. Their functional status was evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and the Global Assessment Scale. Medical comorbidity was assessed with the Duke Severity of Illness Checklist. The Hamilton Rating Scale for Depression and Beck Depression Inventory were used to measure depressive severity. Assessments were conducted at baseline and at 1, 2, 4, and 8 months after randomization. RESULTS: At baseline, patients reported substantial impairments in the functional domains as assessed by the SF-36 and Global Assessment Scale. Severity of general medical illness and depression were not correlated. Greater medical comorbidity was associated with diminished physical, but not psychological, functioning. Mean scores on SF-36 scales and the Global Assessment Scale improved significantly during the 8 months of follow-up. Patients assigned to protocol treatments showed greater improvement, compared with those assigned to usual care, on the SF-36 mental summary scale and most individual scales but not on the SF-36 physical summary scale. However, patients who completed protocol treatment also experienced significant improvement on the physical summary scale. Medical comorbidity was only a weak predictor of outcome. CONCLUSIONS: Primary care patients with major depressive disorder report substantial impairments in physical, psychological, and social functioning on initial assessment. Severity of baseline medical comorbidity did not correlate with severity of depression and only weakly correlated with functional status at 8 months. Functional impairments improve with time, but standardized depression-specific treatment is associated with greater improvement in more domains of functioning than is a physician's usual care.

Adolescent↗
PubMed1997

Using interpersonal psychotherapy (IPT) in a combined psychotherapy/medication research protocol with depressed elders. A descriptive report with case vignettes.

One hundred eighty subjects at least 60 years of age with recurrent unipolar major depression were recruited to participate in a depression treatment protocol. All patients received drug therapy with nortriptyline (NT) and interpersonal psychotherapy (IPT) with an experienced clinician. Acutely, 81% of subjects showed a full response to combined treatment. In the initial 127 subjects, the most common problem areas in therapy were role transition (41%), interpersonal disputes (34.5%), and grief (23%). Case vignettes are presented and discussed. The combination of IPT and NT showed a powerful antidepressant effect. IPT was readily adaptable to the needs of depressed elders.

Aged↗