Evolution of histamine H2-receptor antagonist use in an ambulatory elderly population: A 14-year overview

The purpose of this study was to determine the frequency and pattern of histamine H₂-receptor antagonist drug use in an ambulatory elderly population of individuals over 65 years of age from 1978 to 1992. A longitudinal health screening programme of ambulatory elderly participants was employed to conduct a series of cross-sectional studies over a 14-year period. Participants in the first period (1978–79) included 855 (37.1%) men and 1448 (62.9%) women. The use of histamine H₂-receptor antagonist increased from 0.8% of the population in the 1978–79 period to 7.0% in the 1991–92 period. There was no statistically significant correlation between drug use and age (p = 0.8114) or sex (p = 0.9229) at the 1991–92 time period. In the 1991–92 time period, cimetidine and ranitidine combined, accounted for 86.0% of all reported histamine H₂-receptor antagonist. Over the 14-year period of study there has been a nearly constant increase of histamine H₂-receptor antagonist use in this elderly population.     

The interaction of antidepressant drugs with enteric 5-HT7 receptors

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.     

Delayed emergence of antidepressant efficacy following withdrawal in olfactory bulbectomized rats

Repeated antidepressant treatment attenuates the step-down passive avoidance deficit which is induced by olfactory bulbectomy in rats. Using a shuttlebox passive avoidance procedure, the effects of antidepressants were investigated after various drug withdrawal intervals. Imipramine, amitriptyline, doxepin, bupropion and mianserin were effective at 48 and usually 72 hours after withdrawal, but no significant attenuation of the deficit was seen 4 hours after withdrawal from any antidepressant tested. At least 4 to 7 days of imipramine treatment were required for efficacy. A high dose of d-amphetamine (5 mg/kg) produced similar results while tranylcypromine and haloperidol were inactive at all withdrawal intervals tested. The olfactory bulbectomy syndrome may reflect functional derotonin deficiency, which would be ameliorated through antidepressant-induced alterations in serotonin receptor sensitivity.     

Cardiovascular effects of paroxetine, a newly developed antidepressant, in anesthetized dogs in comparison with those of imipramine, amitriptyline and clomipramine

The cardiovascular effects of various antidepressant drugs including paroxetine, imipramine, amitriptyline and clomipramine, administered intravenously, have been assessed. Paroxetine, imipramine, amitriptyline or clomipramine potentiated the response to norepinephrine (0.1 microgram/kg, i.v.) on systemic blood pressure, while paroxetine, imipramine and amitriptyline weakened the response to tyramine (30 micrograms/kg, i.v.). A marked decrease in systemic blood pressure was observed after large doses of each drug (3 and 10 mg/kg of paroxetine; 1-10 mg/kg of imipramine, amitriptyline or clomipramine); and half of the animals died following administration of 10 mg/kg of imipramine, amitriptyline or clomipramine. Paroxetine did not show a marked effect on heart rate at a dose of up to 3 mg/kg, although 0.1-3 mg/kg of imipramine, amitriptyline or clomipramine dose-dependently caused tachycardia. ECG disturbances were observed in animals administered 10 mg/kg of imipramine, amitriptyline or clomipramine; but in contrast, 10 mg/kg of paroxetine caused only slight changes in the ECG. Prolongation of atrio-ventricular conduction time was observed with all the drugs. It was concluded that the effects of paroxetine on the canine heart are more mild in comparison with other tricyclic antidepressants used, although its pharmacological features are essentially similar to those of other drugs.     

Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression.

Doxepin is closely related in structure and general pharmacological properties to other tricyclic antidepressant drugs such as amitriptyline and imipramine. It combines antidepressant activity with a sedative effect and in this respect resembles amitriptyline, with which it shares a similar profile of clinical action. The mood elevating effect of doxepin appears to be similar to that of amitriptyline but is probably less marked than that of imipramine and in some studies has been slower to take effect than imipramine. At dosages which have achieved a similar overall response rate, doxepin tends to cause fewer or less troublesome side-effects than imipramine, amitriptyline or amitriptyline-prephenazine. The more marked sedative properties of doxepin make it more useful than imipramine in depressed patients with sleep distrubances and in depression associated with anxiety. The benzodiazepines remain the drugs of choice in anxiety states. but when anxiety is accompained by significant depression, doxepin is more effective than chlordiazepoxide or diazepam. Doxepin is usually well tolerated, and in particular by the elderly and those with cardiovascular disease. Side-effects are similar in nature to those of other tricyclic antidepressants, with dry mouth, drowsiness and constipation being the most common. Postural hypotension is uncommon. Although doxepin appears to cause fewer cardiovascular side-effects in usual therapeutic doses, it has an intrinsic cardiotoxicity on overdosage similar to other tricyclics.     

Effects of chronic antidepressant treatment on serotonin receptor activity in mice

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.     

Antibiotic use in elderly hospital inpatients before and after the introduction of treatment guidelines

Objective — (1) To establish the pattern of antibiotic use in elderly hospital inpatients, using data to draw up antibiotic treatment guidelines; (2) To assess the short-term and longer-term impact of the guidelines on antibiotic use and their acceptability to medical staff. Method — Antibiotic use was assessed in relation to suitability for site and severity of infection, appropriateness of drug choice, outcome of therapy and cost, before, immediately after and 10 months after guideline introduction. Acceptability to medical staff was gauged through a questionnaire. Setting — Geriatric hospital inpatients in long-stay, assessment and GP-supervised wards in the Grampian region of Scotland (phase 1: 324 patients; phase 2: 302 patients; phase 3: 263 patients). Key findings — The antibiotic prescribed was appropriate for site and severity of infection in 92 per cent of patients in phase 1, but was a policy drug in only 56 per cent. After guideline introduction, adherence to policy did not improve, but use of non-policy drugs without identified reason fell from 24 per cent in phase 1 to 13 per cent in phase 3. Adjustment of antibiotic dose for renal function increased from 73 per cent in phase 1 to 86 per cent in phase 3. Duration of treatment for a single infection was significantly reduced in phase 3, but outcome and cost were unchanged after guideline introduction. Medical staff were supportive of the guidelines and felt they had changed their prescribing practices. Conclusion — Antibiotic treatment guidelines did not have a major impact on antibiotic use, although some positive trends were observed. New ways of promoting adherence to guidelines need to be explored.     

High dose tertiary amine tricyclic antidepressants in the treatment of severe refractory depression: The central role of plasma concentration estimations

The relationships between dosage, plasma concentration, antidepressant response and toxicity were investigated in 24 highly selected patients with severe, refractory major depression who were prescribed amitriptyline, clompramine or dothiepin at high dosage (150–525 mg/day), usually in combination with lithium or other psychotropics. of serious adverse effects 83 per cent were encountered when tricyclic antidepressant (TCA) plasma concentrations exceeded 400 mcg/1. Therapeutic drug monitoring of high dose TCAs is useful in minimizing the risk of toxicity and in revealing poor compliance, undertreatment and pharmacokinetic interactions which can mitigate against drug efficacy. The value of carbamazepine in the management of refractory depression in the context of unipolar affective disorder is put into question.     

Behavior pharmacology of maprotiline, a new antidepressant]

The effect of maprotiline (N-methyl-9, 10-ethanoanthracene-9 (10H)-propylamine) on animal behavior was investigated in mice and rats and compared with those of amitriptyline and imipramine. Maprotiline inhibited reserpine hypothermia in mice and tetrabenazine ptosis in rats, while it potentiated the effects of methamphetamine, L-DOPA and apomorphine in mice, in a similar manner to that of amitriptyline and imipramine. Maprotiline was more potent than anitriptyline and imipramine in antagonizing haloperidol-induced catalepsy as well as in suppressing muricide induced by either olfactory bulbectomy or delta-9-tetrahydrocannabinol in rats. Maprotiline potentiated anesthesia induced by thiopental or ether in mice to a lesser degree than did amitriptyline, and failed to counteract the lethal effect of physostigmine or oxotremorine tremor in mice, indicating that this drug has no central anti-cholinergic effect. Maprotiline markedly inhibited hyperemotionality of the rat with either septal lesions or olfactory bulb ablations, suggesting that it does have a tranquilizing effect. Inhibition of conditioned avoidance response of the rat in the shuttle box and reduction of methamphetamine group toxicity with maprotiline were similar to those with amitriptyline. Maprotiline exaggerated pentetrazol convulsion, decreased muscle tone and impaired coordinated motor activity in mice to a much lesser degree than amitriptyline and imipramine. LD50 of maprotiline was approximately twice that of imipramine and three times that of amitriptyline. These results indicate that maprotiline is a new type of antidepressant, has a low toxicity and shares both potent antidepressant and some tranquilizing effect, without possessing central anticholinergic action.     

Trazodone Hydrochloride: A Wide Spectrum Antidepressant with a Unique Pharmacological Profile

Trazodone is a new antidepressant agent that was recently introduced in the United States. It has a unique pharmacological profile that is not typical of either tricyclic or monoamine oxidase inhibitor antidepressants. As such it represents a new class of antidepressant drugs. The efficacy of trazodone has been clearly established in comparative studies with imipramine and amitriptyline. Major depression is the principal indication for its use, but good results have been shown in a wide variety of depressive subtypes. Of particular importance is the low frequency of adverse reactions seen with this drug.     

Assessment by antipyrine test of bupropion enzymic induction in elderly depressed patients

Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism-inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half-life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme-inducer.     

Tricyclic antidepressant plasma level monitoring: intraindividual variability in everyday practice

Summary The intraindividual variability of tricyclic antidepressant plasma levels (amitriptyline, clomipramine, imipramine and desimipramine) has been examined twice in 127 depressed outpatients. The dosage, route of administration, concomitant drug therapy and clinical condition were identical on the two occasions, which were 1 to 2 months apart.The mean plasma levels of the antidepressant drug and its main metabolite did not differ significantly in the first and second blood samples, indicating little intraindividual variation.     

A method of monitoring drugs for adverse reactions II. Amitriptyline and cardiac disease

Summary A hospital based drug information system has been used to investigate a suspected association between unexpected death and the administration of the tricyclic antidepressant, amitriptyline in patients with a diagnosis of cardiac disease. The hospital information system made it possible to establish that 6 out of 53 such patients died suddenly and unexpectedly following the administration of the drug compared with no deaths in 53 control patients matched for age, sex, diagnosis and duration of stay. This high frequency of unexpected death was not found in patients without cardiac disease receiving amitriptyline nor in patients with cardiac disease receiving imipramine. It was observed that the cardiac patients receiving imipramine comprised a geriatric population occupying long stay beds whereas the amitriptyline patients occupied acute medical beds. It is concluded that amitriptyline should be used with caution in patients with cardiac disease. The importance of the accurate recording of medical information is stressed and the potentialities of hospital information systems are discussed.     

Reliable HPLC method for therapeutic drug monitoring of frequently prescribed tricyclic and nontricyclic antidepressants

A new high-performance liquid chromatography method is presented for the determination of 10 frequently prescribed tricyclic and nontricyclic antidepressants: imipramine, amitriptyline, clomipramine, fluoxetine, sertraline, paroxetine, citalopram, mirtazapine, moclobemide and duloxetine. The simple and accurate sample preparation step, consisted of liquid:liquid extraction with recoveries ranging between 72% and 86%, except for moclobemide (59%). Separation was obtained using a reverse phase Select B column under isocratic conditions with UV detection (230 nm). The mobile phase consisted of 35% of a mixture of acetonitrile/methanol (92:8, v/v) and 65% of 0.25 mol L(-1) sodium acetate buffer, pH 4.5. The standard curves were linear over a working range of 2.5-1000 ng mL(-1) for moclobemide, 5-2000 ng mL(-1) for citalopram, duloxetine, fluoxetine, 10-2000 ng mL(-1) for sertraline, imipramine, paroxetine, mirtazapine and clomipramine. The intra-assay and inter-assay precision and accuracy were studied at three concentrations (50, 200, and 500 ng mL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 8.8%, and all inter-CVs were less than 10%. Limits of quantification were 2.5 ng mL(-1) for moclobemide, 5 ng mL(-1) for citalopram, duloxetine and amitriptyline, and 10 ng mL(-1) for mirtazapine, paroxetine, imipramine, fluoxetine, sertraline, and clomipramine. No interference of the drugs normally associated with antidepressants was observed. The method has been successfully applied to the analysis of real samples, for the drug monitoring of ten frequently prescribed tricyclic and non-tricyclic antidepressant drugs.     

A SepPak HPLC method for tricyclic antidepressant drugs in human vitreous humor

Death from tricyclic antidepressant overdose has become an all-too-common occurrence. Several factors, including postmortem concentration changes, can render blood and tissue samples useless for the determination of antidepressant drug concentrations. We present here an efficient method of solid-phase extraction for these drugs from vitreous humor and a reversed-phase, isocratic high-performance liquid chromatographic method for the simultaneous quantitation of amitriptyline, doxepin, and imipramine and their desmethylated metabolites.     

A two-week treatment with antidepressants does not increase the density of 3H-prazosin binding sites in the cerebral cortex of elderly rats

The effect of repeated administration of antidepressants (imipramine, amitriptyline, citalopram) on the 3H-prazosin binding to alpha 1-adrenoceptors in the cerebral cortex of elderly (12-14-month old) rats was studied. Additionally, the effect evoked by imipramine was also studied in their young (2-3-month old) counterparts. Imipramine increased the Bmax value by 27% in young animals, while imipramine, amitriptyline and citalopram did not change the 3H-prazosin binding (Bmax, KD) in elderly rats. The obtained results demonstrate that the ability of antidepressants to increase the number of alpha 1-adrenoceptors in the rat cerebral cortex disappears with age.     

Evaluation of amoxapine

The pharmacology, pharmacokinetics, clinical trials, side effects, and dosage of amoxapine are reviewed. Amoxapine is a tricyclic dibenzoxazepine antidepressant that is chemically similar to the antipsychotic agent loxapine. In animal tests, amoxapine and its metabolites block reuptake of the neurotransmitter norepinephrine, with little effect on serotonin. It is rapidly and virtually completely absorbed when administered orally; peak serum concentrations occur one to two hours after ingestion. Amoxapine is widely distributed throughout body tissues and is 90% bound to serum proteins. Aromatic hydroxylation in the liver produces two major metabolites, which are excreted in the urine primarily but also in the feces. Amoxapine's elimination half-life is eight hours; one of the metabolites has a long half-life (30 hours). In clinical trials, amoxapine has been compared with amitriptyline and imipramine in several types of depressed patients. In some studies, amoxapine's therapeutic effects were measurable earlier (at one or two weeks after initiation of therapy) than those of the amitriptyline or imipramine, but generally only a portion of the depression-rating scales yielded statistically significant differences. Side effects noted during amoxapine therapy include hypotension (42%), drowsiness (14%), xerostomia (14%), constipation (12%), blurred vision (7%), fatigue (5%), and vertigo (5%). Amoxapine is approved by FDA for use in patients with neurotic or reactive depressive disorders, endogenous or psychotic depression, and depression accompanied by anxiety or agitation. The usual adult dosage is 200-300 mg daily, either in divided doses or a single bedtime dose. Amoxapine is a safe and effective antidepressant with no striking advantages over other available agents.     

Repeated treatment with imipramine or amitriptyline increases the locomotor response of rats to (+)-amphetamine given into the nucleus accumbens

Effects of bilateral injections of (+)-amphetamine (5 micrograms/0.5 microliter) into the nucleus accumbens were investigated in rats treated repeatedly with imipramine or amitriptyline. Repeated but not acute administration of either drug enhanced the locomotor hyperactivity induced by (+)-amphetamine given 2 or 72 h after the last dose of antidepressant. The results indicate that the increased responsiveness of the mesolimbic dopaminergic system may be involved in the action of antidepressant drugs.     

Initial severity and diagnosis influence the relationship of tricyclic plasma levels to response: a statistical review

There is considerable controversy about the clinical value of monitoring tricyclic antidepressant plasma levels. To investigate this issue the authors pooled data from 17 published plasma level studies of imipramine, amitriptyline, or nortriptyline, involving over 400 patients. The findings suggest that tricyclic antidepressant plasma level monitoring is important primarily for patients who are severely depressed or who have endogenous features. Monitoring is especially important for such patients who are treated with amitriptyline or nortriptyline, since failure to respond may be associated with very low or very high plasma levels. These data have implications for tricyclic antidepressant plasma level monitoring and future research.