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PubMed1983

Bupropion and amitriptyline in the treatment of depressed patients.

Bupropion, a specific dopamine reuptake inhibitor, was compared to amitriptyline in two multicenter studies involving 183 depressed outpatients and inpatients. Initial results from these ongoing studies provide additional evidence of the antidepressant activity of bupropion. At the end of the treatment periods (6 weeks for inpatients and 13 weeks for outpatients), bupropion appeared to be at least as effective as amitriptyline. However, bupropion exerted a slightly but nonsignificantly smaller overall therapeutic effect than amitriptyline during the first 4 weeks of drug treatment. Slight weight loss and dopaminergic side effects, such as insomnia, nausea/vomiting, and anorexia, were somewhat more common among bupropion-treated patients. Compared to bupropion, amitriptyline induced more weight gain and had more anticholinergic, antihistaminic, and antiadrenergic side effects. In view of its numerous sites of action, amitriptyline does not appear to be the ideal antidepressant. It remains to be demonstrated whether bupropion has any advantage over secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.

Adolescent↗

PubMed1984

Stabilized analysis of antidepressant drugs by solvent-recycled liquid chromatography: procedure and proposed resolution mechanisms for chromatography.

In this efficient extraction and isocratic liquid-chromatographic procedure for measuring eight antidepressant drugs in serum (amoxapine, 8-hydroxyamoxapine, doxepin, desmethyldoxepin, imipramine, desipramine, amitriptyline, and nortriptyline), they are extracted from serum as a group by use of disposable solid-phase cyanopropyl columns; the eluate is injected directly onto a Zorbax cyanopropyl analytical column. This sample preparation circumvents potential problems of drug instability associated with the usual evaporating/concentrating techniques. Recycling the acetic acid/acetonitrile/n-butylamine mobile phase not only maintains a stable, cost-effective system, it also prolongs column life. Standard curves for all eight drugs are linear to 1000 micrograms/L; the detection limit is 8-10 micrograms/L. For all drugs and metabolites, within-run CVs were 0.9 to 2.2%, between-run CVs 2.1 to 3.8%. Analytical recovery of the solid-phase extraction step was 85 to 100% (mean = 94.5%) for all analytes. Standards and controls, stored frozen in drug-free serum, are stable for at least six months. We also report a study of separation mechanisms.

Antidepressive Agents, Tricyclic↗

PubMed1984

The treatment of tricyclic antidepressant overdose with repeated charcoal.

Activated charcoal given repeatedly through a nasogastric tube to three patients in coma from amitriptyline overdose greatly accelerated tricyclic elimination: the apparent half-life fell below 10 hours for each patient to as low as 4 hours. This contrasts with extended half-lives for amitriptyline elimination averaging 36.8 hours and regularly over 60 hours previously reported for overdoses treated without repeated charcoal. The enterohepatic recirculation of amitriptyline and nortriptyline appears to be a major influence on keeping their blood levels up. In one case, intravenous diazepam inhibited tricyclic elimination.

Adolescent↗

PubMedDate not supplied

Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: effect on dopaminergic and serotonergic functions.

The effect of prolonged administration of the clinically effective and specific serotonin (5-HT)-uptake-inhibitor, citalopram, has been studied in rats on behavioural measures of dopaminergic (DA) and serotonergic activity and on DA D-2, 5-HT2, alpha 1- and beta-adrenergic receptor number and affinity in vitro. Thirteen days treatment with citalopram in the diet (40 mg/kg/day) did not change receptor binding for either of the ligands studied, although citalopram was detected in high concentrations in brain and plasma and induced a 75% depletion of 5-HT in whole blood. This citalopram dose-regimen was followed by a potentiated hypermotility response to d-amphetamine. Also DA-dependent hypermotility induced by methylphenidate and (+)-3-PPP was increased. In contrast, the 5-HT2-receptor mediated head shake syndrome induced by 1-5-HTP or quipazine was decreased after prolonged citalopram treatment. Two weeks oral bolus treatment (10 mg/kg once or twice daily) with the 5-HT-uptake-inhibitors citalopram, fluoxetine, zimelidine, cyanimipramine or paroxetine induced d-amphetamine potentiation, whereas amitriptyline, nortriptyline, imipramine, iprindole, and mianserin treatment showed no effect. It is suggested that d-amphetamine potentiation induced by citalopram is mainly dependent on DA mechanisms, and that this profile is characteristic for preferential 5-HT-uptake-inhibitors. The lack of correlation between behavioural effect and receptor changes was important. Since citalopram has been shown to have clinical antidepressant activity, it is concluded that down-regulation of beta-adrenoceptors is not a prerequisite for antidepressant action.

Animals↗

PubMed1984

Liquid-chromatographic determination of two antidepressants, trazodone and mianserin, in plasma.

Plasma containing trazodone or mianserin was extracted. The organic phase containing trazodone was evaporated and the residue was reconstituted in dilute acid. Mianserin was back-extracted from the organic phase with dilute acid. Both drugs were chromatographed on mu Bondapak C18 columns, with phosphate/acetonitrile as the mobile phase. Peak-height ratios of drug/internal standard were linearly correlated with concentrations between 25 and 2000 micrograms/L for trazodone, and between 25 and 200 micrograms/L for mianserin, with respective between-run CVs of 4.7% and 7.6%. Detection limits were 5 ng. Of some common drugs and metabolites examined, nortriptyline co-elutes with the internal standard used in the trazodone assay, while flurazepam co-elutes with mianserin. Concentrations of trazodone in 26 patients ranged from 73 to 1678 micrograms/L. For two geriatric patients, concentrations were about 2000 micrograms/L. For two overdose patients, they were about 5000 micrograms/L. The concentration of mianserin was 27 micrograms/L for a volunteer treated with a single 40-mg oral dose.

Chromatography, Liquid↗

PubMed1984

Liquid-chromatographic determination of eight tri- and tetracyclic antidepressants and their major active metabolites.

A "high-performance" liquid-chromatographic method is presented for monitoring the therapeutic concentrations, in plasma, of eight tri- and tetracyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, doxepin, clomipramine, maprotiline, and protriptyline) and their major active metabolites. One of two internal standards is added to 0.5 mL of drug-containing plasma, the pH is adjusted to about 9.5 with borate buffer, and the sample is extracted with isoamyl alcohol in hexane. The extracts are chromatographed on a column of silica and absorbance of the effluent is measured at either 214 or 254 nm. Chromatographic response is linearly related to concentration for all components over a 5-500 ng range. Analytical recovery of the drugs and metabolites from plasma is approximately 75 to 85% at low and high concentrations. Within-run and day-to-day precision (CV) is less than 5% for both high and low concentrations of most of these drugs and metabolites. Parallel analysis of clinical samples by gas chromatography indicates that results by the two techniques are comparable. We report some results of therapeutic monitoring of clinical samples.

Antidepressive Agents↗

PubMed1984

Polymorphic drug oxidation in humans.

Genetic polymorphisms in the oxidative metabolism of debrisoquine, mephenytoin, phenformin, sparteine, and tolbutamide have been discovered during recent years. Among these pharmacogenetic conditions, polymorphic oxidation of debrisoquine and sparteine has been intensively studied. Two phenotypes, the extensive (EM) and the poor (PM) metabolizers, have been observed in all populations so far investigated. The PM phenotype exhibits a grossly impaired or nearly absent capacity to metabolize these drugs. The incidence of the PM phenotype in European populations ranges from 5 to 9%. Pronounced variations in the incidence of the PM phenotype have been demonstrated among different ethnic groups. The metabolism of debrisoquine and sparteine is determined by two alleles at a single gene locus; PMs are homozygous for an autosomal recessive gene. Because of markedly impaired metabolism, the PM phenotype develops side effects if normal doses of debrisoquine and sparteine are administered. Defective metabolism in the PM phenotype is not restricted to debrisoquine and sparteine. Impaired metabolism of guanoxan , phenformin, perhexiline, methoxyamphetamine, phenacetin, encainide, metoprolol, alprenolol, bufuralol, nortriptyline, and desipramine have been described. As a consequence of impaired metabolism of these drugs, toxicity and therapeutic failure are observed in the PMs. With regard to molecular mechanisms, studies with microsomes from human liver provide evidence that in the PM phenotype a cytochrome P-450 isozyme is either missing or functionally inadequate.

Cytochrome P-450 Enzyme System↗

PubMed1981

Effects of psychotropic drugs on human sperm motility.

Imipramine has been shown to have a potent inhibitory effect on sperm motility in vitro. Because of the frequent chronic use of antidepressants in treatment of depression, we investigated the in vivo effects of desmethylimipramine and lithium carbonate on sperm function in patients suffering from clinical depression. We also studied the in vitro effects of a series of neurotrophic agents on sperm motility. There were no significant differences in sperm count, viability, or motility between a group of patients diagnosed as having clinical depression and a group of semen donors with normal sperm characteristics. Three weeks of continuous therapy with desmethylimipramine or lithium carbonate resulted in a significant decrease in sperm viability but no significant change in sperm count or motility. The in vitro drug studies demonstrated that imipramine hydrochloride, desmethylimipramine, chlorpromazine, trifluoperazine, and nortriptyline hydrochloride were all potent inhibitors of sperm motility, whereas lithium carbonate had no effect on motility.

Adult↗

PubMed1983

Determination of the antidepressants maprotiline and amoxapine, and their metabolites, in plasma by liquid chromatography.

Maprotiline, amoxapine, and their metabolites were determined in plasma by three separate procedures, each of which involves a three-step extraction followed by reversed-phase separations. Amoxapine, maprotiline, and N-desmethylmaprotiline can be measured with use of a conventional C-18 column with 10% carbon load, but analyses for 7- and 8-hydroxyamoxapines require a small (5-microns) particle size, high carbon load, 20% C-18 column with 0.2 mol/L phosphate as mobile phase. Within-run and day-to-day CVs were 5% and 8%, respectively. Peak-height ratios were linearly correlated with concentrations between 0 and 400 micrograms/L. Detection limits ranged from 1 to 3 ng. Interference studies indicated that nortriptyline co-elutes with maprotiline. Assays of patients' plasma showed substantial amounts of these drugs and most of their metabolites, but only trace amounts of 7-hydroxyamoxapine.

Amoxapine↗

PubMed1983

Urinary MHPG excretion and treatment with desipramine or amitriptyline: prediction of response, effect of treatment, and methodological hazards.

Urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was measured in 49 unipolar depressed outpatients to examine the relationship between pretreatment MHPG levels and therapeutic response to desipramine and amitriptyline and to determine the effects of these agents on MHPG excretion. Pretreatment MHPG excretion was greater in amitriptyline responders than amitriptyline nonresponders, but no different in desipramine responders compared to desipramine nonresponders. Pretreatment MHPG excretion did not differentiate desipramine from amitriptyline responders. Treatment for 3 weeks was associated with a decrement in MHPG excretion, particularly in the desipramine responders and combined desipramine and amitriptyline responders. Among patients within the postulated optimal desipramine plasma level range and patients with plasma amitriptyline plus nortriptyline levels greater than 70 ng/ml, high pretreatment MHPG excretion predicted therapeutic response and response was accompanied by a reduction in MHPG excretion. The interpretation of these findings is possibly confounded by the demonstration of a poor correlation (r = 0.61) between duplicate MHPG samples analyzed by a widely employed gas chromatography method and a gas chromatography/mass spectrometry technique. The methodological pitfalls encountered in the course of this investigation and their possible implications for similar studies are discussed.

Adult↗

PubMed1983

Differential-reinforcement-of-low-rate 72-second schedule: selective effects of antidepressant drugs.

The effects of antidepressant drugs in rats responding under a differential-reinforcement-of-low-rate 72-sec schedule were assessed. Seven clinically used tricyclic antidepressant drugs (imipramine, desipramine, chlorimipramine, protriptyline, nortriptyline, amitriptyline and doxepin), two atypical antidepressants (iprindole and mianserin) and a monoamine oxidase inhibitor (tranylcypromine) dose-dependently reduced response rate and increased reinforcement rate. Nomifensine, an atypical antidepressant which has been reported to have psychomotor stimulant properties and abuse potential, increased response rate and decreased reinforcement rate. Chlorpromazine, an antipsychotic agent, and diphenhydramine, an antihistamine, have been reported to produce effects similar to antidepressants in several behavioral tests, but neither of these drugs mimicked the actions of antidepressants on responding under a differential-reinforcement-of-low-rate 72-sec schedule. Chlorpromazine decreased response rate but did not increase reinforcement rate. Diphenhydramine did not have consistent effects but tended to decrease reinforcement rate. These findings suggest that behavior maintained by the differential-reinforcement-of-low-rate schedule may be selectively affected by antidepressants that have no psychomotor stimulant properties.

Animals↗

PubMed1980

[Effects of mianserin on functions of ascending and descending monoaminergic systems, using experimental models (author's transl)].

Studies were carried out to evaluate the antidepressant action of Mianserin as related to noradrenergic and serotonergic systems. The actions of known tricyclic anti-depressants were comparatively investigated together with Mianserin (Organon). Self-stimulation behavior induced by stimulation of the posterior hypothalamus and substantia nigra was unaffected by Mianserin and imipramine, was suppressed with chlorpromazine and markedly enhanced by methamphetamine. The enhancement due to methamphetamine was suppressed by both Mianserin and chlorpromazine, and was potentiated by imipramine. Mianserin, imipramine and amitriptyline enhanced the rolling movements induced by methamphetamine in rats in which the nigro-striatal dopaminergic system was destroyed by the injection of 6-hydroxydopamine. The excitation induced by ldopa administration, of isocarboxazid treated mouse was enhanced by Mianserin in doses over 25 mg/kg and by imipramine or amitriptyline. The excitation of MK-486 treated mouse, induced by L-5HTP was suppressed by Mianserin, nortriptyline augmented the excitation. The head twitches induced by 5HTP were reduced to 1/10 in onset frequency by Mianserin, 1 mg/kg, p.o. The suppressive potency of amitriptyline in this model was less than 1/5 of that of Mianserin. The potentiation of the flexor reflex of hind limbs of the spinal rat induced by the pretreatment with isocarboxazid and l-dopa, 20 hours after the reserpinization, was markedly suppressed by Mianserin and amitriptyline, but unaffected by imipramine nor chlorimipramine. The potentiation of the extensor reflex of hind limbs of the spinal rat, induced 20 hours after the reserpinization by pretreatment with isocarboxazid and 5-HTP was suppressed by Mianserin, even in a low dose of 0.5 mg/kg, and by amitriptyline in a dose of 10 mg/kg. As far as monoaminergic mechanisms are concerned, the mode of antidepresant action of Mianserin is probably different from that of tricyclic antidepressants.

5-Hydroxytryptophan↗

PubMed1980

[Metabolism and blood levels study of antidepressants: a rationale of their therapeutical use (author's transl)].

The authors show with some examples the interest of pharmacokinetics for the optimization of the therapeutical use of antidepressive agents. They give some indications about bioavailabilty, metabolism and half-life of these compounds and note the importance of the individual variations. They also analyze the studies on the possible relations between the clinical response and the steady-state plasma levels of the unchanged drug and/or its active metabolite. The relation between these two parameters would be linear for imipramine, amitriptyline, clomipramine, doxepine, dibenzepine, and curvilinear for nortriptyline, desipramine, protriptyline, maprotiline and mianserine, especially in endogenous depression. From a previous pharmacokinetic study calculations allow to predict the steady-state plasma concentrations. The question of the side effects and drug interactions is considered.

Antidepressive Agents↗

PubMed1981

[Drug therapy of depression: benefits and limits of blood levels of tricyclic antidepressants].

The introduction of sensitive methods has rendered possible a multitude of studies on the relationship between plasma levels of tricyclics and their clinical effectiveness. However, there are conflicting reports concerning the existence of a "therapeutic window" for the usual antidepressives such as amitriptyline, nortriptyline, chlorimipramine, imipramine, desipramine and maprotiline. The dosage is not indicated routinely but may provide useful hints when the patient does not respond to treatment or does not take the prescribed medication regularly (non-compliance). Plasma measurements of tricyclics have served to investigate the interaction of other drugs, the advantages of single or multiple dosage, the influence of the patient's age and sex and the existence of active metabolites. Other questions have been raised concerning the real efficacy of the drugs, and also concerning the type of depression which responds to this treatment.

Antidepressive Agents, Tricyclic↗

PubMed1982

Quantitative liquid-chromatographic technique for the simultaneous assay of tricyclic antidepressant drugs in plasma or serum.

A quantitative "high-pressure" liquid-chromatographic assay for tricyclic antidepressant drugs in plasma or serum is described in which amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyldoxepin are separated with a 10-micrometer particle size silica column and a methanol/NH4OH/NH4NO3 solvent system. The drugs and two internal standards are extracted with hexane/isoamyl alcohol, the solvent layer is evaporated at 40 degrees C, and the drugs are detected at 254 nm. Drug concentrations are linear with absorbance from 25 to 1000 micrograms/L; within-assay and between-assay CVs are less than or equal to 10%.

Antidepressive Agents, Tricyclic↗

PubMed1982

Sample preparation and liquid-chromatographic analysis for tricyclic antidepressants in serum.

We report two separate sample-preparation procedures and a "high-pressure" liquid-chromatographic method for quantitating nine tricyclic antidepressant drugs: trimipramine, doxepin, amitriptyline, imipramine, desmethyldoxepin, nortriptyline, desipramine, maprotiline, and protriptyline. The drugs are extracted from 1 mL of serum by a single manual hexane extraction or by using DuPont's PREP I Automated Sample Processor. The drugs from either process are chromatographed on a mu-Bondapak-CN column with a mobile phase of acetonitrile/methanol/Na2HPO4, 5 mmol/L (60/15/25 by vol), pH 7.0, at a flow rate of 2.0 mL/min. Absorbance at 254 nm is linear with drug concentration from 25 to 1000 mg/L for each drug. With the manual extraction procedure the detection limit was 10 mg/L, absolute recovery 20-44%, within-run precision (CV) 10.1%, and run-to-run precision 11.1%. The performance of automated sample extraction was better, with a detection limit of 5 mg/l, absolute recovery 72-97%, within-run precision 6.1%, and run-to-run precision 6.6%.

Antidepressive Agents, Tricyclic↗

PubMed1982

Effects of tricyclic antidepressant and anticholinergic drugs on fixed-interval responding in the squirrel monkey.

Squirrel monkeys responded under fixed-interval schedules in which the first response after a fixed time period resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. tricyclic antidepressant drugs markedly increased responding in 3 of 10 monkeys studied; less marked but reliable increases in responding were seen with 3 others, whereas the remaining 4 monkeys showed no increases in responding. Increases in responding were observed with amitriptyline HCl (0.1-17 mg/kg), imipramine HCl (0.3-17 mg/kg), chlorimipramine HCl (0.3-17 mg/kg), nortriptyline HCl (1-17 mg/kg) and desmethylimipramine HCl (1-17 mg/kg). Amitriptyline was most potent and desmethylimipramine least potent. The pattern of individual differences in the effects of the antidepressants was matched by a similar pattern of differences in the effects of atropine sulfate (0.03-1.7 mg/kg) and scopolamine HBr (0.003-0.3 mg/kg). That is, atropine and scopolamine increased responding only in those monkey showing increases in responding with the antidepressant drugs. In contrast, all monkeys showed increases in responding with the histamine H1 antagonist diphenhydramine HCl (0.3-17 mg/kg). The order of potency of the antidepressant drugs for producing response rate increases (i.e., amitriptyline greater than imipramine greater than desmethylimipramine) is the same as that reported by others for the affinity of these drugs for muscarinic binding sites in rat brain. This correspondence in relative potencies in addition to the similar pattern of individual differences produced by the antimuscarinic and antidepressant drugs suggests that the increases in responding observed were mediated by antimuscarinic properties of the antidepressant drugs.

Animals↗

PubMed1982

[Clinically significant inherited differences in the mode of action of drugs].

An important source of interindividual differences in drug action are inherited differences in the pharmacokinetics and pharmacodynamics of many drugs. For most enzymatic reactions of drug biotransformation in the liver, genetic polymorphisms have been observed which lead to a decreased rate of metabolism and/or a different pattern of metabolites in certain subpopulations, ethnic groups or families. Examples of frequent polymorphisms in drug-metabolizing enzymes are deficient N-acetyltransferase (50-70% of the population) and deficient debrisoquine hydroxylase (10% of the population). "Slow acetylators" inactivate isoniazid, hydralazine, procainamide, phenelzine, dapsone, sulfamethazine (sulfadimidine), sulfapyridine and nitrazepam at a decreased rate. The molecular genetic defect causing deficient debrisoquine hydroxylation is still unclear and also affects the metabolism of phenytoin, phenacetin, guanoxan, sparteine, methoxyamphetamine, nortriptyline, encainide, perhexiline and probably other drugs. A relationship has been observed between the defect of metabolism and the clinical effects and toxicity of the drugs involved.

Acetyltransferases↗