Influence of neuroleptics on the metabolism of tricyclic antidepressants--in vitro experiments with rat liver microsomes.

The influence of two neuroleptics--the phenothiazine perazine and the butyrophenone haloperidol--on the metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), and chlorimipramine (CMI) was studied in vitro in isolated liver microsomes of female Sprague-Dawley rats. The rats were pretreated over 10 days with either NaCl solutions or with 1, 3, and 10 mg/kg haloperidol or 5 and 15 mg/kg perazine, respectively. The microsomal fraction was incubated with various concentrations of antidepressants. The drugs and their metabolites were analyzed by high-performance liquid chromatography (HPLC). Neither pretreatment with haloperidol nor perazine had any significant influence on the demethylation and N-oxidation activity of the microsomes. Benzylic 10-hydroxylation of AMI or IMI or 10- and 11-hydroxylation of CMI was inhibited significantly by pretreatment with perazine, as was 2-hydroxylation of IMI and CMI, whereas 8-hydroxylation of CMI was not influenced. The inhibition was dose dependent. With haloperidol, only the high dose of 10 mg/kg caused a significant inhibition of benzylic 10-hydroxylation, whereas phenolic hydroxylation was not influenced. The inhibition was much lower than for perazine. Comparing the results with pharmacokinetic studies in humans revealed a good agreement in metabolic pathways. The study could therefore be important in the choice of neuroleptic drugs in combination therapy.

Schizophrenic patients treated with high dose phenothiazine or thioxanthene become deficient in polyunsaturated fatty acids in their thrombocytes.

Total fatty acids were analysed in thrombocytes of schizophrenic patients treated with a "high dose" or "low dose" monotherapy of neuroleptic drugs phenothiazine or thioxanthene. The ratio of the very long chain fatty acid hexacosanoic acid to the long chain fatty acid docosanoic acid (C26:0/C22:0) increased in the "high dose" and "low dose" groups as compared to healthy untreated controls (P less than 0.05). The polyunsaturated fatty acid arachidonic acid decreased in the "high" and "low dose" groups (P less than 0.01 and P less than 0.05). The polyunsaturated fatty acids alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid were not detectable in most of the "high dose" schizophrenic patients, however, they were found in the "low dose" group and in the controls. There was a negative correlation between the daily dosage of phenothiazine and the percentages of the polyunsaturated fatty acids arachidonic acid and alpha-linolenic acid+eicosapentaenoic acid+docosahexaenoic acid in thrombocytes (r = -0.87, P less than 0.01 and r = -0.81, P less than 0.01). Two patients of the "high dose" group with an especially high and long lasting monotherapy of neuroleptics were nearly devoid of polyunsaturated fatty acids in their thrombocytes. Untreated schizophrenic patients exhibited a fatty acid pattern in their thrombocytes not markedly different from that of the healthy untreated control group. We conclude that neuroleptic drugs phenothiazine or thioxanthene can alter the fatty acid pattern of thrombocytes.

Comparison of growth hormone and prolactin stimulation induced by chlorimipramine and desimipramine in man in connection with chlorimipramine metabolism.

In order to compare the effects of chlorimipramine (CI) and desimipramine (DMI) on growth hormone (GH) and on prolactin (PRL) secretion equal doses of 25 mg CI or DMI were administered i.v. to 12 healthy subjects each. In this dose, DMI, which primarily inhibits norepinephrine (NE) uptake, induced a significantly higher GH stimulation, compared to CI, whereas CI, which primarily inhibits serotonin (5-HT) uptake induced a significantly higher PRL stimulation, compared to DMI. Following DMI administration, an increase in GH (greater than 7.5 ng/ml) was found in all subjects, after CI in only about 50% of the subjects. The varying interindividual GH secretions after CI are discussed on the basis of the different plasma levels of CI and of its metabolite desmethyl-chlorimipramine (DCI), which is a NE uptake-inhibitor.

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes.

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.

The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression.

RATIONALE: A serotonergic dysfunction is supposed to play a pathogenetic role in depression, but there is a considerable number of non-responders in the acute treatment of depression with serotonergic agents like SSRI. Thus, an indicator of central serotonergic activity could lead to a more specific pharmacological treatment of depression. In animal and human data there is a growing amount of evidence that a strong loudness dependency of late auditory evoked potentials (LDAEP) is an indicator of low serotonergic activity and vice versa. OBJECTIVE: In 29 depressive inpatients (DSM-III-R diagnosis 296.x in 28 patients, 300.4 in one patient), the hypothesis was tested that a strong LDAEP prior to treatment can predict a better clinical outcome under SSRI treatment over 4 weeks. RESULTS: Patients with a strong pre-treatment LDAEP had a significantly greater decrease of depressive symptoms (Hamilton Scale for Depression) after 4 weeks than patients with a flat LDAEP. Significantly more responders fell into the group with a high LDAEP. Contrary to what might be expected, a second recording in a subsample of 19 patients after 4 weeks of treatment failed to show changes in the LDAEP. CONCLUSION: Our finding confirms the hypothesis that a strong LDAEP, indicating a low serotonergic activity, is related to a favorable response to acute SSRI treatment in depression. The LDAEP is a promising tool for the prediction of response to serotonin agonists in depression and it seems to be of clinical importance.

Nonlinear pharmacokinetics of chlorimipramine after infusion and oral administration in patients.

In this study the pharmacokinetics of 75 mg and 150 mg chlorimipramine after infusion and tablets was followed for four weeks in chronically treated patients. The clearance was found to be dose dependent. From the time course of the metabolite desmethylchlorimipramine in plasma it can be concluded, that chlorimipramine tablets are resorbed totally. No correlation between pharmacokinetic and improvement parameters could be found. Doubling of the dosage leads to 3 fold chlorimipramine and 4 fold desmethylchlorimipramine concentrations. The estimated half lives are higher than known hitherto. Especially for chronic treatment with 150 mg chlorimipramine, plasma concentration monitoring is recommended, because 20% of the patients did not reach steady state for chlorimipramine and 60% for desmethylchlorimipramine, in these 4 weeks.

Endogenous opiates increase pain tolerance after stress in humans.

This study investigates the role of endogenous opioids in the regulation of pain in humans. Two groups of healthy volunteers were subjected to different stress situations (cold pressor and arithmetic). In a double-blind design the changes in pain tolerance after stress were measured after an injection of either 0.8 mg naloxone or placebo. The cold pressor test raised the pain threshold in the placebo-treated group, but not in the naloxone-treated group. Mental arithmetic had no effect on pain perception. One can conclude therefore that physical stress may change pain perception depending upon the secretion of endogenous opioids.

Quantitative high-performance liquid chromatographic assay for the determination of maprotiline and oxaprotiline in human plasma.

A procedure is described which permits the determination of maprotiline and oxaprotiline in human blood or plasma at therapeutic concentrations. The biological fluids are extracted with base and the extract is injected into a high-performance liquid chromatograph. The substances are detected by a UV detector operating at 214 nm, amitriptyline being used as internal standard. Concentrations as low as 2 ng per sample can be measured.

On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients.

The antidepressant effect of amitriptyline was studied in 28 endogenous depressive patients. They received 150 mg amitriptyline once nightly in a sustained release form for 4 weeks. Blood samples were drawn 12 hrs. after medication. Amitriptyline concentrations were between 35--300 ng/ml Nortriptyline concentrations were between 20--330 ng/ml. No correlations were found between plasma concentrations of amitriptyline, nortriptyline, or their sum, and the clinical outcome of treatment. Plasma levels of amitriptyline depended on neither the age nor the sex of the patients. A significant correlation was found between the ratio of nortriptyline to amitriptyline concentrations in serum (demethylation ratio) and clinical improvement. The demethylation ratio appeared to be relatively constant after a few days of treatment. The results suggest that monitoring the demethylation ratio of endogenous depressive patients treated with amitriptyline may predict therapeutic effects of the treatment. They also suggest that a balance between noradrenergic and serotonergic mechanisms is necessary to improve antidepressant treatment with amitriptyline.

Determination of benperidol in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the quantitative determination of benperidol in human plasma using haloperidol as internal standard is described. The method involves liquid-liquid extraction, separation of the substances on a reversed-phase column C18 followed by ultraviolet detection at 254 nm. The mobile phase consists of 32% acetonitrile in 0.05 M potassium dihydrogen phosphate buffer (pH 2.8). The detection limit is 0.5-1.0 ng/ml using 2- or 4-ml plasma samples.

4-methoxy-3-hydroxyphenylglycol as an internal standard for the determination of 3-methoxy-4-hydroxyphenyglycol in urine: results obtained in depressed patients and healthy controls.

A modification of the method developed by Dekirmenjian & Maas (1970) Anal. Biochem. 35, 113-122) is described for the determination of 3-methoxy-4-hydroxyphenylglycol in urine. The use of 4-methoxy-3-hydroxyphenylglycol as an internal standard improves the accuracy, simplicity and reproducibility. Therefore, the method is suitable for routine determination in laboratories without gas chromatography/mass spectrometry equipment. Some results obtained in depressed patients and healthy controls are presented.

Assay for maprotiline in human serum with improved sensitivity and selectivity.

The use of a photoreactor and fluorescence detection enables measurement of the tetracyclic antidepressant drug 3-(9,10-dihydro-9,10-ethanoanthracene-9-yl)-N-methylpropylamine (maprotiline) with a sensitivity of 100 pg/ml serum. This detection system is highly specific and enables the measurement of very low concentrations in the presence of high concentrations of other drugs that are often found in patient samples. The mean free portions of maprotiline and desmethylmaprotiline were found to be 2.2% and 1.5%, respectively.

Single oral dose pharmacokinetics of amitriptylinoxide and amitriptyline in humans.

Eleven healthy volunteers were examined in a pharmacokinetic study. After oral administration of 50 mg amitriptylinoxide or 50 mg amitriptyline the plasma levels of amitriptylinoxide and its main metabolites amitriptyline and nortriptyline were investigated over 24 hours. The results indicate that amitriptylinoxide is more rapidly absorbed than amitriptyline and eliminated with a mean half-life of 1.5 hours. The change with time in the levels of amitriptyline formed from the oxide is similar to that of amitriptyline after ingestion of amitriptyline. However, the plasma concentration of amitriptylinoxide, reflected by the area under the time curve (AUC), exceeds that of its metabolite amitriptyline twelvefold.

A highly sensitive and precise radioenzymatic assay for plasma epinephrine and norepinephrine.

A modification of the procedures for simultaneous radiometric determinations of plasma epinephrine (E) and norepinephrine (NE) was developed. High performance liquid chromatography (HPLC) is excellently suited to separate the radioactive products of the enzymatic methylation of catecholamines. The time-saving procedure shows significant advantages as against the conventional method of isolating normetanephrine and metanephrine by thin layer chromatography. The high sensitivity (detection limit = 1 pg), specifity, and good precision (cv = 6%) of this assay are demonstrated.

Long-term effects of tricyclic antidepressants on norepinephrine kinetics in humans.

The nature of the discrepancy between short-term pharmacokinetic data (hours) on the one hand and long-term pharmacodynamic effects and the clinical latency of therapeutic amelioration on the other hand by tricyclic antidepressants is still unclear. A relapsed sensibilization of neuronal, immunologic, and endocrinologic systems by changes in receptor sensitivity has been proposed. However, the discrepancy may have a strong influence on many aspects of antidepressive therapy in humans. The aim of our study was to demonstrate long-term pharmacodynamic effects by single-dose antidepressive treatment in humans by measuring heart rate parameters in response to neurochemical parameters. 25 young healthy probands, divided into three treatment groups (amitriptyline, n = 10; clomipramine, n = 10; placebo, n = 5), were challenged by a noradrenaline infusion test at baseline and one and 21 days after a single dose of antidepressant. Heart rate and blood pressure as well as plasma levels of antidepressants and of noradrenaline and adrenaline were measured in response to noradrenaline infusion test. Noradrenaline infusion rate to reach an increase in blood pressure of RR > 30 mmHg was significantly decreased for both antidepressants on day 1. The same effect was true for the amitriptyline group on day 21. Furthermore, pretreated probands respond to antidepressants in a different way when compared to untreated probands. Like depressed patients under therapy they respond with a dramatic increase in sensitivity of the alphal-adrenergic receptor. We could demonstrate that the long-term pharmacodynamic effects have a strong influence on antidepressive therapy. A prolonged pharmacodynamic effect influences further clinical studies as well as our thinking about adverse drug effects. In clinical studies, washout periods may be to short to overcome the benefits of a previous medication. Adverse drug effects are often seen during periods when drugs were changed. The negative effect may be due to an additional effect of both medicaments.

[Non-fatal effect of highly toxic amitriptyline level after suicide attempt. A case report]. / Nichtletale Wirkung hochtoxischer Amitriptylin-Spiegel nach Suizidversuch. Ein Fallbericht.

Pharmacotherapeutic intervention in psychiatric patients often bears the risk of drug abuse for suicide attempts. Especially intoxication with tricyclic antidepressants, e.g., amitriptyline, may cause severe complications such as cardiac arrhythmia. Even under intensive care conditions, 2-3% of intoxicated patients still die. Here, we report on a depressed female patient who, thanks to timely and intense intervention, survived a suicide attempt with amitriptyline despite highly toxic plasma levels.

Quality control of amitriptyline and nortriptyline plasma level assessments: a multicenter study.

Numerous studies report about the relationship between the clinical effectiveness of amitriptyline (At) and the plasma level of this drug and of its most important metabolite, nortriptyline (Nt). These agents are therefore very frequently examined for clinical applications and for research programmes in specialized laboratories. The experience with antiepileptic drugs suggests the necessity of quality controls for antidepressants also. Therefore, five institutions in Western Europe performed two such experiments within a year. Two kinds of blood samples were sent for analysis: 1. plasma samples spiked with different quantities of At and Nt from an untreated subject; 2. plasma samples from patients treated with clinical doses of At. Each laboratory happened to use a different analytical method: TLC, HPLC, GC-NPD, GC-FID and GC-MS. The results clearly show the usefulness and the necessity of quality controls for this category of drugs as well. They form the basis for the improvement of the methods of each laboratory in particular. In this context, intralaboratory quality controls are also possible, if one disposes of two different methods. The findings of this study suggest that published reports on relationships between clinical and pharmacological parameters should be considered critically as to possible methodological bias.

[Controlled study on the possible benefits of combination therapy with chlorimipramine and haloperidol inpatients with endogenous depression]. / Kontrollierte Studie über die möglichen Vorteile einer Kombinationstherapie mit Chlorimipramin und Haloperidol bei endogen Depressiven.

Ther is some clinical evidence that neuroleptics are able to increase the therapeutic effect of antidepressive drugs. From a theoretical viewpoint this could be due to influences on pharmacokinetic or receptor sensibility. In a controlled trial on 20 endogenous depressives the advantage of a combined medication of 150 mg Chlorimipramine and 9 mg p.d. Haloperidol (given over six days) were tested. Neither during the combined medication, nor after discontinuation of haloperidol, this treatment regimen proved better clinical results. According to the literature serum levels of chlorimipramine were higher in the experimental group, not the levels of desmethyl-chlorimipramine.

Unstable anticoagulation in the course of amitriptyline treatment.

A potential drug-drug interaction between the tricyclic antidepressant amitriptyline and the oral anticoagulant phenprocoumon, causing intensified hypo- and/or hyperprothrombinemic effects, was investigated. In seven patients simultaneously receiving amitriptyline and phenprocoumon the course of the Quick values and the amitriptyline and phenprocoumon dosages were registered. The resulting data represented graphically was additionally compared with data and diagrams gained from a control group of seven phenprocoumon patients not receiving amitriptyline. Whereas in the control group the average Quick values (or the target International Normalized Ratio) lay within the required therapeutic range, massive fluctuations were seen in the amitriptyline-treated patients. These fluctuations did not disappear until the amitriptyline medication was discontinued. Whether our findings are actually due to a clinically relevant drug-drug interaction needs to be investigated in further controlled studies based on a larger number of patients, the more so as no comparable investigations and only few references to this subject are to be found in the literature. Should an amitriptyline influence on the frequently prescribed coumarin derivative be proven, an increased risk of rethrombosis or bleeding complications in patients receiving both amitriptyline and phenprocoumon would appear to be indicated.