Dose-response relationship of sertindole and haloperidol using the pharmacopsychometric triangle.

OBJECTIVE: Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains. METHOD: Selected Positive and Negative Syndrome Scale (PANSS) subscales and the Simpson-Angus scale were tested for validity. Standardized effect sizes [last observation carried forward (LOCF)] at endpoint were calculated. RESULTS: The scales were found to be valid instruments. The PANSS(11) psychotic subscale showed clinically significant effect sizes for all doses of sertindole (12, 20, and 24 mg) and haloperidol (4, 8, and 16 mg). Extrapyramidal effects were evident for all doses of haloperidol, but absent for the lower doses of sertindole. The PANSS(6) depression subscale, a proxy measure of quality of life, showed a clinically significant effect for sertindole 20 mg and no effect for haloperidol. CONCLUSION: This re-analysis confirmed the antipsychotic effect and absence of extrapyramidal effects for sertindole and, in addition, showed a clinically significant antidepressant effect. A profile for bipolar states emerged.

Lack of citalopram effect on oral digoxin pharmacokinetics.

The effect of chronic administration of citalopram on the single oral dose pharmacokinetics of digoxin was evaluated in 11 healthy adult subjects in an open, one-way crossover study. Subjects received 1 mg digoxin on day 1. Serial blood samples and total urine were collected over 192 hours, followed by an 11-day washout period. On days 22 through 50, subjects received 40 mg citalopram once daily. On day 43, a single dose of 1 mg digoxin was coadministered; again, serial blood samples and total urine were collected over 192 hours after the digoxin dose. There were no statistically significant differences in any of the digoxin pharmacokinetic parameters (AUC(0-->24), AUC(0-->infinity), Cmax, tmax, t(1/2), CL/F, CLrenal, and Ae(0-->infinity)), and the 90% confidence intervals for treatment differences for the parameters (except for tmax) were all within 80% to 125%. Concomitant digoxin administration did not significantly affect citalopram pharmacokinetics. The treatment was well tolerated by all subjects; no serious adverse events and no clinically significant ECG changes were observed. These data suggest that it is unlikely that concomitantly administered citalopram would have any significant effect on serum digoxin concentrations in patients who are receiving chronic digoxin therapy.

Cardiac safety of citalopram: prospective trials and retrospective analyses.

The selective serotonin reuptake inhibitors (SSRIs) are believed to have a more benign cardiovascular safety profile than do the tricyclic antidepressants. The effects of the SSRI citalopram on cardiac conduction and repolarization have been extensively evaluated, both in prospective studies in volunteers and patients and in retrospective evaluations of all electrocardiographic (ECG) data from all clinical trials conducted from 1978 through 1996 (a total of 40 studies). A randomized, double-blind, placebo-controlled study was conducted in healthy volunteers (N = 23) to assess intraindividual variability of the QTc interval, as well as possible changes during treatment with placebo or citalopram, and its correlation to plasma drug levels. To document any dose-related changes, ECGs were performed at baseline and at the end of study in three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly patients (N = 1,460) with major depression and/or dementia. Finally, more than 6,000 ECGs (N = 1,789 citalopram-treated patients) collected from all clinical trials conducted from 1978 through 1996 were reassessed in a standardized manner to identify any effects of citalopram on ECG parameters. Results of both prospective and retrospective analyses showed that the only effect of citalopram on ECG findings is a small reduction in heart rate (< or = 8 beats per minute). There were no significant effects on PQ, QRS, or QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization during short- or long-term treatment.

Comparison of the tolerability and efficacy of citalopram and amitriptyline in elderly depressed patients treated in general practice.

The enhanced sensitivity of the elderly to the side effects produced by tricyclic antidepressants (TCAs), and the frequency and type of adverse events, have made the treatment of depression in this group difficult. The selective serotonin reuptake inhibitors (SSRIs) have been reported to produce significantly fewer undesirable side effects and display better tolerance than TCAs. We compared the therapeutic actions and side effects produced by citalopram, the most selective SSRI available, with amitriptyline in a group of elderly patients (aged 65 and older) diagnosed with major depression. In a double-blind, double-dummy, parallel-group, multicenter comparison of citalopram (20 or 40 mg/day) and amitriptyline (50 or 100 mg/day), patients who did not respond to placebo during a 1-week single-blind phase were randomly assigned to receive citalopram or amitriptyline for 8 weeks. Efficacy measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Scale (HAMD), and Clinical Global Impressions. Both drug treatments produced equivalent time-related declines in severity of depression, so that by 8 weeks slightly more than 50% of the patients in each group experienced marked recovery, defined as MADRS scores < or = 12. Amitriptyline produced a greater overall incidence of adverse events, including a significantly higher (P < 0.001) percentage of patients reporting dry mouth (34% vs. 7%), as well as a significantly higher (P < 0.02) incidence of somnolence. Constipation and fatigue also occurred more frequently in the amitriptyline than in the citalopram group. For only one event (nausea) did the citalopram group report a significantly greater (P = 0.012) incidence (12.8% vs. 4.8%). On the basis of these results, it was concluded that citalopram is as effective an antidepressant as amitriptyline in the treatment of the depressed elderly. Because of its low incidence and low magnitude of side effects, citalopram seems especially useful in private practice.

Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Citalopram: interaction studies with levomepromazine, imipramine, and lithium.

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.

Citalopram versus mianserin. A controlled, double-blind trial in depressed patients.

In a double-blind trial, comprising 60 endogenously depressed patients, citalopram was compared with mianserin. Fifty-eight patients completed the 6-week trial period with ratings and side effect recordings at weeks 0, 1, 2, 4, and 6. Both drugs were administered as a single evening dose, 20-80 mg (most frequently 40 mg) for citalopram and 60-120 mg (most frequently 90 mg) for mianserin. CPRS (Subscale for Depression) total scores showed a highly significant reduction in both groups with a significant difference in favour of citalopram after 1 and 2 weeks. Based on the Global Evaluation of the Severity of Illness there were 18 complete and three partial responders on citalopram and 13 complete and four partial responders on mianserin. Six patients on citalopram and one patient on mianserin showed mild or moderate side effects, but no cardiovascular side effects were recorded. The authors conclude that citalopram is a safe antidepressant drug, presumably better than mianserin.

Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram. A double-blind comparison of three dose levels.

Three dose levels (5, 25, and 50 mg once daily) of the selective serotonin uptake inhibitor citalopram were compared in a four-week, double-blind trial in depressed patients. Serum levels of citalopram and desmethylcitalopram, and the inhibitory effect of serum on serotonin uptake by fresh platelets, were assessed once weekly during the trial. The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Asberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg. Marked improvement was seen in ten patients with steady state levels in the range 70 to 335 nM. The ten nonendogenously depressed patients had steady state levels from 15 to 620 nM; complete remission was seen in the three with the lowest levels (15-25 nM). No significant correlation was found between serum drug level and the few reported side effects.

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.

Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram.

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mumol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mumol/kg for 13 days and after oral bolus injection (49 mumol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.

Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram.

The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW = 405) was given in the diet, 99 or 25 mumol/kg daily, for 13 days or orally, 49 mumol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75-90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie- Hoffstee analysis. No changes were seen in Bmax and Kd for beta-receptors (3H-dihydroalprenolol) in frontal cortex, occipital + temporal cortex, whole cortex and limbic structures, 5-HT2 receptors (3H-spiroperidol) in frontal and whole cortex, alpha 1-receptors (3H-prazosin) in "rest of brain" and DA D-2 receptors (3H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 mumol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer " atypical " antidepressants.(ABSTRACT TRUNCATED AT 250 WORDS)

Presence of chlorprothixene and its metabolites in breast milk.

Chlorprothixene (CPX) and CPX sulphoxide were demonstrated in breast milk from two psychotic mothers taking 200 mg CPX daily. The milk concentrations of CPX were 120 to 260% greater than in plasma. The estimated amounts of drug administered in breast milk to one of the infants were 15 and 26 micrograms/day for CPX and CPX sulphoxide, respectively. Accordingly, the infant dose of the parent compound would be only 0.1% of the maternal dose/kg body weight. It is not likely that CPX or its metabolite would exert any immediate pharmacological effects in the nursing infant. However, the long term effect of low doses of neuroleptic drugs in the developing infants is not yet known.

Studies on acute toxicity and drug levels of citalopram in the dog.

Electrocardiographic and haemodynamic changes have been studied in conscious dogs after a sublethal oral dose (20 mg . kg-1) of citalopram. Furthermore, the effects of continuous intravenous infusion of citalopram (10 mg . kg-1 per hour) have been studied in conscious and anesthetized dogs. The findings have been related to plasma levels of citalopram. Severe convulsive attacks occurred in conscious dogs after infusion of 21.3 or 26.5 mg . kg-1 and after the oral dose. The convulsions were successfully treated with diazepam. In contrast convulsions were not seen in the anesthetized dogs. They died from respiratory arrest after infusion of 42.2 or 61.3 mg . kg-1. Atrioventricular and intraventricular conduction was unchanged and electrocardiographic changes were negligible. Sinus tachycardia which could be reversed by diazepam and moderate haemodynamic changes were seen. Since no electrocardiographic changes were seen in conscious dogs even during pauses in the convulsive seizure it is concluded that citalopram does not exert cardiotoxic effects in the dog. Good correlation was found between general clinical findings and citalopram levels in plasma. Conscious dogs were exposed to drug levels exceeding those of the average patient by a factor of about 20, while anesthetized dogs had considerable higher concentrations.

Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect--a phase II study.

In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed.

The kinetics of citalopram: single and multiple dose studies in man.

The kinetics of citalopram were studied in a group of volunteers after oral (8 subjects) and intravenous (4 subjects) single doses and repeated oral administration (7 subjects). Inter- and intraindividual variation was limited and linearity of kinetics indicated. Systemic and apparent oral clearance estimates (mean 0.42 l plasma/min.) were similar, indicating roughly complete systemic availability. The presence of unchanged drug in urine, corresponding to 1/7 of the dose, suggests elimination by renal as well as hepatic processes. The data from the intravenous test revealed two compartment kinetics; the total volume of distribution was estimated to about 1150 l and that of the central compartment to 175 l. Upon repeated administration steady-state conditions were generally achieved after one week in agreement with the 33 hrs half-life of elimination. Citalopram peak concentrations were reached within 2-4 hours after the daily dose and maximally two-fold variation was recorded in the 24 hrs dose interval. The levels of a main pharmacodynamically active metabolite were roughly half as high as the drug levels.

Initial, clinical trial of a new, specific 5-HT reuptake inhibitor, citalopram (Lu 10-171).

Ten endogenously depressed inpatients were treated once daily for at least 4 weeks with 40-50 mg citalopram (Lu 10-171) - a specific serotonin reuptake inhibitor. The Hamilton rating scale for depression and global assessment indicated pronounced or moderate response in seven patients and slight or no response in three. Side effects were few, mild and transient and neither anticholinergic nor cardiotoxic effects were observed. No difference was observed between responders and non-responders as regards psychopathology, plasma levels or uptake inhibition. It is concluded, that citalopram seems to possess antidepressant properties and that controlled trials are wanted to evaluate its therapeutic value as well as the underlying hypothesis of serotonin - deficient depressions.

Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels.

Serum concentrations of clopenthixol and flupenthixol have been determined during a four weeks dosage interval in patients treated with intramuscular injections of clopenthixol decanoate or flupenthixol palmitate in Viscoleo. Maximal drug levels were attained by the end of the first week after injection of either preparation. A period of exponential decline was then recorded. The half-lives were estimated to 19 days for clopenthixol and 17 days for flupenthixol. These half-lives most likely refer to the rate of release from the oil depot and not to elimination of drug. The mean ratio between maximal and minimal drug levels was 2.5 for clopenthixol and 3.7 for flupenthixol. Systemic clearance was estimated to about 0.7 l/min and 0.5 l/min, respectively. Significant correlation was found between the administered doses and recorded serum levels, between doses and estimated areas under the serum concentration curves, and also between areas and drug levels. The data indicate more limited individual variability than that seen with other psychotropic drugs, given orally. The study clearly demonstrates, that significant serum levels of active drug is maintained throughout the dosage interval by intramuscular injection of clopenthixol decanoate or flupenthixol palmitate in Viscoleo every fourth week.

Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. IV. Serum levels and clinical outcome.

Two pharmacolkinetic parameters viz. the minimum serum concentration in the dosage interval and the sera under the serum concentration curve have been correlated to 14 parameters for clinical outcome, viz. total points and factor points from the three rating scales, BPRS, CPRS, and side effects scale, in a double blind clinical trial of clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. No statistically significant correlations were observed. It is of some interest, however, that the results suggest that the treatment of individual patients with neurleptics may be adjusted by means of repeated ratings, residual percentage, changes in psychopathology, and determinations of serum concentrations. Our results do not indicate any optimal concentration range for these depot neuroleptics in the maintenance phase of schizophrenia. The so-called therapeutic window as to neuroleptics obviously varies with regard to the phase of the disease as well as the patients' social situation.

A specific method for assay of drug levels in serum of patients treated with clopenthixol decanoate injections.

A fluorimetric method is presented for the simultaneous and specific assay in serum of clopenthixol decanoate, clopenthixol and a clopenthixol metabolite, deprived of the ethanol group in the side chain. The separation is achieved by extractions and thin layer chromatography and fluorescence brought about by treatment with sulphuric acid. The limit of detection in 3 ml serum samples is about 2 ng/ml for clopenthixol and mtabolite, and somewhat higher for the ester. In addition serum data are presented for patients treated with intramuscular injections of 100-600 mg clopenthixol decanoate in Viscoleo every second week. Relatively stable (mean max./min. ratio about 2; maximum after 3-7 days) clopenthixol levels were recorded through-out the dosage interval. Somewhat lower metabolite levels were found. There was no evidence for the presence of clopenthixol decanoate.

Pharmacokinetic aspects on once-daily nortriptyline administration.

Steady state nortriptyline plasma levels have been studied in 21 endogenously depressed patients treated with a single 150-mg morning dose and compared to theoretical curves, calculated from previously known kinetic data. Fairly good agreement between predicted and experimentally found concentrations was observed. The fluctuation between maximal and minimal drug levels within the dosage interval was found to be more pronounced than with a t.i.d. dosage regimen, but still limited (mean ratio = 1.54; range = 1.0--2.16), and the minimum levels (mean = 102 ng/ml; range 46--250 ng/ml) were well compatible with published t.i.d. data. The biological half-life (mean = 39 h; range 24--86 h) agreed well with previously published data for volunteers. It is concluded that once-daily administration of nortriptyline results in relatively flat concentration curves as one would expect from the kinetic features of the drug. The clinical outcome is discussed in a separate paper.