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In an open, uncontrolled trial flupenthixol was administered to 45 patients with endogenous depression. The drug was markedly effective in eight patients, effective in nine patients, fairly effective in 12 patients, and ineffective or aggravating in 16 patients. Four patients showed transient manic symptoms. Dosage was 1-3 mg daily. In 36 patients flupenthixol was used in combination with previously administered tricyclic antidepressants, and in nine patients it was used alone. Clinical effect was quickly apparent. It appeared within 1 week in 63% and within 2 weeks in 93% of subjects. Side-effects were observed in 13 patients: insomnia, five patients; slight extrapyramidal symptoms, nine patients. Sedative-hypnogenic effects were rarely seen. In 71% of 17 patients in whom the drug was found to be markedly effective or effective, flupenthixol's influence on psychomotor retardation was particularly striking. Other clear benefits were relief of depressive mood, psychic anxiety, and agitation. It is recommended that flupenthixol is given, as supplementary medication, to patients (1) whose depressive symptoms other than psychomotor retardation have already improved with current tricyclic antidepressants, and (2) in whom, before antidepressant medication, psychomotor retardation is a principal feature.

A double-blind study which compared the effects of nomifensine and nortriptyline was carried out in outpatients with retarded depressions. It demonstrated that nomifensine has distinct antidepressive and activating effects. 40 patients (17 male and 23 female) with either endogenous, endogenous/reactive or reactive depression were divided into two treatment groups of 20. During the 21-day study, all patients were given three 50-mg capsules of either nomifensine or nortriptyline per day. With the aid of a depression scale, devised by Pöldinger, a significant improvement in the psychic symptoms was noted both in the nomifensine and in the nortriptyline group. There was no evidence of a significant difference between the two drugs. From the results of the study, it can be concluded that nomifensine is suitable for the treatment of patients with retarded depressions.

Eighteen depressed outpatients were treated for 6 wk with a mean daily dose of 121 mg of nortriptyline. The mean plasma level was 138 ng/ml during treatment. Therapeutic response was monitored by the Zung Self-Rating Depression Scale and the Hamilton Depression Scale administrered by two psychiatrists blind to the tricyclic used, dose, and plasma levels. Eight patients recovered (Hamilton less than or equal to 6) by the fourth week and 12 by the sixth week. During the steady-state (wk 4 to 6) there was a positive correlation between the weekly Hamilton scores and the weekly nortriptyline levels (p less than 0.01). The 9 patients with mean plasma levels between 50 and 139 ng/ml had a better therapeutic response after 6 wk measured by percent recovered (p less than 0.005). Zung score (p less than 0.05), and Hamilton score (p less than 0.025) than the 9 patients with mean plasma levels between 140 and 260 ng/ml.

A double-blind randomized study was performed in 86 depressed out-patients, in order to compare the efficacy and tolerance of mianserin (30 to 60 mg daily) with that of nortriptyline (75 to 150 mg daily). Both drugs were administered for 6 weeks after a wash-out period of 1 week. The Hamilton Rating Scale for Depression was used weekly and the Clinical Global Impression Scale at the end of treatment. Both preparations proved to be effective, with no significant differences in response. However, tolerance in the mianserin group was much better than in the nortriptyline group. Significant differences were found mainly in the incidence and severity of tachycardia, dry mouth, constipation, sweating, insomnia, agitation and oedema.

A double-blind study comparing the effects of nomifensine and nortriptyline, which was carried out exclusively on outpatients with retarded depressions, showed nomifensine to have a distinctive antidepressive and activating effect. 40 patients (17 male and 23 female) with either endogenous, endogenous/psychogenic or psychogenic depression were divided into two treatment groups (20 patients to each group). During the 21-day study, all patients were given three 50 mg capsules of nomifensine or nortriptyline per day. With the aid of a depression scale, a significant improvement in the psychic symptoms was noted both in the nomifensine and the nortriptyline group. There was no evidence of a significant difference in the two drugs. The data obtained from the dropouts suggest that nomifensine had a better effect. From the results of the study, it can be concluded that nomifensine is suitable for the treatment of patients with retarded depressions.

In the first experiment the influences of a single oral administration of a new antidepressant, Y-8894 50 mg, nortriptyline 50 mg, and placebo on physiological and psychological parameters were evaluated by a double-blind, crossover method in 10 healthy male volunteers. As the second experiment eight elderly healthy men were also recruited to examine the clinical pharmacology of Y-8894. Y-8894 50 mg showed no significant anticholinergic, sedative, or cardiovascular effect on any of the measures used in young subjects. In the elderly Y-8894 50 mg increased pulse rate (P less than 0.05-0.01), lowered systolic blood pressure (P less than 0.05-0.005), and decreased salivary flow (P less than 0.05) compared with those of pre-drug baseline. C.f.f. was improved after Y-8894 50 mg, but not significantly. Neither psychomotor performance nor immediate memory was influenced after either treatment in young subjects. Furthermore, in the elderly Y-8894 50 mg did not affect these parameters. In the elderly both k21 and ke were smaller, t1/2,z was longer, and AUC was larger compared with young subjects (P less than 0.01). In conclusion, Y-8894 50 mg seemed to lack the anticholinergic, sedative and cardiovascular effects which were observed after nortriptyline 50 mg in young subjects. In the elderly some affects were recognized, in part, due to pharmacokinetic alteration.

In a 5-week study of 22 depressed patients treated with nortriptyline, significant changes in plasma levels, both elevated and reduced, were deliberately produced in the third and fourth weeks of each patient's treatment. Correlation of plasma nortriptyline levels and changes in the severity of depression, as measured by the Hamilton Depression Scale, showed no significant relationships. The implications of the study are discussed.

The observation that fatalities from tricyclic antidepressant (TCA) overdose are associated with heart block and/or arrhythmias has led to concern about the cardiovascular effects of TCAs. Contrary to expectations, studies have shown TCAs to be relatively safe in patients without heart disease. However, it is unclear whether these drugs are also safe in patients with heart disease. This prospective study compared the risk of cardiovascular complication at therapeutic plasma concentrations of TCAs in 196 depressed patients, 155 with normal electrocardiograms and 41 with either prolonged PR interval and/or bundle-branch block. The prevalence of second-degree atrioventricular block was significantly greater in patients with preexisting bundle-branch block (9%) than in patients with normal electrocardiograms (0.7%). Orthostatic hypotension occurred significantly more frequently with imipramine than with nortriptyline, and in patients with heart disease.

Intracardiac conduction studies using His bundle electrography (HBE) were performed in 14 patients admitted to hospital following an overdosage of one of the tricyclic antidepressant drugs and in another 12 patients before and during administration of therapeutic doses of nortriptylline. Amongst the former group, 7 of 8 patients showed impaired distal intracardiac conduction (H-V interval) following overdosages of nortriptyline, imipramine or amitriptyline but none of the 6 patients with doxepin overdosage. The prolonged H-V interval had returned to normal at a repeat study 7 days later. In the therapeutic dose study, 5 of 12 patients showed an increase in the H-V interval by more than 10 msec during treatment with nortriptyline. Four of these 5 patients had plasma nortriptyline levels of over 200 ng/ml. Tricyclic antidepressant drugs show a quinidine-like effect in toxic, and in some patients, in therapeutic doses. This finding may having a bearing on the treatment of cardiac arrhythmias in patients following overdosage with these drugs and may provide a clue to the reported increase in the incidence of sudden deaths in 'cardiac patients' following therapeutic doses of such agents.

A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried out in patients with painful diabetic polyneuropathy. A visual analog scale was used to evaluate the relief of pain or paresthesia. Significant relief of both pain and paresthesia was obtained with this combination. The differences were statistically significant. Side effects were frequent but not usually severe enough to lead to cessation of these medications.

Eight patients with major depression but otherwise healthy underwent radionuclide cardiography before and during nortriptyline treatment. The second examination was performed when the nortriptyline plasma concentration was within the therapeutic range (60-150 micrograms X l-1). Heart rate, arterial blood pressure, left ventricular ejection fraction, left ventricular volumes, systolic pressure-volume ratio, and cardiac output were determined. Heart rate increased in mean by 13% (P less than 0.05). All other variables were unchanged. We conclude that nortriptyline in therapeutic doses produces no major adverse effect on left ventricular function. Routine radionuclide cardiography might be a suitable method to detect among those treated with tricyclic antidepressants the occasional susceptible patient. This may particularly apply to patients with known heart disease and to elderly patients.

Body weight and appetite were evaluated in 40 depressed outpatients from a private psychiatric practice who were receiving low-modest doses of tricyclic antidepressants. Amitriptyline (maximum of 150 mg/day), nortriptyline (maximum of 50 mg/day), and imipramine (maximum of 80 mg/day) were given for an average of 6 months of treatment. There was a mean weight increase of 1.3-2.9 lbs/month, which led to an average total weight gain of 3-16 lbs, depending on drug, dose and duration. These weight increases were linear over time and were accompanied by marked increases in the preference for sweets. Ultimately, excessive weight gain was the most common cause of discontinuation of treatment, occurring in one-half of the patients. Significant weight loss occurred upon discontinuation of drug. These findings show that chronic administration of low-modest doses of tricyclic antidepressants frequently cause considerable weight gain and can significantly interfere with the ability to provide long-term maintenance therapy.

The present study was done in double blind during 6 weeks on 36 depressed patients having a minimal score of 15 on the Hamilton rating scale. Seventeen received mianserin and nineteen nortriptyline. A comparable therapeutic efficacy was observed for both drugs, without significant differences for the delay of action or the activity during 6 weeks. The number of side-effects was much more elevated for nortriptyline, and a significant difference was particularly observed for the frequency and severity of tachycardia, dry mouth and oedema.

Pharmacokinetic factors may contribute to altered nortriptyline effects in the elderly. Plasma concentrations of nortriptyline's principal metabolite, E-10-hydroxynortriptyline, tend to be greater than nortriptyline, increase with age, and may contribute to cardiotoxicity. Electrocardiogram changes were evaluated in 21 ambulatory, elderly, depressed outpatients who were treated with therapeutic doses of nortriptyline. Resting electrocardiograms were obtained before and after 6 weeks of treatment. Plasma samples were assayed simultaneously for nortriptyline, E-, and Z-10-hydroxynortriptyline. Three subjects developed a first degree atrioventricular block and one developed a right bundle branch block during treatment. Mean daily nortriptyline dose and steady state plasma level in these subjects did not differ from those who did not develop conduction defects, but E-10-hydroxynortriptyline levels were significantly higher. Overall, there were significant correlations between changes in the PR interval and QRS duration with plasma concentrations of nortriptyline, E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline, and the sum of nortriptyline and its 10-hydroxynortriptyline metabolites. Multiple regression analyses suggested that increases in PR interval were associated with increasing nortriptyline concentration, while increases in QRS duration and Q-Tc intervals were associated with increasing Z-10-hydroxynortriptyline concentration. E- and Z-10-hydroxynortriptyline may contribute substantially to the cardiac conduction effects of nortriptyline treatment and may be of particular importance in the elderly.

Pharmacokinetic, therapeutic effects, and side effects of nortriptyline were studied in geriatric depressed patients treated with a standard dose of 150 mg/day. Plasma levels and elimination half-life of nortriptyline were no different in geriatric patients than younger patients. The antidepressant therapeutic effects of nortriptyline appeared to be similar in geriatric patients as in younger depressed patients. Geriatric patients experienced few subjective side effects of nortriptyline. Overall, the drug produced no clinically significant changes in several parameters of the EKG, and no geriatric patient experienced tachycardia on nortriptyline. Nortriptyline did induce significant orthostatic hypotension in the systolic component, but not in the diastolic component. However, the orthostatic hypotension produced by nortriptyline was not greater in geriatric patients than in younger patients treated with the same dose.

Cases of profound hypoglycemia after the initiation of tricyclic antidepressant therapy in two patients taking sulfonylureas are described. To the authors' knowledge, this is the first report of a potential drug interaction between tricyclic antidepressants and sulfonylureas.

Patients disabled by tinnitus show a high prevalence of major depression. Furthermore, tinnitus produces patterns of disability similar to those produced by major depression. To explore further this link between tinnitus and depression, and to investigate the efficacy of treating depression in the treatment of tinnitus, a single-blind, placebo-washout, nonrandomized pilot study of the tricyclic antidepressant nortriptyline (hydrochloride) was undertaken in disabled tinnitus patients who also met diagnostic criteria for major depression. Nineteen patients began the study, two responded to placebo, and two dropped out prior to completion. Fourteen considered their tinnitus improved, and 12 chose to continue taking nortriptyline after the study. Depression severity decreased, on the average, by 65% (p less than .0001). Tinnitus loudness measured by audiometric matching decreased by a mean of 10 dB or 50% (p less than .02). Self-reports of tinnitus loudness and severity, somatic and psychologic symptoms, and psychosocial dysfunction all showed significant improvement with treatment. These results suggest that what initially appears to be an irreversible otologic disability in these patients may be in large part a reversible psychiatric disability.

Sir Martin Roth has stated, "where there is depression, there is hope," to emphasize the fact that depression can be a treatable source of excess disability, even when it is superimposed upon irreversible chronic medical illness. Both the potential benefits and the risks of antidepressant medications are increased in the frail elderly. This article presents an approach toward defining who should be treated and for ensuring that elderly patients receive adequate treatment.

Body weight change was monitored in 73 hospitalized depressed patients treated with one of four antidepressants for 1 month. After a 2-week medication-free period, patients were randomly assigned to treatment with amitriptyline, nortriptyline, desipramine, or zimelidine. By the end of 1 month, treatment with all three tricyclic compounds promoted weight gain, with the greatest increase observed during amitriptyline treatment; less weight was gained by patients treated with nortriptyline and desipramine. In contrast, most patients treated with zimelidine showed no weight gain and, in many cases, demonstrated weight loss. Weight change during treatment was not associated with age, sex, severity of depression, obesity, weight loss during depression, or clinical response.

Out of 24 patients with endogenous depression, 21 completed the treatment with nortriptyline 150 mg as once-a-day dosage. The therapeutic effect was good and at any rate not inferior to that of dosages several times a day. Side effects were only little pronounced and at any rate not more marked than after dosages several times a day. Out of regard for the administrative and psychological advantages of the once-a-day dosage this form should be preferred, not least in the out-patient treatment with nortriptyline of endogenous depression.

In a study to determine the nature and frequency of cardiac side effects during long-term administration of tricyclic antidepressant drugs in usual dosages in the aged, 32 geriatric patients were followed for an average of 36.6 weeks. Ten of them received amitriptyline in a daily dosage of 20-75 mg for 53 weeks (average); in 2, electrocardiographic side effects developed, viz, inversion of the T waves or evidence of acute coronary insufficiency. Imipramine was administered to 21 patients in a daily dosage of 20-100 mg (average, 66 mg) over a period of 40 weeks; in 3 instances major side effects developed--intermittent left bundle-branch block, acute coronary insufficiency with node dysfunction, or T-wave inversion with sinus tachycardia; in 1 instance there was a minor side effect, viz, tachycardia only. In 1 patient, acute myocardial infarction developed after two 10-mg doses of nortriptyline. Five of the 7 patients with cardiac side effects had prior organic heart disease. It was concluded that the incidence of cardiac side effects in aged persons given tricyclic antidepressant drugs in the usual therapeutic dosages for a prolonged period is great enough to warrant frequent careful monitoring of cardiac status during therapy.

Previous studies of the effect of tricyclic antidepressants on left ventricular function in depressed patients with moderate to severe ventricular impairment have focused primarily on imipramine hydrochloride. In a prior study, we found that although imipramine had no effect on ejection fraction as measured by first-pass radionuclide angiography, the treatment could not be tolerated by 50% of the patients because of intolerable drug-induced orthostatic hypotension. Nortriptyline hydrochloride is an effective antidepressant that, in depressed patients without heart disease, causes significantly less orthostatic hypotension than imipramine. To see if this advantage could be safely extended to patients with congestive failure, we measured the effect of nortriptyline on ejection fraction and blood pressure in 21 depressed patients with left ventricular impairment. Ejection fraction was unchanged by nortriptyline treatment, and orthostatic hypotension developed in only one (5%) of 21 patients. Nortriptyline emerges as a relatively safe treatment for depression in patients with left ventricular impairment.

Forty female patients suffering for long periods from frequency, urgency, and dysuria without any definite organic cause received nortriptyline chloride for three weeks. In 75 percent there was either considerable improvement or total disappearance of urinary complaints. At the same time the in vitro effects of the drug were tested using the isometric muscle contraction technique. Nortriptyline was found to have anticholinergic properties. The importance of this effect in the clinical study and the possible mode of action of the drug are discussed.

The authors describe a patient who developed congestive heart failure and had a high plasma concentration of 10-hydroxynortriptyline. They discuss the need for further research to define the contribution of antidepressants' active metabolites to toxic and therapeutic effects.

The effect of nortriptyline against ventricular arrhythmias was determined in 16 cardiac patients with 30 or more ventricular premature depolarizations per hour. Nortriptyline was administered orally, 0.5 mg/kg body weight per day, and increased by 0.5 mg/kg per day every third day until ventricular premature depolarizations were suppressed (greater than or equal to 80%), adverse effects occurred or a total daily dose of 3.5 mg/kg per day was given. Each patient had daily 24 hour continuous electrocardiograms, 12 lead standard electrocardiograms and physical examination; blood pressure was measured in the supine and standing position four times a day. Each patient also had radionuclide angiography at rest to measure ejection fraction before and at the effective or maximal dose. Thirteen patients (81%) had an antiarrhythmic response and 11 met the study criterion of at least 80% improvement. Doses ranged from 50 to 200 mg/day (mean 111 +/- 45), steady state plasma concentration ranged from 46 to 410 ng/ml (mean 153 +/- 96) and half-life of elimination of nortriptyline was 4 to 22 hours (mean 13 +/- 4). Administration of nortriptyline did not depress mean ejection fraction (before 42 +/- 12%, after 41 +/- 12%); it was associated with an orthostatic decrease in systolic blood pressure (mean -13 +/- 13 mm Hg). Nortriptyline is an effective antiarrhythmic agent which may be given twice a day even in patients with impaired ventricular function.

A 61-year-old man with end-stage renal disease developed severe hyperventilation following nortriptyline hydrochloride usage for depression. He required mechanical ventilation and paralysis to correct severe respiratory alkalosis. To our knowledge, nortriptyline usage has not been previously associated with hyperventilation.

Seven male inpatients suffering from acute schizophrenia were treated with chlorpromazine elixir 100mg 8-hourly for 9 weeks. Nortriptyline 50mg 8-hourly was added during weeks 4, 5 and 6. Plasma chlorpromazine concentrations, antipyrine plasma half-life, blood pressure, pulse rate, pupil size, salivation, handwriting and clinical state were measured at weekly intervals. Plasma chlorpromazine concentrations rose when nortriptyline was added, and the antipyrine plasma half-life was prolonged. Blood pressure dropped on institution of chlorpromazine and dropped further with the addition of nortriptyline. The pulse rate rose in a parallel fashion. Pupil size, salivation and handwriting were diminished by chlorpromazine, but hardly affected further by nortriptyline. The addition of nortriptyline dramatically reversed the therapeutic actions of chlorpromazine, mainly through pharmacodynamic interaction. It is concluded that this combination is potentially deleterious, and must be used with care.

An assessment of the side effects of therapeutic doses of tricyclic anti-depressant drugs was attempted in 32 patients with depressive illness. The patients studied had no evidence of clinical heart disease or hypertension and were not receiving any other drugs. Moderate increase in heart rate and mild prolongation of atrioventricular conduction occurred. No significant effect on the corrected QT interval or blood pressure was found. There was no correlation between the increased heart rate, prolongation of the atrioventricular conduction time (PR interval) and plasma nortriptyline levels measured in 20 out of 32 patients.