Imipramine Therapy Research Articles

A model of panic and agoraphobic development.

A model for the development of agoraphobia with panic attacks is proposed. The initiating clinical manifestation is the sudden appearance of spontaneous panic. The inter-panic chronic anxiety may have several components: i.e. conditioning, increasing autonomic distress, and sensitization to the panic leading to avoidance. The illness course is quite variable but usually chronic. The spontaneous panic is blocked by imipramine with primary pharmacological anti-panic effects. However, no direct effect of imipramine upon either anticipatory anxiety or avoidance behaviour is hypothesized. Among the psychotherapies, direct in vivo exposure mobilizes the patient more rapidly than office based therapy. Our data are consonant with the theory that the avoidances of agoraphobia are secondary to spontaneous panic attacks, and that the primary benefits of imipramine and exposure therapy are in their respective effects on panic and avoidance. Moreover, laboratory challenge studies, brain imaging studies, and genetic studies all point to a biological diathesis for panic disorder.

Cognitive-Behavioral Psychotherapy for Separation Anxious Children Exhibiting School Phobia

Two children—a 10-year-old boy and a 12-year-old girl—who exhibited severe school phobia (nonattendance for 6 consecutive weeks before referral), participated in an intervention program based on a psychodynamically oriented cognitive approach. The children were “nonresponders” both to imipramine therapy and to enrollment in a program to combat depression. The six-step program included the assessment of (a) cognitive analysis of the child: (b) environmental analysis; and (c) cognitive analysis of the parents; followed by (d) cognitive self-instructing of children; (e) cognitive restructuring of parents; and (f) environmental restructuring. Both children improved rapidly: subject 1 returned to school by week 4; subject 2 by week 2. The authors' approach to combating school phobia is described; more rigid research designs to evaluate the program are suggested.

The use of imipramine in minor motor seizures

A study is presented of 15 pediatric patients treated with imipramine for uncontrolled seizures during the past two years. Of these patients, 53% had an initial reduction of seizures of greater than 80%. At one year, 26% were still seizure-free. Drop attacks were especially responsive to therapy; 100% ( 7 7 ) responded initially to imipramine therapy. Most patients studied had been receiving valproate and another major antiepileptic drug prior to imipramine therapy. This study confirms previous reports and suggests that the use of imipramine in combination with other antiepileptic drugs provides excellent results, particularly in patients with drop attacks.

Conservative Treatment of Female Stress Incontinence with Imipramine

The results of a clinical study of conservative treatment of women with stress incontinence are presented. A daily dose of 75mg. imipramine hydrochloride was given for 4 weeks. Special attention was paid to the effects of imipramine on the functional urethral length and maximum urethral closure pressure. A total of 21 women (71 per cent) stated that they were continent after treatment with imipramine, while 9 (29 per cent) did not improve and treatment was stopped. According to our results, imipramine extended the functional urethral length and made it independent of stress factors in women who were continent after treatment with imipramine. In patients with persistent incontinence the functional urethral length was extended significantly but was shortened with stress despite imipramine therapy. We believe that imipramine could be an alternative treatment in selected cases with stress incontinence.

Clinical efficacy and electrophysiology of imipramine for ventricular tachycardia

Invasive electrophysiologic studies were performed before and during treatment with imipramine in 18 patients with inducible ventricular tachycardia (VT). All received imipramine, 50 mg twice daily for 3 days, and then 100 mg twice daily for 3 days. Imipramine increased the infranodal conduction times (HV) (from 58 ± 7.8 to 65 ± 10 ms) and QRS duration (from 133 ± 21 to 153 ± 39 ms) and significantly decreased sinus cycle length (from 875 ±145 to 711 ± 116 ms) and maximal corrected sinus nodal recovery time (from 457 ± 656 to 380 ± 603 ms). The Wenckebach cycle length tended to decrease and the QT interval to increase, but these changes were not statistically significant. Atrial and ventricular refractory periods, atrioventricular nodal conduction times and induced VT cycle length did not change significantly. Imipramine prevented induction of VT in 2 patients, and VT was more difficult to induce in 1 patient. These 3 patients received chronic imipramine therapy. The 2 patients in whom no VT could be induced while taking imipramine have had no recurrence of arrhythmia at 6 and 12 months of follow-up. The third patient died suddenly 4 months after discharge from the hospital. One patient had worsening of arrhythmias while taking imipramine and 61% had minor adverse effects. The mean combined plasma imipramine and desmethylimipramine concentration at the time of the repeat electrophysiologic study was 227 ± 114 ng/ml. Imipramine is effective against VT in some patients; however, like other type I antiarrhythmic drugs, the rate of efficacy is low.

What is the rate of recurrence of panic attacks once you stop imipramine therapy?

What is the rate of recurrence of panic attacks once you stop imipramine therapy?

Pheochromocytoma Unmasked by Desipramine Therapy

Excerpt Three previous case reports have described hemodynamic abnormalities precipitated or triggered by imipramine therapy and leading to recognition of pheochromocytoma (1-3). It has been uncert...

Imipramine disposition in alcoholics.

The disposition of orally administered imipramine (IMI) was studied in 11 depressed alcoholic and 12 depressed nonalcoholic male inpatients. Subjects received 50 mg three times daily for at least 10 days to ensure steady state. Following a temporary discontinuation of therapy, several blood samples were drawn over a 40-hour period. Imipramine, desipramine, and their 2-hydroxylated metabolites were measured in plasma using a high performance liquid chromatography assay. Eight hours following the last dose, alcoholics has significantly lower IMI (50 +/- 41 versus 106 +/- 46 ng/ml; p less than 0.005) and 2-hydroxyimipramine (12.8 +/- 7.5 versus 22.6 +/- 9.8 ng/ml; p less than 0.01) levels than controls. The mean terminal half-lives in the two groups were nearly identical (16.3 +/- 6.7 hours in alcoholics versus 17.1 +/- 5.4 hours in controls). Beck Depression Inventory scores were significantly reduced during IMI therapy (p less than 0.001) in the non-alcoholic controls, whereas no change was observed in the alcoholic group. These results are consistent with either a decrease in oral bioavailability of IMI in alcoholics or, assuming complete absorption, an increase in intrinsic clearance of 2.5 fold (2444 +/- 1151 versus 986 +/- 438 ml/min; p less than 0.005) over the clearance found in control subjects. The latter seems a more likely result of chronic ethanol intake. The fact that lower levels of IMI in the alcoholic group were accompanied by a lack of efficacy in relieving depressive symptomatology suggests that whether through an effect on bioavailability or intrinsic clearance, ethanol consumption is an important consideration when recommending tricyclic therapy.

Plasma concentration monitoring of hydroxylated metabolites of imipramine and desipramine.

Steady-state serum concentrations of imipramine (IMI), its demethylated metabolite desipramine (DMI), and the active, hydroxylated metabolites, 2-hydroxy-imipramine (2-OH-IMI) and 2-hydroxy-desipramine (2-OH-DMI) were monitored in 126 psychiatric patients receiving IMI therapy. DMI and 2-OH-DMI concentrations were determined in a similar group of 61 DMI-treated patients. Although significant correlations exist between hydroxy metabolite and precursor concentrations, considerable variability was also found. Mean (+/- SD) ratios for the IMI patients were: 2-OH-IMI:IMI = 0.27 (+/- 0.19) and 2-OH-DMI:DMI = 0.56 (+/- 0.30). The ratio of DMI:IMI for males and 2-OH-DMI:DMI for females decreased with age (r = -0.42 and -0.32, respectively, p less than 0.01). Variable metabolite concentrations and the uncertainty of their relative psychoactivity may contribute to the difficulties in relating antidepressant efficacy to serum concentrations of the administered IMI or DMI.

Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy

This report describes a middle-aged female who received imipramine for 7 days, developed severe cholestatic jaundice with features similar to primary biliary cirrhosis, and then improved clinically over the next 12 mo. Biochemical and histologic abnormalities persisted over a 14-yr period of follow-up, though subsequent administration of haloperidol may have influenced the long-term course. High levels of circulating immune complexes were also found 14 yr later, which raises questions about the relationship of primary biliary cirrhosis to drug-induced liver injury. A review of the literature on imipramine- and phenothiazine-related hepatic injuries reveals multiple similarities, and this case provides further evidence for a common hepatic reaction to the two drugs.

Tricyclic antidepressants in serum by a Clin-ElutTM column extraction and high pressure liquid chromatographic analysis.

We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.

Announcements

Request for Agoraphobic Patients A controlled trial of imipramine and behaviour therapy in the treatment of agoraphobia is being conducted at the Maudsley Hospital. We would be grateful for referral of patients suffering from agoraphobia who are able to attend on an out patient basis. The patients would be offered early assessment interviews, and those found suitable would begin treatment in the near future. Referral letters should be addressed to Dr I. M. Marks or Dr R. S. Stern, The Maudsley Hospital, Denmark Hill, London SE5 8AZ.

Toxicological evaluation of imipramine in combination with adriamycin and strophanthin.

Chronic oral administration of imipramine to rats caused characteristic changes of the electrocardiogram (ECG), i.e. prolongation of the PR interval, widening of the QRS complex, and increase in T-wave voltage. The cardiotoxic anthracycline antibiotic adriamycin induced dose-dependent widening of the QRS complex. This effect on intraventricular conduction was not enhanced in rats receiving both drugs. The high adriamycin dose (5 x 4 mg/kg) abolished imipramine-induced prolongation of the PR interval and T-wave elevation. This was not seen with the low adriamycin dose (20 x 1 mg/kg). Imipramine prolonged survival time of rats treated with toxic doses of adriamycin, but enhanced growth retardation in animals receiving the low adriamycin dose. Chronic treatment with increasing doses of strophanthin induced significant flattening of the T wave in rats with and without imipramine therapy, but did not influence the changes of the ECG or body weight gain caused by imipramine. It is concluded that the combined use of imipramine and adriamycin or strophanthin did not lead to a serious enhancement of the toxicity of the tricyclic antidepressant.

Electrocardiographic monitoring of enuretic children receiving therapeutic doses of imipramine.

The authors studied the monthly electrocardiographic tracings of 27 children with normal cardiovascular function receiving imipramine therapy for enuresis. They found no substantial EKG changes in any of these children, who were receiving doses of 25 to 75 mg of the drug. They conclude that electrocardiographic monitoring may be essential only when more than 25 to 75 mg of imipramine is given and that it should be established that the patient's cardiovascular function is normal before the drug is administered.

Triiodothyronine thyrotoxicosis. Induction by desiccated thyroid and imipramine.

A 10-year-old girl with congenital hypothyroidism was maintained for many years on a regimen of desiccated thyroid, 150 mg daily. Estimation of serum thyroxine (T 4 ), free T 4 , and triiodothyronine (T 3 ) uptake levels indicated a euthyroid state. Imipramine hydrochloride (Tofranil), 25 mg daily, was added for control of enuresis. Severe clinical thyrotoxicosis developed. The T 4 level was 9.2μg/100 ml. At this time, imipramine therapy was discontinued and the patient again became clinically euthyroid. Imipramine has demonstrable sympathomimetic activity. Circulating T 3 levels were estimated after discontinuing imipramine treatment and were greatly elevated. We suggest that this child may have had clinically unrecognizable T 3 thyrotoxicosis shown by the addition of sympathomimetic medication. Determination of T 4 , free T 4 , and T 3 uptake may not be sufficient to adequately define the thyroid status of patients receiving thyroid.

Imipramine for Nightmares

To the Editor.— In connection with the question by Dr. Leo Sell and the answer by Dr. Anthony Kales (227:1066, 1974), I would like to draw your attention to clinical observations we have made in a study of 12 sleepwalking and pavor nocturnus children. We used 25 to 50 mg of imipramine before bedtime with great success. From the psychotherapeutic point of view, although imipramine does not modify the personality structure, it does alleviate the symptoms and brings a certain degree of relaxation and well-being that is therapeutic in itself. It is of interest to note that even enuretic children who did not respond to imipramine therapy as far as their bed-wetting was concerned, were helped in alleviating pavor nocturnus or nightmares. There was no substitution of symptoms, regardless of whether the child was in psychotherapy or only seen in follow-up. At present, our procedure is as follows: We start

Studies of enuresis: Part VI. Observations on sphincter-augmenting effect of imipramine in children with urinary incontinence

In this double-blind, placebo-controlled study of 73 enuretic children, objective evidence of increased involuntary sphincter tone was demonstrated in more than 50 per cent of children who were “cured” or markedly improved on imipramine therapy. No such response was demonstrated in the control group. The evidence strongly suggests that imipramine, a known adrenergic-potentiating agent, exerts its beneficial effect in the juvenile incontinence syndrome primarily by augmentation of the muscular tone of the involuntary urethral sphincter by sensitizing the alpha adrenergic receptors of the internal sphincter to sympathetic motor innervation. Only 4 of the children obtained a permanent cure from the five- to six-month course of treatment followed by gradual withdrawal of imipramine. Several children with demonstrable obstructive disorders were temporarily “cured” or markedly improved during the period of drug treatment. Accordingly, although imipramine is highly useful as an ancillary agent in treating enuresis and juvenile urinary incontinence, it should not be regarded as a useful agent of permanent cure or as a diagnostic screening agent to select or exclude children with an organic basis for their symptoms.

Imipramine therapy and seizures: three children treated for hyperactive behavior disorders.

The authors report three cases of children who developed seizures while receiving imipramine treatment for hyperactive-aggressive behavior disorders; all three children had organic brain disease but no previous history of seizures. Two of the children remained seizure-free after anticonvulsant medication was added to the imipramine regimen. The authors suggest that clinicians prescribing imipramine be alert to the possible complication of seizures.

IMIPRAMINE TREATMENT OF ENURESIS-Reply

To Editor.—The comments by Mofenson and co-workers must be considered seriously by any physician prescribing a potentially toxic medication. As popularity and availability of specific drugs increase, so will incidence of overdosage and abuse. Penny, in 19681reviewed reported instances of childhood imipramine poisoning and mentioned that the number would likely increase. There has even appeared a report of severe hypotension due to imipramine therapy wheretherepeutic dosageshave been employed.2 The incidence of toxic overdoses due to imipramine will decrease greatly if physician: Thoroughly educates parents to use and abuse of medication and importance of keeping all medications out of reach of children. Individualizes patients chosen to undergo imipramine therapy with careful follow-up of efficacy and indicated laboratory measurements. Employs use of strip packaging techniques from

ECG CHANGES IN FATAL IMIPRAMINE (TOFRANIL) INTOXICATION

A case of poisoning with imipramine (Tofranil) has been followed by serial ECG tracings in an 11-month-old boy. Profound alteration of his myocardial function has been observed during the first 18 hours following absorption of the drug; these cardiovascular perturbations lead to irreversible cerebral damage. Because of the atropine-like effect of the drug and the report of alteration in the ECG tracing of adult patients under imipramine therapy, it is advised that all children under such therapy be checked with an occasional ECG for possible change in myocardial function.