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To the Editor.— Hyponatremia and the syndrome of inappropriate antidiuretic secretion (SIADH) have been associated with the administration of a number of medications. We would like to add our case report to that of Luzecky et al,1who first reported the association of SIADH with the administration of amitriptyline. Report of a Case.— A 51-year-old woman was treated for depression with amitriptyline hydrochloride, 50 mg three times per day. She was otherwise in good health and was receiving no other medications. Six weeks after starting the amitriptyline treatment, she was found in her home in a comatose state. Shortly after admission to the hospital, she had a generalized tonicoclonic seizure. There had been no history of excessive water intake noted by the family. The patient was said to have behaved normally on the morning of her admission. Physical examination was unremarkable, except for conspicuous lethargy. There was no evidence

• A randomized, controlled trial compared the combination of amitriptyline hydrochloride and short-term interpersonal psychotherapy, either treatment alone, and a nonscheduled treatment control group in ambulatory acute, nonbipolar, nonpsychotic depressives. Results show the efficacy of both psychotherapy and amitriptyline in overall symptom reduction. Amitriptyline and psychotherapy were about equal, and the effects of both treatments in combination were additive. The additive effect of combined treatment was largely due to the differential effects of the two treatments. Amitriptyline had its effect mainly on the vegetative symptoms of depression such as sleep and appetite disturbance, these occurred early in treatment, often within the first week. Psychotherapy had its effect mainly on mood, suicidal ideation, work, and interests; these effects occurred slightly later, at four to eight weeks.

Fifty-nine patients referred for painful diabetic neuropathy of the lower extremities were evaluated for depression and response to antidepressant drug therapy in a double-blind controlled study. All patients were found to have substantial degrees of depression during psychiatric interview and by Kupfer-Detre test scores (8.1±0.6, as compared with control values of 4.0 to 4.3±0.2). Treatment with imipramine hydrochloride or amitriptyline hydrochloride resulted in complete remission of lower extremity pains in all patients in 10±2 weeks, with concomitant relief of depression and return of depression test scores to 3.8. These results suggest that the syndrome of painful diabetic neuropathy of the lower extremities represents a depressive equivalent in a large proportion of cases and that treatment with imipramine or amitriptyline is a successful mode of therapy for such persons. ( JAMA 243:1147-1150, 1980)

• In a double-blind, placebo, controlled clinical study, lasting 12 weeks, 48 male and 48 female ambulatory schizophrenic patients were randomly assigned to one of four treatments: placebo; amitriptyline hydrochloride, 125 mg/day; perphenazine, 20 mg/day; or amitriptyline-perphenazine, 20 mg/day. Treatment groups contained an equal number of male and female patients. Perphenazine alone or in combination was substantially more effective in reducing psychopathological disorder than was the placebo, but there was no evidence to indicate the superiority of the amitriptyline-perphenazine combination over perphenazine alone. Amitriptyline alone was not substantially better than placebo and could not be considered an efficacious medication for the maintenance treatment of these patients. Less response to treatment was made by patients with longer-term records of prior hospitalizations.

To the Editor.— It would be helpful to know what changes in weight have occurred after several months of combined phenothiazine and antidepressant therapy in the patients reported by Davis et al (238:2291-2292,1977) in the article entitled "Peripheral Diabetic Neuropathy Treated With Amitriptyline and Fluophenazine." I have used the combination of amitriptyline hydrochloride and thioridazine quite successfully to control chronic pain patterns seen with postherpetic neuralgia and postthoracotomy incisional pain. Although these combinations work well, excessive weight gain has been a drawback in most patients after treatment of several months. The question is raised because the group of patients presented by Davis et al are diabetic. Without this information, some concern must be entertained before committing diabetic patients to long-term phenothiazine and antidepressant therapy.

To the Editor.— The cardiovascular dynamics of tricyclic antidepressant (TCA) overdoses have been the subject of several recent reports.1-5Several clinical variables, in particular the ECG, have been proposed as guides to the severity of the poisoning. Tachycardia and QRS prolongation are particularly important signs.3In the absence of plasma level determinations, QRS prolongation is the most reliable indicator of a serious overdose.4There is one previous report of an amitriptyline hydrochloride overdose with toxic plasma levels in which the QRS intervals were normal and the only ECG abnormality was a sinus tachycarida.5We report a case of a TCA overdose involving doxepin hydrochloride (Sinequan) with an entirely normal ECG. Report of a Case.— A 49-year-old woman with a long history of psychiatric disorders was brought to the emergency room of Naval Regional Medical Center, Portsmouth, Va, after her husband found her in a somnolent state.

• We present the results of a direct comparison of phenelzine sulfate and amitriptyline hydrochloride therapy in 105 depressed patients. We believe this is the first definitive double-blind controlled clinical trial of a monoamine oxidase inhibitor and a tricyclic antidepressant in the outpatient setting. The results show both antidepressants to be effective, with the similarities between the two exceeding the differences. Both drugs had marked antidepressant and antianxiety effects. Phenelzine tended to exert a stronger antianxiety action; amitriptyline was more effective in reversing weight loss and improving sleep. The incidence of two side effects, sedation and orthostatic hypotension, was almost identical. Dry mouth was more prevalent with amitriptyline. We discuss the indications for the differential clinical use of both drugs in depressed outpatients.

To the Editor.— I was struck by the simultaneous appearance of the comments in the LETTER section (243:1133, 1980) regarding the use of tricyclic antidepressants for chronic pain and the article on "Depression Masquerading as Diabetic Neuropathy," (243:1147, 1980) by Roger W. Turkington, MD. In the article I was tremendously impressed that all patients studied with diabetes and leg pain were found in interviews to be depressed before treatment, that a relatively low dosage of tricyclic antidepressants (100 mg at bedtime of amitriptyline hydrochloride or imipramine hydrochloride) was 100% effective (higher dosages are estimated to be effective at approximagely 70% to 80% ), that no patients receiving the tricyclic drug therapy complained of constipation or dizziness, and that there was so little placebo effect from diazepam in a group of depressed patients. It is also unusual that patients would respond within three days, that sleeping patterns would take three weeks to return

THE USE of tricyclic antidepressant medications is increasing as a form of self-poisoning. There have been a number of reports of the anticholinergic effects of amitriptyline hydrochloride and imipramine hydrochloride. 1 Although many cases of cardiotoxicity have been reported, 2 there is little information concerning the treatment of the serious cardiac complications. Physostigmine salicylate has been used successfully to treat the central effects of tricyclic antidepressants, such as agitation, seizures, and coma, as well as their peripheral effects, such as tachycardia. 1 We have used this drug in treating a young woman who had a cardiac arrest subsequent to an amitriptyline overdose. To our knowledge, this is the first reported case of amitriptyline poisoning in which malignant arrhythmias and conduction defects were successfully treated with physostigmine. Report of a Case A 22-year-old woman ingested an estimated 750 to 1,000 mg of amitriptyline hydrochloride (Elavil) on March 25, 1975. She was

Steady-state plasma tricyclic antidepressant levels were determined in 65 patients undergoing treatment for depression with either amitriptyline hydrochloride or nortriptyline hydrochloride to determine if common factors such as age, race, sex, or smoking status were predictors of steady-state drug levels that have been shown to vary up to 36-fold. Evaluation of these factors did not disclose differences in the rate of demethylation of amitriptyline to nortriptyline, or steady-state tricyclic levels in the amitriptyline-treated patients. No differences were found in the nortriptyline-treated patients except regarding race. Black patients had significantly higher (50%) nortriptyline plasma levels than did white patients, which may explain the more rapid response to tricyclic treatment demonstrated in blacks. Decreased rates of nortriptyline metabolism in blacks can result in Increased side effects and treatment failure if the therapeutic plasma range is exceeded. (JAMA238:2167-2169, 1977)

To the Editor.— Davis et al are thanked for their recent BRIEF REPORT on the treatment of peripheral diabetic neuropathy treated with amitriptyline hydrochloride and fluphenazine hydrochloride (238:2291, 1977). It is heartening for those who treat neuritis to see that there is still active thinking regarding an effective treatment. Their article has prompted me to review my experience with the treatment of diabetic neuropathy over the past two years. My files contain some 31 cases treated with combinations of tricyclic antidepressants and neuroleptic agents (antipsychotic agents). My results, using combinations of the tricyclic agents (amitriptyline, imipramine, and doxepin), along with one of the neuroleptic agents (fluphenazine, trifluoperazine, chlorpromazine, thioridazine, haloperidol, or chlorprothixene), has not been so successful. I have tried these agents in varying doses, mainly exceeding those of Davis et al, but without any notable success. I learned about this treatment at a number of meetings, where I found

Bulimia is an eating disorder characterized by a pattern of episodic binge-eating. Patients with this eating disorder frequently demonstrate depressive symptoms when seen for evaluation. A familial association between bulimia and affective disorders has also been suggested. The authors report a placebo-controlled, double-blind trial of amitriptyline hydrochloride in a series of 32 female outpatients who satisfied DSM-III criteria for bulimia. The results of this study indicated that amitriptyline hydrochloride at a dosage of 150 mg at bedtime had significant antidepressant activity in this group of patients. Patients in both the placebo and active drug group also received a minimal behavioral treatment program in addition to drug therapy. Both groups demonstrated considerable improvement in eating behavior. The magnitude of this improvement was dramatic and not anticipated. The drug was well tolerated and was not associated with weight gain or increased carbohydrate craving.

THIS article illustrates the rapid reversal of coma due to amitriptyline hydrochloride overdose by the administration of physostigmine salicylate. Physostigmine is the only commonly used specific cholinesterase inhibitor that readily penetrates the blood brain barrier. 1 Slovis et al 2 reported that physostigmine rapidly restored alertness and reversed tachycardia in four patients with amitriptyline intoxication. Rumack 3 reported the successful use of physostigmine to treat children who became intoxicated by various agents with anticholinergic properties as well as the tricyclic antidepressants. Report of Cases Case 1.— A 27-year-old woman was admitted in coma to Martin Army Hospital on April 2, 1974. History provided by a friend indicated that after an alleged altercation with her estranged husband, the patient ingested 20 amitriptyline hydrochloride tablets (50 mg) and about 20 diazepam tablets (5 mg). When discovered by a neighbor, approximately 10 to 12 hours later, she could not be aroused. When seen

• Postherpetic pain persisting one month or longer occurs in 9% to 14% of patients with herpes zoster, diminishing with time. The incidence and duration are directly related to age. The pathologic features have been described but the pathogenesis of postherpetic neuralgia is unknown. Treatment remains difficult. It is reasonable to hope for a reduction in pain from severe to mild in two of three cases. There is evidence to support the use of low doses of tricyclic antidepressants, especially amitriptyline hydrochloride, with gradual small increments, and also the use of phenothiazines. Corticosteroids may exert a preventive effect when used in the acute phase. There is some support for the use of local physical modalities. Neurosurgical procedures are a possibility in failed medical cases. Controlled studies of newer approaches are necessary.

Plasma concentrations of tricyclic antidepressants were monitored during treatment of 126 patients. Noncompliance in taking medication was suspected in 19 patients because of unusually low plasma concentrations in relation to the presumed dose. Determinations of plasma concentrations may also be useful for detecting inadequate treatment as judged by levels below the presumed therapeutic range. Attempts to correlate plasma concentrations with clinical response to amitriptyline hydrochloride and nortriptyline hydrochloride failed, probably because of the heterogeneity of depressive syndromes being treated. Plasma concentrations were correlated highly with dose in the case of amitriptyline, less so in the case of other drugs. Amitriptyline and imipramine hydrochloride generally produced plasma concentrations of the parent drug and metabolite higher in nanograms per milliliter than was the daily dose in milligrams; nortriptyline and desipramine hydrochloride did the opposite. ( JAMA 241:2530-2533, 1979)

Thirty-three outpatients with primary nonbipolar depression received individual treatment with either cognitive therapy alone (n = 18) or cognitive therapy plus amitriptyline hydrochloride pharmacotherapy (n = 15). All patients were treated according to a protocol specifying a maximum of 20 sessions during a 12-week period. Both groups showed statistically significant and clinically meaningful decreases in depressive symptoms. No differences emerged between the two groups in terms of the magnitude of the decrease in depressive symptoms. The addition of tricyclic antidepressant medication did not improve the response obtained by cognitive therapy alone, during the short-term treatment phase. Although there was a nonsignificant trend suggesting greater stability of gains for the combined treatment at a one-year follow-up, the patients had more therapy during the follow-up period. There was no evidence of any negative interaction between cognitive therapy and pharmacotherapy, although evidence for any positive additive or interactive effect was meager.

Amitriptyline hydrochloride (Elavil) is frequently used in treating mild to moderate depressive states. A survey of 346 persons enrolled in a methadone maintenance program showed that 86 (25%) had admitted taking amitriptyline with the purpose of achieving euphoria. Thin-layer chromatography of random urine specimens over five months showed that 34% of the patients had a positive result for amitriptyline at least once during this time. These results suggest that misuse of amitriptyline is not uncommon and should be carefully considered prior to prescribing this agent to narcoticdependent persons. ( JAMA 240:1372-1373, 1978)

The compounds that are called tricyclic antidepressants (doxepin hydrochloride, amitriptyline hydrochloride, imipramine hydrochloride, trimipramine maleate, nortriptyline hydrochloride, protriptyline hydrochloride, and desipramine hydrochloride) were discovered to have antidepressant efficacy beginning in the 1950s, shortly after chlorpromazine hydrochloride was found to be effective for treating psychoses. Researchers took compounds from the shelves of pharmaceutical houses that were similar to chlorpromazine in structure and pharmacology to look for other agents for the treatment of psychoses. The antihistamine imipramine was the first drug in this group to be shown to be effective as an antidepressant after it failed to demonstrate antipsychotic efficacy. 1 Soon after the tricyclic antidepressants became available for use clinically, it was learned that these compounds were potent inhibitors of the presynaptic uptake of norepinephrine and serotonin. These early findings represent some of the cornerstones of the biogenic amine hypothesis of mood disorders. More recently, we have learned about the effects

Skin blisters with underlying sweat gland necrosis have been reported in cases of poisoning due to barbiturates, methadone, diazepam, and carbon monoxide. 1-4 We describe a patient in whom similar lesions developed after ingesting toxic amounts of amitriptyline hydrochloride and clorazepate dipotassium. Report of a Case A 23-year-old woman was in a comatose condition when admitted to the hospital. Blisters on erythematous bases were present on her right knee and on the medial and dorsal aspects of her left foot. They were 6 cm, 3 cm, and 2 cm in diameter, respectively, Histologic sections of a skin biopsy specimen from a blister margin on the left foot demonstrated an intraepidermal vesicle (Fig 1) with underlying sweat gland necrosis (Fig 2). The urinary amitriptyline level was 11.4 mg/dL (when blood levels of amitriptyline are in the therapeutic range, the urine concentration is usually 7 mg/dL). (Because blood levels of amitriptyline obtained

To the Editor.— Oral mannitol has been used as a colonic cleaning agent to prepare patients for surgery and for roentgenographic and endoscopic procedures and as a hyperosmotic agent to treat constipation. 1 The following case report describes the previously unreported hazard of pneumatic explosion of the colon following the use of oral mannitol as a cathartic agent. Report of a Case.— A 52-year-old man was admitted for evaluation of chronic low-back pain and modification of analgesic usage. Constipation requiring over-the-counter laxatives was incidentally noted. Medications, which on admission included up to 150 Percodan and Tylox tablets per month, were changed to methadone hydrochloride; dexamethasone hydrochloride; amitriptyline hydrochloride; fluphenazine hydrochloride; intravenous plasma protein fraction, human (Plasmanate); clonidine hydrochloride; oxybutynin chloride; Naldecon; Urised; and tolmetin sodium. He was initially treated for constipation with Fleet enemas, oral mineral oil, milk of magnesia, and bisacodyl tablets, with minimal results. An abdominal roentgenogram, performed

To the Editor.— Serious adverse reactions, including death, have been reported following the combined use of a drug with monoamine-oxidase-inhibiting properties and a number of drugs or foods, including the tricyclic antidepressants such as imipramine hydrochloride and amitriptyline hydrochloride. Furazolidone is a synthetic antimicrobial nitrofuran used for specific and symptomatic treatment of bacterial or protozoal diarrhea and enteritis. Inhibition of monoamine oxidase by furazolidone has been demonstrated. In the following case, a toxic psychosis resulted when furazolidone was taken by a person already taking amitriptyline. Report of a Case.— A 49-year-old woman with symptoms of depression was treated with amitriptyline hydrochloride, 75 mg daily, beginning April 22, 1970. Her depression improved rapidly and the amitriptyline was continued at the same dosage. She also continued to take estrogenic substances conjugated, 1.25 mg daily, which she had taken since a hysterectomy and oophorectomy in 1958. On May 22 a physician prescribed furazolidone

A hypersensitive, 47-year-old man was adequately treated with guanethidine sulfate, 75 mg/day. Because of depression he was treated with amitriptyline hydrochloride, 25 mg, three times daily, and 300 mg of guanethidine sulfate was required for adequate control. Administration of amitriptyline was discontinued and the patient experienced pronounced orthostatic hypotension with 87.5 mg of guanethidine sulfate daily. After five days of amitriptyline hydrochloride therapy, 150 mg/day, the effects of guanethidine were again eliminated. The hypotensive effect of guanethidine did not return until 18 days after amitriptyline therapy was discontinued.

In recent years there has been a marked increase in the introduction and use of psychopharmacological agents in clinical medicine. One of the newer drugs, amitriptyline hydrochloride (Elavil), 5-(3-dimethylaminopropylidene)-dibenzo [a,d] [1,4] cycloheptadiene hydrochloride, structurally and pharmacologically resembles imipramine (Tofranil), an antidepressant with anticholinergic, antihistaminic, and tranquilizing properties. 1,7 Both drugs have had favorable therapeutic results and have therefore experienced rapid, widespread clinical usage. 1-3 The two drugs differ pharmacologically from other psychotherapeutic compounds in that they are not monoamineoxidase inhibitors 4 (Figure). The purpose of this communication is (1) to present the symptoms and postmortem findings in an infant who died after the accidental ingestion of a massive amount of amitriptyline hydrochloride and also (2) to report the ineffectiveness of peritoneal dialysis in removing the ingested drug. Report of a Case A 15-month-old white female was admitted to the Stanford Medical Center Emergency Room in June 1961, approximately 45 minutes

A case is described of urinary retention lasting 27 days after 15 days' treatment with amitriptyline hydrochloride (Tryptizol). The interesting features are 1) the long duration of the condition after the drug was stopped and 2) the failure of a cholinergic drug (carbachol) to counteract the anti-cholinergic activity of Tryptizol. The case demonstrates the necessity for daily examination for urinary retention of patients receiving amitriptyline HCL, particularly of cases who cannot be expected to make spontaneous complaint of urinary symptoms, due to dementia, depression or apathy.