US3737549A - Method of treating depression - Google Patents

Abstract

AN IMPROVED METHOD OF TREATING DEPRESSION USING THYROTROPIN RELEASING AGENT OR L-PYROGLUTAMYL-L-HISTIDYLL-PROLINAMIDE AS THE ANTI-DEPRESSANT AGENG.

Description

United States Patent Ofic- 3,737,549 Patented June 5, 1973 3,737,549 METHOD OF TREATING DEPRESSION Nicholas Peter Plotnikolf, Village of Lake Bluff, Ill., assignor to Abbott Laboratories, North Chicago, Ill. No Drawing. Filed Mar. 20, 1972, Ser. No. 236,180 Int. Cl. A61k 27/00 US. Cl. 424-274 1 Claim ABSTRACT OF THE DISCLOSURE An improved method of treating depression using thyrotropin releasing agent or L-pyroglutamyl-L-histidyl- L-prolinamide as the anti-depressant agent.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method of treating depression.

There are a number of clinically effective anti-depressant agents which are currently used in the treatment of patients sufliering from moderate to severe depression. Such agents include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, doXepin, prothiadin, Triavil (perphenazine and amitriptyline hydrochloride), Etrafon (perphenazine and amitriptyline hydrochloride), chlorimipramine, noxiptilin and the like. While the above agents have been found to be effective in treating the symptoms of moderate to severe depression, there are several drawbacks to their use.

In most moderately to severely depressed patients, no clinical effect is observed for the first 10 to 14 days of drug administration. This delay in the onset of action of the anti-depressant agent is particularly serious in depressed patients with suicidal tendencies, or in those patients who are severely agitated. Such patients must be sedated or restrained until a clinical anti-depressant effect is observed. Other patients either do not respond to drug therapy or have become refractory to drug therapy. Such patients are generally subjected to electroshock therapy, which has a one percent mortality rate, alone or in combination with various transquilizers, anti-depressants, sedatives and the like.

Furthermore, many of the depressed patients on drug therapy are often hospitalized when drug therapy is initiated because of the high suicide risk during the latency period. For such patients, shortening the period of onset of action is highly desirable.

Thus, there exists a need of improved methods of treating the symtpoms of moderate to severe depression. The present invention provides such a method.

A neurosecretory product known as thyrotropin releasing hormone, hereinafter referred to as TRH, is an extremely useful drug and laboratory tool. It is currently used as a diagnostic agent for evaluating pituitary gland functions. TRH was heretofore isolated by multi-step fractionation of hypothalamic extracts. This complex isolation yielded the valuable, but expensive product. It has now been established that L-pyroglutamyl-L-histidyl-L-prolinamide, a synthetic product, hereinafter referred to as (pyr)g1u-his-pro (NH exhibits the same chemical and hormonal properties of the porcine TRH (Folkers et al., Biochem. and Biophys. Research Comm. 39; No. 1: 110- 113 (1970)).

It has now been found that when 100-800 mcg. of

(pyro)glu-his-pro (NI-I or TRH is administered to moderately to severely depressed patients, definite mood elevation is observed within 23 hours following a single dose and that 24 hours following administration of a single dose, the patients are more cheerful and aware of feeling much better.

The anti-depressant activity of TRH was first established in mice using the modified dopa test [Everett, Fed. Proc. 23, p. 198 (1964)]. The responses in the modified dopa test are graded 1+ for slight increase in activity, 2+ for moderate activity and 3+ for market effects. In the modified dopa test, TRH exhibited marked activity at dosages of 0.4 and 0.8 mg./kg. both by the oral and the intraperitoneal routes. Moderate activity was observed at 0.2 mg./kg. i.p. and slight activity at 0.2 mg./kg. p.o. and 0.1 mg./kg. p.o. and i.p.

In depressed patients, mood elevation has been observed within 23 hours following a single iv. close of either 100, 200, 400 or 800 mcg. of TRH. Twenty-four hours following administration of a single dose, the patients were more cheerful and no side effects were observed.

The rapid onset of action makes TRH a particularly useful anti-depressant agent for the reasons described hereinabove.

The compound useful in the practice of this invention can be formulated into various pharmaceutical dosage forms such as tablets, capsules, pills, sterile aqueous or non-aqueous solutions for parenteral administration, and the like, for immediate or sustained release, by combining one or more of the active compounds with suitable pharmaceutically acceptable carrier or diluents according to methods well known in the art. Such dosage forms may additionally include excipients, binders, fillers, flavoring and sweetening agents and other therapeutically inert ingredients necessary in the formulation of the desired pharmaceutical preparation.

The following examples are illustrative of suitable dosage formulations useful in the practice of this invention.

EXAMPLE 1 Tablets containing 400 mcg. of TRH and having the following composition are prepared according to methods well known in the art.

TRH mc 400 Starch mg 20 Colloidal silica mg 4 Magnesium stearate mg 1 EXAMPLE 2 References Cited Folkers et al., Biochem. & Biophys. Research Comm, 39; No. 1, -113 (1970).

STANLEY J. FRIEDMAN, Primary Examiner