United States Patent (19) (11) 4,310,524 Wiech et al. 45 Jan. 12, 1982 (54) TCA COMPOSITION AND METHOD FOR McMillen et al., Fed. Proc., 38,592 (1979). RAPD ONSET ANTDEPRESSANT Sellinger et al., Fed. Proc., 38,592 (1979). THERAPY Pandey et al., Fed. Proc., 38,592 (1979). 75) Inventors: Norbert L. Wiech; Richard C. Ursillo, Primary Examiner-Stanley J. Friedman both of Cincinnati, Ohio Attorney, Agent, or Firm-Millen & White 73) Assignee: Richardson-Merrell, Inc., Wilton, Conn. (57 ABSTRACT A method is provided for treating depression in a pa (21) Appl. No.: 139,498 tient therefrom and requiring rapid symptomatic relief, (22 Filed: Apr. 11, 1980 which comprises administering to said patient concur 51) Int. Cl. .................... A61K 31/33; A61K 31/135 rently (a) an effective antidepressant amount of a tricy clic antidepressant or a pharmaceutically effective acid (52) ...... 424/244; 424/330 addition salt thereof, and (b) an amount of an a-adrener 58) Field of Search ................................ 424/244, 330 gic receptor blocking agent effective to achieve rapid (56) References Cited onset of the antidepressant action of (a), whereby the PUBLICATIONS onset of said antidepressant action is achieved within Chemical Abst., vol. 66-72828m, (1967), Kellett. from 1 to 7 days. Chemical Abst, vol. 68-94371a, (1968), Martelli et al. A pharmaceutical composition is also provided which is Chemical Abst., vol. 74-86.048j, (1971), Dixit et al. especially adapted for use with the foregoing method. Holmberg et al., Psychopharm., 2,93 (1961). Svensson, Symp. Med. Hoechst., 13, 245 (1978). 17 Claims, No Drawings 4,310,524 1. 2 TCA COMPOSITION AND METHOD FOR RAPID SUMMARY OF THE INVENTION ONSET ANTIDEPRESSANT THERAPY In a method aspect, the present invention provides a method for treating depression in a patient suffering BACKGROUND OF THE INVENTION 5 therefrom, and requiring rapid symptomatic relief, which comprises administering to said patient concur This invention relates to a method for acclerating the rently (a) an effective antidepressant amount of a tricy rate of onset of antidepressant action of clinically effec clic antidepressant or a pharmaceutically effective acid tive tricyclic antidepressants (TCA's) by combining addition salt thereof, and (b) an amount of an a-adrener them with synergistic a-adrenergic receptor blocking O gic receptor blocking agent effective to achieve rapid agents (a-blockers). The invention also relates to a onset of the antidepressant action of (a); whereby the pharmaceutical composition suitable for use with the onset of said antidepressant action is achieved within foregoing method. from 1 to 7 days. The use of tricyclic antidepressants is well known. In a composition aspect, the present invention pro One of the disadvantages of these agents is that the 15 vides an antidepressant composition which is suitable onset of antidepressant therapeutic activity is slow, for use with the above method. often requiring several weeks before a satisfactory ef fect is achieved. In cases of severe depression, where DETAILED DESCRIPTION OF THE suicide is a serious risk, a rapid onset of antidepressant INVENTION activity is highly desirable. 20 The tricyclic antidepressants used in the method of More recently, combinations of tricyclic antidepres the invention are defined pharmacologically by their sants and phenothiazines or butyrophenone antipsy ability to significantly lower (3-adrenergic receptor chotic agents have been used to substantially accelerate density in rat cerebrocortical tissue after prolonged/- the onset of antidepressant activity. The present inven chronic administration, whereas single or short-term 25 administration fails to achieve significant (3-receptor tors are not aware of any reports of clinical use of the lowering. The broad scope of this class of antidepres TCA/a-blocker combinations of this invention in anti sants is described in Fielding et al., Eds., “Industrial depressant therapy. Pharmacology, Vol. II, Antidepressants,' pages 3–43 Holmberg et al., in Psychopharm., 2, 93(1961), re (Futura Publishing Co., Inc., Mount Kisco, N.Y., 1975). ported a study of how the TCA imipramine modified 30 Prominent among the tricyclic antidepressants are the effects of the a-blocker yohimbine in 7 subjects (4 the linear tricyclics, e.g., imipramine, desipramine, ami schizophrenics, 1 alcoholic and 2 psychopaths). No triptyline, nortriptyline, protriptyline, doxepin, ketipra depressives were studied using the combination. mine, mianserin, dothiepin, amoxapine, dibenzepin, Svensson, in a symposium on Depressive Disorders, melitracen, maprotiline, flupentixol, azaphen, and re May 9-11, 1977, published in Symp. Med. Hoechst, 13, 35 lated compounds showing similar activity. Angular 245-254 (Schattauer, Stuttgart and New York, 1978), tricyclics include indriline, clodazone, nonifensin, and suggested the theoretical possibility of enhancing the related compounds. A variety of other structurally di effect of tricyclic antidepressants especially secondary verse antidepressants, e.g., iprindole, wellbatrin, niala amine types such as desipramine, with yohimbine. In mide, phenelzine and tranylcypromine have been the single experiment reported, the firing rate of a nora shown to produce £3-receptor subsensitivity upon drenergic cell in the locus coereleus of a rat was inhib chronic administration, as reported by Sellinger et al. ited by desipramine and the inhibition was then antago and Pandey et al. In Fed. Proc., 38,592 (1979). They are nized by a more than three-fold excess of yohimbine. functionally equivalent to the tricyclic antidepressants Animal studies of the effects of the a-blockers dibo and are therefore included within the scope of the in Zane and prazosin on rats fed rather high chronic doses 45 vention. Thus, the term tricyclic antidepressant is in of desipramine were reported by McMillen et al., Fed. tended by the present inventors to embrace the broad Proc., 38,592 (1979). class of antidepressants described above together with Attempts to correlate o-receptor effects or firing related compounds sharing the common property that rates of norepinephrine neurons in the locus coereleus they all depress cerebrocortical g-adrenergic receptor with both the chemical intensity and temporal activity 50 density on chronic administration. profiles of antidepressants has been less than successful. The a-adrenergic receptor blocking agents of this invention include: yohimbine, piperoxan, mianserin and However, recent research has shown that the antide metiamide which are primarily a 2-blockers; prazosin, pressant activity of a wide variety of antidepressant thymoxamine, dibozane and clozapine which are pri drugs as well as of chronic electroshock is well corre 55 marily a 1-blockers; and phentolamine and phenoxyben lated with a g-receptor assay in an animal model. Spe zamine which have substantially equal blocking effects cifically, the temporal profile of the onset of antidepres on a 1-receptors and d2-receptors, or pharmaceutically sant activity in humans closely parallels the decrease in acceptable acid addition salts thereof. Contemplated f3-adrenergic receptor density in rat cerebrocortical equivalents include other a-blockers which are struc tissue, as determined by a measurement of the binding of 60 turally and/or pharmacologically related to the forego tritiated dihydroalprenolol (H-DHA) using liquid scin ing, e.g., corynanthine which is a stereoisomer of yo tillation spectrometry. Thus, this method of assay of himbine and has similar pharmacological properties, antidepressant drugs in rats by its capability to decrease tolazoline which is an analog of phentolamine and has braing-adrenergic receptors using the ligand H-DHA similar uses, and dibenamine which is structurally and is far superior to any previously described method, 65 pharmacologically related to phenoxybenzamine. since the effect is common to all known antidepressants Drugs are classified as a -blockers and/or a2 block and measures the time of onset of the antidepressant ers according to their ability to inhibit different effects activity as well. of norepinephrine, as reviewed by Starke, "Regulation 4,310,524 3 4. of Norepinephrine Release by Presynaptic Receptor density. The criticality of the dosage levels is shown by Systems," Rey, Physiol. Biochem. & Pharmacol, 77, 1 the fact that administration of 1 mg/kg twice daily of (1977). yohimbine instead of 2 mg/kg in the foregoing experi The tricyclic antidepressant and/or the a-blocker ment resulted in only a marginal reduction of 6-adren may be administered in the form of a pharmaceutically ergic receptor density. acceptable acid addition salt, e.g., salts with inorganic In the method for treating depression of the present acids such as, for example, hydrochloric, hydrobromic, invention, a dosage level of from 0.1 to 5 mg/kg of body sulphuric, phosphoric acids and the like and with or weight of the patient per day of the tricyclic antidepre ganic carboxylic acids such as, for example, acetic, sant is combined with a dosage of from 0.1 to 10 mg/kg propionic, glycolic, lactic, pyruvic, malonic, succinic, 10 of patient body weight per day of d-blocker, or a phar fumaric, malic, tartaric, citric, ascorbic, maleic, hydrox maceutically acceptable acid addition salt of one or ymaleic and dihydroxymaleic, benzoic, phenylacetic, both of the foregoing. Preferably, the combination is 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cin administered three times daily in equal dosages. Pre namic, salicylic,