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, 4-aminosalicylic, 2-phenoxybenzoic, ferred dosages ranges for the tricyclic antidepressants 2-acetoxybenzoic, mandelic acid and the like. The salts 15 and representative a-blockers are shown in Table 1. may be prepared by adding an organic or mineral acid to a solution of the free base in an organic solvent, and TABLE 1. further purified by chromotography and/or recrystalli Preferred Dose zation. Compound Range-mg/kg/day 20 Tricyclic antidepressant 1.5-4.0 The tricyclic antidepressants imipramine, desipra a-blocker mine, amitriptyline, nortriptyline, and doxepin are avail Yohimbine 0.2-1.0 able commercially, and their syntheses are well known Piperoxan, phentolamine, to those skilled in the art. Related tricyclic antidepres prazosin, phenoxybenzamine 0.5-2.0 Mianserin, dibozane, thymoxamine 1.0–4.0 sants are accessible by analogous synthetic pathways. Clozapine 2.0-6.0 The ot-blockers are likewise either available commer 25 cially or by well known synthetic pathways. Metiamide 5.0-100 One of the disadvantages of the tricyclic antidepres sants is that, used alone, their onset of activity is slow, Preferred and especially preferred ratios of TCA to requiring several weeks before an acceptable level of representative a-blockers in the method and composi antidepressant activity is shown. In cases of severe de 30 tion of the invention are given in Table 2 (wt. TCA/wt. pression, where suicide is a serious risk, this slow onset a-blocker). of activity can be a great handicap. Increasing the dos TABLE 2 age will accelerate the decrease in f3-receptor density Prefd. wt. Esp. Prefd. and the onset of antidepressant activity, but toxic side Combination ratio wit. ratio effects are produced which militate against such dosage 35 TCA/yohimbine 10-40 15-25 levels. TCA/phentolamine 1-10 2-4 In accordance with this invention, surprisingly the TCA/prazosin 2-50 5-20 TCA/phenoxybenzamine or administration of a combination of a relatively low, piperoxan or dibozane 2-40 3-10 non-toxic dose of a tricyclic anti-depressant and an or thymoxamine a-blocker will accelerate the onset of antidepressant TCA/clozapine 0.2-4 0.5-1 activity such that a clinical reversal of the depressive TCA/metianide 0.15- 0.2-0.3 state will be achieved within from 1 to 7 days. TCA/nianserin 0.3-6 1-2 While not wishing to be bound by a particular mecha nism, it appears that the onset of antidepressant activity The method of the present invention may be effected is due to a decrease in S-adrenergic receptor density 45 with either oral or parenteral administration of the and is accompanied by a2-receptor subsensitization, drugs, in solid or liquid form, and in the presence of a resulting in a higher synaptic concentration of norepi pharmaceutically acceptable carrier if desired. Solid nephrine and increased postsynaptic (31-receptor stimu dosage unit forms, e.g., capsules, pills, tablets and the lation. An effective antidepressant combination thus like are suitable for administration of the combination of appears to act by stimulating an increase in norepineph 50 drugs. Individual solid dosage units may contain, in rine release while inhibiting the feedback mechanism addition to the active ingredients, a pharmaceutically which attempts to compensate by an increase in norepi acceptable carrier, e.g., starch, sugar, sorbitol, gelatin, nephrine uptake. lubricants, silicic acid, talcum, and the like. Alterna It has been found experimentally that daily intraperi tively, liquid dosage forms for either oral administration toneal administration of 5 mg/kg of desipramine does 55 or sterile injectible solutions are suitable for used with not appreciably lower the density of 6-adrenergic re the present method. More than one form of administra ceptors in rat cerebrocortical tissue, as determined by tion may be use where such is found to be clinically the binding of 3H-DHA in the model described herein useful. For example, the first few administrations may above, after administration for 28 consecutive days. be by injection, and subsequent treatment continued Significant reduction in S-adrenergic receptor density 60 using capsules or tablets once the patient's condition is can be achieved with 42 days of chronic desipramine sufficiently improved. Examples of suitable dosage treatment. This closely parallels the time of develop forms are given hereinbelow, although the invention is ment of antidepressant activity in human patients. The not limited in any way by the examples chosen, since co-administration of desipramine with the a-blockers these modes of administration are generally known to yohimbine or prazosin for 4 days at a dosage level of 5 65 the art. mg/kg once daily of desipramine and 2 mg/kg twice Administration of the combination is desirably ef. daily of yohimbine or 5 mg/kg twice daily of prazosin, fected in from 1 to 4 portions daily, preferably by oral produces a marked reduction of g-adrenergic receptor administration, e.g., capsules or tablets, thrice daily, 4,310,524 5 6 e.g., with meals. Each dosage unit will contain from about 1 to about 750 mg, preferably from about 20 to EXAMPLE 2 about 500 mg, and most preferably from about 40 to Pill Formulation about 100 mg of the tricyclic antidepressant or a phar maceutically aceptable acid addition salt thereof, and Pills illustrative of the composition of the invention, from about 1 to about 2000 mg of the a-blocker or a and suitable for use in the method of the invention may pharmaceutically acceptable addition salt thereof. Pre be prepared as follows. As in Example 1, the pill formu ferred amounts of the a-blockers are readily determined lation is designed for administration to a patient weigh from the preferred ratios of TCA/a-blockers in Table 2 ing about 80 kg, and designed for thrice daily adminis hereinabove. 10 tration. Preferred dialy dosage ranges for the antidepressants are shown in Table 3. Per Pil TABLE 3 (a) Imipramine hydrochloride 100 mg Normal daily Recommended 15 (b) Phenoxybenzamine hydrochloride 30 mg Antidepressant dosage (mg) maximum dose (mg) (c) Corn starch 85 mg (d) Liquid glucose 3 ml Imipramine 100-200 300 Desipramine 100-200 300 Doxepin 75-150 300 Amitriptyline 100-200 300 The pills are prepared by blending the active ingredi Nortriptyline 75-100 100 20 ents (a) and (b) and the corn starch, then adding the Protriptyline 15-40 60 liquid glucose with thorough kneading to form a plastic Iprindole 100-200 300 mass from which the pills are cut and formed. Mianserin 00-200 300 Analogously to Example 1, other TCA's and a Tranylcypromine 100-200 300 blockers may be substituted to produce analogous pills 25 according to the invention. The following examples are illustrative but not limita tive of the method and the composition of the present EXAMPLE 3 invention. Other suitable modifications and adaptations Gelatin Capsule Formulation to the variety of conditions and parameters normally encountered in clinical antidepressant therapy and 30 Hard gelatin capsules illustrative of the composition which are obvious to those skilled in the art are within of the invention, and suitable for use in the method for the spirit and scope of this invention. treating depression of the invention are prepared as follows. Each dosage unit is designed for administration EXAMPLE 1. to a patient weighing about 80 kg, and thrice daily ad Tablet Formulation 35 ministration is envisioned. An illustrative tablet formulation suitable for use in making up the antidepressant composition of the inven Per Capsule tion and suitable for use in the method for treating de (a) Amitriptyline hydrochloride 75 mg pression of the invention is as follows. The proportions 40 (b) Clozapine hydrochloride 50 mg are designed for administration to a patient weighing (c) talc 20 mg about 80 kg in a regimen wherein administration is thrice daily. A capsule is prepared by passing dry powdered ac tive ingredients (a) and (b) and powdered talc in the (a) Desipramine hydrochloride 50 g 45 above proportions through a fine mesh screen and mix (b) Yohimbine hydrochloride 10 g (c) Wheat starch 7g ing them well. The powder is then filled into No. 0 hard (d) Lactose 20 g gelatin capsules at a net fill of 145 mg per capsule. (e) Magnesium stearate g Analogous capsules are prepared analogously to the above, using proportional amounts of other TCA's and 50 A granulation obtained upon mixing the lactose with /or a-blockers as shown in Example 1. a portion of the starch and a granulated starch paste We claim: made from the remainder of the strach is dried, 1. In a method for treating depression by administer screened, and mixed with the active ingredients (a) and ing to a patient suffering therefrom an effective antide (b) and the magnesium stearate. The mixture is com 55 pressant amount of imipramine or desipramine or a pressed into 1000 tablets each weighing 88 mg. pharmaceutically acceptable acid addition salt thereof, Analogously, an equal weight of imipramine, doxe the improvement which comprises accelerating the pin, amitriptyline nortriptyline or protriptyline may be onset of antidepressant action of said antidepres substituted for desipramine to produce tablets accord sant by concurrently administering to said patient ing to the invention. an a-adrenergic receptor blocking agent, said Substitution of 25g of phentolamine, 8g of prazosin, blocking agent being yohimbine, piperoxan, 10 g of one of piperoxan, phenoxybenzamine, dibozane prazosin, phentolamine, metiamide, phenoxybenza or thymoxamine, 40 g of mianserin, 70 g o clozapine or mine, thymoxamine, dibozane, clozapine, or mians 200 g of metiamide, or a pharmaceutically acceptable erin, or a pharmaceutically acceptable acid addi acid addition salt thereof, for the 10 g of yohimbine 65 tion salt thereof; wherein said blocking agent is hydrochloride in any of the foregoing, with a propor administered in an amount effective to achieve the tional adjustment of the amounts of (c)-(e) will result in onset of said antidepressant activity within from 1 tablets according to the invention. to 7 days. 4,310,524 7 8 2. The method of claim 1, wherein the a-adrenergic tion salt thereof is from 0.2 to 1.0 mg per kg of patient blocking agent is yohimbine or a pharmaceutically ac body weight per day. ceptable acid addition salt thereof. 50. The method of claim 3, wherein the amount of 3. The method of claim it, wherein the a-adrenergic piperoxane, phentolamine, prazosin or phenoxybenza blocking agent is prazosin, piperoxan, phentolamine or mine or a pharmaceutically acceptable acid addition salt phenoxybenzamine or a pharmaceutically acceptable thereof is from 0.5 to 2.0 mg per kg of patient body acid addition salt thereof. weight per day. 11. The method of claim 6, wherein the amount of 4. The method of claim 1, wherein the o-adrenergic mianserin, thymoxamine or dibozane or a pharmaceuti blocking agent is mianserin, thymoxamine or dibozane O cally acceptable acid addition salt thereof is from 1.0 to or a pharmaceutically acceptable acid addition salt 4.0 mg per kg of patient body weight per day. thereof. 12. The method of claim 5, wherein the amount of 5. The method of claim 1, wherein the a-adrenergic clozapine or a pharmaceutically acceptable acid addi blocking agent is clozapine or a pharmaceutically ac tion salt thereof is from 2.0 to 6.0 mg per kg of patient ceptable acid addition salt thereof. 15 body weight per day. 6. The method of claim , wherein the a-adrenergic 13. The method of claim 6, wherein the amount of blocking agent is metiamide or a pharmaceutically ac metiamide or a pharmaceutically acceptable acid addi ceptable acid addition salt thereof. tion salt thereof is from 5.0 to 10.0 mg per kg of patient 7. The method of claim 1, wherein the amount of the body weight per day. antidepressant or pharmaceutically acceptable acid ad 14. The method of claim 9, wherein the antidepres sant is desipramine in an amount of from 1.5 to 4.0 mg dition salt thereof is from 0.1 to 5 mg per kg of patient per kg of patient body weight per day. body weight per day, and the amount of the a-adrener 15. The method of claim 10, wherein the antidepres gic blocking agent or pharmaceutically acceptable acid sant is desipramine in an amount of from 1.5 to 4.0 mg addition salt thereof is from 0.1 to 10 mg per kg of 25 per kg of patient body weight per day. patient body weight per day. 16. The method of claim 15, wherein the a-adrener 8. The method of claim , wherein the amount of the gic blocking agent is prazosin or a pharmaceutically antidepressant or pharmaceutically acceptable acid ad acceptable acid addition salt thereof. dition salt thereof is from 1.5 to 4.0 mg per kg of patient 17. The method of claim 15, wherein the a-adrener body weight per day. 30 gic blocking agent is phenoxybenzamine or a pharma 9. The method of claim 2, wherein the amount of ceutically acceptable acid addition salt thereof. yohimbine or a pharamaceutically acceptable acid addi 2. s

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