WO2000041684A1

WO2000041684A1 - A pharmaceutical combination for the treatment of depression

Info

Publication number: WO2000041684A1
Application number: PCT/US1999/029590
Authority: WO
Inventors: Thomas Gary Heffner; Leonard Theodore Meltzer; Atul Chandra Pande; Gary Dennis Tollefson
Original assignee: Warner-Lambert Company; Eli Lilly And Comapny
Priority date: 1999-01-13
Filing date: 1999-12-14
Publication date: 2000-07-20
Also published as: AU2180400A

Abstract

The instant invention is a method for the treatment of depression, especially refractory depression, which comprises administering a combination of a sigma receptor ligand and a serotonin reuptake inhibitor.

Description

A PHARMACEUTICAL COMBINATION FOR THE TREATMENT

OF DEPRESSION

BACKGROUND OF THE INVENTION

Fluoxetine hydrochloride, a marketed antidepressant known as Prozac, of chemical structure

is a serotonin reuptake inhibitor. The compound is taught in United States Patent 4,314,081 which is hereby incorporated by reference.

Igmesine, a drug useful for depression, of chemical structure

has a particular binding affinity for sigma receptors. The chemical name is trans-+-N-cyclopropylmethyl-N-( 1 ,4-diphenyl- 1 -ethyl-3-buten- 1 -yl)- N-methylamine hydrochloride salt. The compound is taught in United States Patent 5,034,419 which is hereby incorporated by reference.

The compound (l-propyl-5-(3-p-tolyl-isoxazol-5-yl)-l, 2,3 ,6-tetrahydro- pyridine), sigma receptor ligand, is taught in United States Patent 5,330,994 which is hereby incorporated by reference. The compound (3-phenyl-l-(l-propryl- l,2,5,6-tetrahydro-pyridin-3-yl)-propan-l-one oxime) is another sigma receptor ligand and is taught in United States Patents 4,798,841; 5,073,561 ; and 4,929,734 which are hereby incorporated by reference. SUMMARY OF THE INVENTION

The instant invention is a new method for treating depression in a mammal in need thereof which comprises administering a combination of a sigma receptor ligand and a serotonin reuptake inhibitor. Sigma receptor ligands useful in the treatment are selected from

SKF- 10,047, dextromethorphan, haloperidol, elipiodil, BMY- 14802, igmesine, JO-1994, NPC-16377, l-propyl-5-(3-p-tolyl-isoxazol-5-yl)-l,2,3,6-tetrahydro- pyridine, and 3-phenyl-l-(l-propryl-l,2,5,6-tetrahydro-pyridin-3-yl)-propan-l-one oxime. Serotonin reuptake inhibitors (SSRI) are selected from: fluoxetine, venlafaxine, citalopram, fluvoxamine, paroxetine, sertraline, milnacipran, and duloxetine. Pharmaceutically acceptable salts of the compounds are also useful.

The combination of igmesine and fluoxetine is particularly useful.

The combinations of the invention are useful in treating depression, especially refractory depression.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effect of igmesine-fluoxetine combination in the Behavioral Despair Test in rats.

Figure 2 shows the effect of igmesine and fluoxetine in the Tail Suspension Test in mice.

DETAILED DESCRIPTION OF THE INVENTION

The instant invention is a combination of the two antidepressants to provide solutions to several problems encountered in the current treatments of patients suffering from depression.

One of the most outstanding advantages to the patient of the invention is the faster onset of action provided by the combination as compared to either a serotonin reuptake inhibitor or a sigma receptor ligand alone. Since there is a shorter interval for the effect to be felt, the patient is at less risk of suicide. - About 15% of the patient population does not respond to any of the current drug therapies as it suffers from refractory depression. The instant combination provides an answer for these patients and for others suffering from depression. The two known compounds act in the body in two distinct and different mechanisms. The combination of a serotonin reuptake inhibitor and a sigma receptor ligand provides a potentiated effect.

The combination has fewer undesired side effects partly because the individual compounds can be administered in lower doses. This leads to better patient compliance since the patient experiences enhanced relief. The protocol useful in the testing of a sigma receptor ligand in combination with a serotonin reuptake inhibitor is as follows.

Patients suffering from Depressive Disorder who have symptoms of at least moderate severity, as judged clinically, are administered in a double-blind, randomized fashion, either igmesine alone, fluoxetine alone, or the combination thereof for a period of no less than 4 weeks and possibly as long as 8 weeks.

During this treatment period, patients are frequently assessed for changes in the severity of depressive symptoms using standard, and commonly utilized rating scales, such as the Hamilton Depression Scale or the Montgomery-Asberg Depression Scale. This method provides a side-by-side comparison of the effects of either drug alone with the combination. Thereby, it can be demonstrated that the combination provides superior antidepressant therapeutic effects than either drug alone.

Combination treatment with igmesine and fluoxetine is more beneficial than fluoxetine alone in the treatment of patients whose depressive illness is refractory to previous drug therapy. This benefit is demonstrated by treating patients with fluoxetine for 8 weeks. All those whose depression is not relieved are randomized in a double-blind manner to treatment with either fluoxetine alone or a combination of fluoxetine and igmesine. The combination is expected to be more effective in relieving depressive symptoms than the continuation of fluoxetine alone.

The unit doses used for antidepressants are usually between 1 and 500 mg, and more particularly between 5 and 200 mg product, depending on the nature and the severity of the condition to be treated. The daily therapeutic doses can be divided into several administrations and are between 5 and 2,000 mg product per day. A daily dosage of 50 to 500 mg product per day divides into 2 to 4 administrations is generally sufficient.

The products according to the instant invention are administered to patients in a form of medicaments suitable for the condition to be treated. The preparations will be, for example, tablets, coated tablets, capsules, powders, solutions, suspensions, gels, or suppositories, depending on the case. The pharmaceutical forms are prepared from the products in the form of the base or their salts and in accordance with the methods usually employed in this industry. In medicament forms of a solid nature, the active principle generally makes up 5% to 90% by weight of the total finished form, and the medicaments thus make up 95% to 10%. For liquid forms, which can be considered as such, the amount of active principle is between 0.1% and 10% by weight of the finished form, and the excipient can thus make up 99.9% to 90% by weight of this form. In treating humans suffering from various psychoses having a depressive component, the compounds of this invention can be given orally or parenterally; oral dosing is preferred. In either instance, it is preferred to use an acid addition salt of the compound formed with a pharmaceutically-acceptable nontoxic acid. For purposes of oral administration, the salt can be mixed with standard pharmaceutical excipients and placed in telescoping gelatin capsules. Similarly, the compound can be mixed with starch, binders, etc. and formulated into tablets, which tablets may be scored for ease of divided dosage administration. For parenteral administration, a water soluble salt of the compound of this invention, which salt is pharmaceutically-acceptable, is dissolved in an isotonic solution and administered intramuscularly, intravenously, or subcutaneously. For chronic administration, the oral pharmaceutical forms are naturally preferred. The dose level should vary from 1- to 50-mg/dose given from 1 to 4 times a day with a total daily dosage of 1 to 200 mg/day/human. Rather than a dose of from 20 to 80 mg per day of fluoxetine, the combination of the instant inventions uses as little as 10 mg of the drug. Rather than a dose of from 25 to 100 mg per day of igmesine, as low a dose as 25 mg can be given. A skilled physician will adjust dose levels as needed. Behavioral Tests

The interaction of igmesine, or other sigma ligands, and fluoxetine, or other SSRIs, to produce antidepressant-like activity in preclinical tests is evaluated in the mouse Tail Suspension Test and rat Swim Despair Test, well- recognized animal tests to predict clinical antidepressant activity.

The interaction of igmesine and fluoxetine, at doses which by themselves are inactive in producing antidepressant-like activity in preclinical, were evaluated in the mouse Tail Suspension Test and the rat Swim Despair Test. In both of these tests, higher doses of igmesine and fluoxetine, when administered alone, were needed to produce antidepressant-like effects.

Forced Swim Behavioral Despair Test in Rats

On Day 1 of the experiment, rats were placed in a small tank of water for 15 minutes. Initially, the animals swam, but could not escape so they stopped swimming. Immediately after the swim session the rats were injected with vehicle or a dose of the test compound. The next day, approximately 24 hours after the first swim session, the animals were injected with vehicle or the test compounds at a specified time prior to the second swim session. The rats were again placed in the water tank. They had learned from the first day that the could not escape the water, so they had very little activity. Revolutions of a wire wheel at the water-air interface, at which the rat directs its activity, was used to quantify the activity of the animal in the tank. This test has been demonstrated to predict antidepressant- like activity.

In these experiments igmesine and fluoxetine, at doses which by themselves did not produce an antidepressant-like effect, when given in combination, produced an antidepressant-like effect, as evidenced by an increase in the number of wheel rotations in the first 5 minutes of the test (see Figure 1).

Figure 1 shows the effect of igmesine (I) and fluoxetine (F) in combination in the Behavioral Despair Test in Wistar-Kyoto rats. Saline is S. The wheel rotations are for 5 minutes total, and the dose is in milligrams per kilograms given IP. The mean is ±SEM; the number was 35-36/group. It is clear from Figure 1 that neither compound alone differs from the vehicle, and that a combination of the two ineffective doses was more than three times as effective. Figure 2 shows the effect of igmesine and fluoxetine in the Tail Suspension Test in CD-I mice. The immobility is given in seconds and the dose in milligrams per kilograms given IP.

The data show that subthreshold doses of the compound, when given in combination, provide an antidepressant effect.

In the mouse Tail Suspension Test model, a mouse was gently suspended by its tail to a force transducer which measured the amount of time the animal struggled. Normally, the mouse struggled for awhile and then quietly hung there. Antidepressants increase the amount of time the mice attempt to escape. In these experiments, igmesine and fluoxetine, at doses which by themselves did not produce an antidepressant-like effect, when given in combination, produced an antidepressant-like effect, as evidenced by a decrease in the immobility time in a 6-minute test (see Figure 1).

In these studies, a dose-response for both igmesine and fluoxetine was determined. Then inactive doses of each agent were administered simultaneously.

This dose combination of 2 inactive doses of 2 different compounds provided antidepressant-like behavioral effects.

Neurochemical Tests

In neurochemical tests in rats, igmesine increases the release of dopamine and norepinephrine while fluoxetine and other SSRIs increase the release of serotonin. Using relatively low doses of each agent, igmesine and fluoxetine, in combination lead to an enhanced release of all 3 transmitters, to a greater degree than low doses of either agent alone.

The following example is for illustration purposes.

Tablets

Fluoxetine 10 mg

Igmesine 20 mg

Polyvinylpyrrolidone 20 mg

Carboxymethyl starch 8.0 mg

Magnesium stearate 2.0 mg

Colloidal silica 0.4 mg

Lactose in a sufficient amount -200.0 mg

Claims

1. A method for treating depression in a mammal in need thereof which comprises administering a combination of a sigma receptor ligand and a serotonin reuptake inhibitor.

2. A method of treatment according to Claim 1 wherein the combination is a sigma receptor ligand selected from: SKF-10,047, dextromethorphan, haloperidol, elipiodil, BMY- 14802, igmesine, JO- 1994, NPC-16377, (3-phenyl-l -(1 -propryl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-propan-l -one oxime) or (l-propyl-5-(3-p-tolyl-isoxazol-5-yl)-l, 2,3, 6-tetrahydro- pyridine), and a serotonin reuptake inhibitor selected from: fluoxetine, venlafaxine, citalopram, fluvoxamine, paroxetine, duloxetine, sertraline, or milnacipran, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical agent which is a combination of a sigma receptor ligand and a serotonin reuptake inhibitor.

4. A combination according to Claim 3 of a sigma receptor ligand selected from: SKF- 10,047, dextromethorphan, haloperidol, elipiodil, BMY- 14802, igmesine, JO- 1994, and NPC-16377 and a serotonin reuptake inhibitor selected from: fluoxetine, venlafaxine, citalopram, fluvoxamine, duloxetine, paroxetine, sertraline, and milnacipran, or a pharmaceutically acceptable salt thereof.

5. A method for treating depression in a mammal in need thereof which comprises administering igmesine or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

6. A method for treating refractory depression in a mammal in need thereof which comprises administering igmesine or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof in a pharmaceutical composition.

7. A method for treating depression in a human subject in need of such treatment which comprises the administration to said human a therapeutically effective amount of fluoxetine or norfiuoxetine or a pharmaceutically acceptable salt thereof in combination which igmesine or a pharmaceutically acceptable salt thereof.

8. A method according to Claim 7 wherein the combination is administered orally.

9. A method according to Claim 7 wherein the fluoxetine and the igmesine are administered as the hydrochloride salt.

10. A method according to Claim 7 in which the daily dosage level of fluoxetine is 8 to 10 mg and igmesine is 15 to 20 mg.

11. A method of treating depression in a human in need of such therapy by administering an effective amount of R(-)fiuoxetine or a pharmaceutically acceptable salt thereof, substantially free of its S(+)stereoisomer in combination with a compound with binding affinity for the sigma receptor.

12. A method of treating depression in a human in need of such therapy by administering S(+) fluoxetine in combination with a compound with binding affinity for the sigma receptor.

13. A method according to Claim 1 1 wherein the compound with binding affinity for the sigma receptor is igmesine or a pharmaceutically acceptable salt thereof.

14. A method for increasing or enhancing the release of 3 transmitters: dopamine, norepinephrine, and serotonin in the brain comprising administering a combination of a compound with binding affinity for the sigma receptor and a serotonin reuptake inhibitor.

15. A method according to Claim 14 wherein the amount of the compound with binding affinity of the sigma receptor is between 15 and 20 mg and the amount of the SSRI compound is between 8 and 10 mg.