WO1998048788A1

WO1998048788A1 - Treatment of depression and anxiety using docosahexaenoic acid or natural antioxidants

Info

Publication number: WO1998048788A1
Application number: PCT/GB1998/001260
Authority: WO
Inventors: David Frederick Horrobin
Original assignee: Scotia Holdings PLC
Current assignee: Scotia Holdings PLC
Priority date: 1997-04-29
Filing date: 1998-04-23
Publication date: 1998-11-05
Anticipated expiration: 1999-10-29
Also published as: AU7222598A

Abstract

Medicament manufacture for depression or anxiety using compositions of natural antioxidants, or compositions of essential fatty acids (docosahexaenoic acid, DHA) optionally with essential nutrients and/or natural antioxidants.

Description

TREATMENT OF DEPRESSION AND ANXIETY USING DOCOSAHEXAENOIC ACID OR NATURAL ANTIOXIDANTS

The invention relates to treatment of depression and anxiety.

GENERAL

Depression and anxiety are among the commonest health problems. Although one can occur without the other, it is also common for the two to occur together since in some respects they appear to be closely related. Around 30% of the population experience an episode of depression or anxiety at some time in their lives. This may often be passed off by using expressions such as "feeling down" or "feeling blue" or being unduly worried. As well as being the cause of great unhappiness for both individuals and those who come into contact with them, depression is dangerous as it is by far the commonest cause of suicide.

The n-3 essential fatty acids (EFAs) are important structural elements of the brain. They are required for normal function of all nerve cells. The n-6 EFAs are also important components of nerve cell membranes. The two types of EFA are metabolised by the pathways shown in Table 1.

TABLE 1

n-6 EFA's n-3 EFA's 18:2n - 6 18.3n - 3 (Linoleic acid, LA) (α-Linolenic acid, ALA) si delta - 6 desaturase I

18:3n - 6 18:4n - 3 (γ - Linolenic acid GLA) (Stearidonic acid) elongation I

20:3n - 6 20:4n - 3 (Dihomo - γ - linolenic acid, DGLA)

-I delta - 5 desaturase I

20:4 n-6 20:5 n-3 (Arachidonic acid, AA) (Eicosapentaenoic acid,EPA)

•I elongation I

22:4n - 6 22:5n - 3 (Adrenic acid, AdrA)

I delta - 4 - desaturase I

22:5n - 6 22:6n - 3 (Docosahexaenoic acid, DHA)

The acids, which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. LA z,z-octadeca - 9,12 - dienoic acid or DHA z,z,z,z,z,z - docosa- 4,7J0J3J6J9 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances.

PRESENT WORK In one aspect of the present work the applicants have noted that three groups of investigators have suggested that in depression there may be a reduced ratio of n-3 EFAs to n-6 EFAs (J.R. Hibbeln et al Am J. Clin. Nutr. 1995 62 1-9; M. Maes et al J. Affective Dis. 1996 38 35-46; P.B. Adams et al Lipids 1996 31 5-157-61) but no actual deficiency of n-3 EFAs has been demonstrated.

However, the applicants have recently measured EFA concentrations in the red blood cell phospholipids of patients with depression and compared these levels with those in normal, control individuals. In normal individuals (n=J5) the concentration was 5.43 + 2.01 mg/lOOmg lipid whereas in matched depressed individuals (n=15) the concentration was 3J 1 + 2.47mg/100mg lipid. This difference was very highly significantly statistically at p>0.009. This demonstrates that in depression there is a deficiency of DHA in red blood cell membranes. The other investigators quoted above did not measure DHA levels in cell membranes and did not demonstrate any actual deficiency of DHA in depression. Since red blood cells are a guide to what happens in the brain, this demonstrates that brain DHA levels are probably reduced.

A deficiency of a substances does not necessarily mean that the substance can be used in therapy. The have applicants therefore tested the administration of DHA in three patients who had developed moderate to severe depression. The aim was to find out whether DHA could relieve depression and, if so what dose might be effective.

The patients were treated with capsules of DHA in triglyceride form and each dose was given for a period of eight weeks. At a dose of 250mg DHA/day, the patients experienced no improvement in depression score. At 500mg/day, two patients experienced a moderate but not complete improvement, but the third experienced no change At lg/day the third patient experienced a modest improvement and in the two patients who had improved on 500mg./day there was near complete resolution of symptoms. At 2g/day the two patients who had recovered remained completely recovered. The third patient improved further but without complete resolution.

These observations show that DHA is able to treat depression and that the effective dose is 350 to 3000mg/day, though higher doses up to for example lOg day could be given.

In another aspect of the present work the applicants have noted that there are many drugs which are able to treat depression and anxiety. However, these do not work in between 25 and 50% of patients. Even when they do work, in some patients they cause side effects such as dry mouth, gastro-intestinal disturbances, excessive sleepiness, blood pressure disturbances, impotence in males, inability to experience orgasm in both sexes, and vague unpleasant feelings or dysphoria which can be very distressing to the patient. There is therefore a considerable need for new approaches to depression.

There is recent evidence that depression and anxiety may be associated with reduced levels of the highly unsaturated n-3 essential fatty acids (Maes M. et al, J. Affective Disorders 1996 38_35-46; Hibbeln J. et al, Am. J. Clin. Nutr. 1995 62 1-9 as cited earlier herein). There may be many reasons for this including inadequate intake of the n-3 EFAs, or abnormalities in desaturation and elongation. Another possibility, however, is that the reduced levels of n-3 EFAs in blood are caused by increased exposure to oxidants such as cigarette smoke or car exhaust fumes or by inadequate intakes of the many different nutritional factors which contribute to the total antioxidant activity of the body, given that n-3 EFAs are highly susceptible to oxidation.

The antioxidant systems of the body are very complex and require the close interaction of many different compounds. Just as providing large amounts of one B vitamin could not compensate for the deficiencies of other B vitamins, so supplying one component of the antioxidant system cannot compensate for others which may be missing. Most clinical trials of antioxidants have made the mistake of giving large amounts of one or other antioxidant without attempting to provide a balanced intake of all the likely antioxidants and related co-factors. The applicants have therefore carried out a study in which those antioxidants and related co-factors most likely to be deficient in normal people were provided and compared with placebo for their effects on depression. The materials which were provided were ascorbic acid (lOOmg), pyridoxine hydrochloride (25mg), beta-carotene (3mg), vitamin E (lOOmg), zinc (4mg), nicotinamide (lOmg) and selenium (450 microg). The figures in brackets represent the amounts provided each day. Placebo capsules contained coconut oil.

The study was performed in patients with peripheral vascular disease who have a known tendency to have depressed mood. 120 patients were entered into the study and by the randomisation process 55 were assigned to receive antioxidant and 65 to receive placebo. They were assessed at baseline on the Hospital Anxiety and Depression (HAD) Scale, a standard instrument for measuring these parameters. They were treated with the antioxidant or placebo for two years. The numbers of patients classified as anxious or depressed on the HAD anxiety and expression sub- scales are shown in Table 2:

TABLE 2

Percentages of patients in the study with anxiety or depression as defined by the Hospital Anxiety and Depression Scale.

Baseline End of Trial Change Anxiety

Antioxidant group 27.6% 17.2% -10.4%

Placebo group 30.8% 38.5% + 7.7%

Depression

Antioxidant group 13.8% 6.9% - 6.9%

Placebo group 5.1% 7.7% + 2.6%

Clearly during the treatment period the numbers of patients who were anxious or depressed decreased substantially in the antioxidant group but increased in the placebo group. The differences between the changes in the two groups were significant at p<0.05.

This study demonstrates that the combined antioxidant mix proposed is effective in improving anxiety and depression.

THE INVENTION

In one aspect the invention lies in use of DHA in a method of making a medicament for treating depression, anxiety, "feeling down" or "feeling blue", by the administration of DHA at 350 to 3g or more (up to lOg) per day, preferably 500 mg to 2g per day, and in such treatment itself. Other fatty acids of the n-3 series, such as alpha-linolenic acid (ALA), stearidonic acid (SA), eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA n-3) may optionally be added, as may fatty acids of the n-6 series such as linoleic acid (LA), gamma-linolenic acid (GLA), dihomogamma linolenic acid (DGLA) and arachidonic acid (AA), at 250 mg to 2000mg/day. Since patients with depression frequently fail to eat properly, the DHA may also optionally be provided with supplements of essential minerals and vitamins. In addition, because EFAs like DHA are easily oxidised, there are advantages in combining it with physiologically effective lipophilic antioxidant compounds such as vitamin E, alpha- lipoic acid and beta-carotene.

The DHA may be administered in any form which is able to raise the levels of DHA in the blood. The oral route is likely to be the one preferred, but topical or parenteral routes are also possible. Appropriate forms of DHA are triglycerides, diglycerides. mono-glycerides, free fatty acid, ethyl or other appropriate esters including derivatives of 1, 2- or 1, 3 -propane diol or of geminal one-carbon diols, anhydrides, amides, cholesterol esters, phospholipids of any type or any other appropriate derivatives. Specific propane diol, geminal one-carbon diol and other derivatives are as disclosed in the applicant's specifications WO 96/34855 (PCT GB 96/01052) and WO 96/34846 (PCT GB 96/01053) to which attention is directed. Use may be made of any appropriate delivery vehicle known to these skilled in the art such as capsules, emulsions, granules, powder, tablets or other appropriate form.

In another aspect the invention lies in the antioxidant mix discussed earlier, both as such and when used in preparation of a medicament for the treatment of anxiety, depression, "feeling down" or "feeling blue". Depression may be in terms of "the blues", unhappiness or feeling low, or any other manifestation of depressed mood, and the invention extends to the treatment itself.

The actives are as set out below in Table 3. The figures represent the daily dose to be administered. The daily dose may be provided in a single capsule, tablet or other solid or liquid dosage form known to those skilled in the art, or may be provided in divided doses to make up the full daily dose. The ingredients may be provided in any form assimilable after oral administration.

TABLE 3

Active Lower Limit Upper Limit

Vitamin C (ascorbic acid) 50mg/day lOg/day

Beta-carotene 2mg/day lOOmg/day

Vitamin B6 (pyridoxine or other forms) 15mg/day lOOmg/day

Zinc (as sulphate, gluconate or other forms) 2mg/day 50mg/day

Nicotinamide or niacin 5mg/day lOOmg/day

Vitamin E 50mg/day lOOOmg/day Selenium (as selenite, selenate, conjugates such as selenomethionine, or other forms) 1 OOmicrog/day 1000 microg/day

Each of the above compounds may be presented in any appropriate biologically available form. The above are necessary actives in the formulation. To them may be added optionally other nutrients but in particular n-3 essential fatty acids such as alpha- linolenic acid (ALA), stearidonic acid (SA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA n-3) and docosahexaenoic acid (DHA). Such fatty acids may be provided in any appropriate form as discussed earlier herein, in a dose ranging from 1 Omg to 1 Og per day. Folic acid may also be a valuable nutrient in anxiety and depression and so it too may be added to the formulation in dose ranging from 10 to 1000 microg/day.

Examples

Formulations of DHAand their use against depression are illustrated below in Examples 1 - 12.

1. 250 mg soft gelatin capsules containing DHA in triglyeride, ethyl ester, diglyceride, monoglyceride, 1,3 -propane diol ester, amide, phospholipid or other bioavailable form to be taken in a dose of 2 to 8 capsules per day.

2. 500 mg DHA capsules as in 1 to be taken at a dose of 1 - 4 capsules/day.

3. As 1 or 2 but with a multi-nutrient formulation either co-administered or forming part of the DHA capsules, with the recommended daily allowances of vitamins of the B group, vitamin C, vitamins A and D, folic acid, bioavailable zinc, selenium and magnesium, and optionally others of the known vitamins and essential minerals.

4. As 1, 2 or 3 but further with effective amounts of lipophilic antioxidants such as vitamin E, beta-carotene or alpha-lipoic acid.

5. lOOOmg DHA capsules as in 1 to be taken at a dose of 1 - 2 capsules/day. 6. An emulsion containing DHA in a concentration of 350mg to 2g in 1 -10 ml to be taken in doses which provide 350mg to 2g/day. Any appropriate emulsifying agent may be used, but the galactolipids are particularly appropriate emulsifying agents. Reference may be made for them to the applicants' PCT specification SE 95/00115 (WO 95 20943) to which attention is directed.

7-12. As in examples 1 - 6 except that 250mg to 2g/day of each of one or more of ALA, SA, DPA, EPA, LA, GLA, DGLA or AA is also provided in the formulation.

Examples of antioxidant formulations as such or for use against depression or anxiety are:-

13. Capsules of ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, vitamin E 100 mg, available zinc 4 mg, nicotinamide 10 mg, beta carotene 3 mg and available selenium 450 microg, or one half or one quarter of those amounts, for administration to give those amounts daily.

14. Capsules as last with 100 mg eicosapentaenoic acid in addition.

15. Capsules as 13 or 14 with 100 microg folic acid in addition.

16. Capsules as 13, 14 or 15 with 200 mg docosahexaenoic acid in addition.

Claims

1. A method of making a medicament for treatment of depression, anxiety, "feeling down" or "feeling blue", and such treatment itself, using DHA in bioavailable form formulated for administration of 350mg to 3g DHA or more (up to lOg) per day. preferably 500mg to 2g.

2. As 1, but with 250 mg to 2g/day of each of one or more other fatty acids also, selected from ALA, SA, EPA, DPA, LA, GLA, DGLA or AA.

3. As 1 or 2, but also with effective amount(s) related to the recommended daily allowances of one or more other essential nutrients such as vitamins of the B group, vitamin C. vitamins A and D, folic acid, and bioavailable zinc, selenium or magnesium.

4. As 1, 2 or 3 but also with effective amounts of one or more lipophilic antioxidants such as vitamin E, alpha-lipoic acid or beta-carotene.

5. The formulation as in claim 1, 2, 3 or 4, per se.

6. A method of making a pharmaceutical or nutritional formulation for treatment of depression, anxiety, "feeling down" or "feeling blue", and such treatment itself, using ascorbic acid (50mg - lOg), beta-carotene (2mg - lOOmg), Vit. B₆ (pyridoxine 15mg - 1 OOmg or equivalent amounts of other forms), zinc (2mg - 50mg), nicotinamide or niacin (5mg - lOOmg), vitamin E (50mg - lOOOmg), and selenium (100 microg - 1000 microg) presented for administration in daily amounts in single or divided doses, each in biologically active form.

7. Method as in claim 6, which provides in addition for administration at lOmg to lOg per day of one or more of ALA, SA, EPA, DPA n-3 or DHA.

8. Method as in claim 6 or 7, which provides in addition for administration at 10 microg to 1000 microg/day of folic acid.

9. The formulations as in claim 6, 7 or 8, per se.