The treatment of depression and pharmaceuticals for this purpose

 

The invention relates to the field of medicine and related antidepressant and treatment of depression using known SFL and IPMS. The invention lies in the fact that the product contains antidepressants selected from SFL classes and SYMPTOM, and additionally folic acid or its predecessor, of which the patient is produced by folate. Daily dose SYMPTOM or SFL matches prescribed for the treatment of depression in the usual way. Daily dose of the precursor of folic acid should be such as to provide a dose of folate 300-5000 micrograms/day. The invention provides greater efficiency and reducing the risk of adverse effects associated with treatment. 2 S. and 3 C.p. f-crystals, 4 PL.

The present invention relates to the treatment of depression and used pharmaceutical drugs.

Depression is one of the most important public health problems, especially in developed countries. At some point life approximately 5-10% of the population is experiencing a General depression, and mild episodes of depression can affect 25% or greater percentage of the population. The world health organization found that depression causes more comprehensive the house, and at work. Depression is the most common cause of suicide. Depression is also associated with other diseases, especially cardiovascular diseases. People, in history there was a General depression, were more than four times inclined to myocardial infarction compared to the norm, even taking into account known risk factors of coronary heart disease (L. A. Pratt et al., Circulation 1996; 3123-3129). After myocardial infarction the risk of death of people with a common depression 3.5 times higher compared to those who do not suffer from depression (N. Frasure-Smith et al., JAMA 1993; 1819-1825). Thus, there is a particular need for an effective treatment of depression, which can be applied, in particular, for people with problems of the cardiovascular system.

In recent years, depression is usually treated with a combination of antidepressants, choose from one of three main groups of compounds. There are tricyclic and tetracyclic antidepressants and related compounds ("tricyclic compounds"); monoamine oxidase inhibitors (MAOIS) and selective or partially selective inhibitors of serotonin uptake (SFL). Tricyclic compounds have multiple and complex mechanisms of action and are associated with many side effects is under suicide. MAOIS inhibit one of the main enzymes involved in the destruction of catecholamines, and can also have many side effects. In patients with cardiovascular disease and tricyclic compounds, and MAOIS must be used with great caution. SFL have a relatively greater selectivity of action in the inhibition of the reuptake of serotonin nerve endings and usually have less side effects in comparison with compounds of other groups. However, due to adverse effects from clinical trials falls almost the same number of patients receiving new antidepressant group SFL, as was the case when using older tricyclic drugs (K. R. Abrams, British Medical Journal, 1998; 316: 1183-4). Recently for General chemistry applications approved a new group of compounds, known as inhibitors of reuptake of norepinephrine (IPMS), which constitute a new class of antidepressants.

Despite the fact that all four classes of antidepressants are undoubtedly effective, many patients insensitive to them. For example, 30-40% of patients do not respond to tricyclic compounds (R. J. Bielski and R. O. Friedel, Archives of General Psychiatry, 1976; 33: 1479-89). Share insensitive to MAOIS such Elirema tests (for example, S. P. Roose et al., JAMA 1998, 279: 287-291). Thus, there is a General need to improve treatment of depression in light of the high personal and economic costs both for the individual and for society, especially for patients with risk of cardiovascular disease. This improvement should include both greater efficiency and reduced risk of adverse consequences.

Folic acid is an essential vitamin C. the recommended daily allowances (RDAs) in the United States is 200 micrograms for men and 180 micrograms for women. Women supposedly pregnant, now it is recommended to take 400 micrograms/day to reduce the risk of spina bifida.

Folic acid is found in many natural forms, which include as its overall structure pteroylglutamic acid. In the intestinal wall they turn into methyltetrahydrofolate acid (MTHF), which is the basic form of the vitamin in the blood. MTHF shows the number of biological effects, but the most important is, apparently, its interaction with homocysteine. Under the influence of the enzyme MTGF-reductase MTHF donates a methyl group to homocysteine to turn it into methionine, which then can the acid homocysteine increases. Homocysteine is associated with cardiovascular toxicity and is growing evidence that low levels of folate can lead to increased levels of homocysteine, which in turn leads to myocardial infarction and other forms of cardiovascular disease (R. Verhoef et al. Current Apinion in Lipidology, 1998; 9: 17-22). Recent data suggest that homocysteine is reduced to a stable level, many people only when folic acid in the amount of 400 micrograms/day or more (Selhub J et al. Journal of Nutrition, 1996; 126: 12585-655): P Verhoef et al, American Journal of Epidemiology 1996; 143: 845-59). Thus, the recommended daily dose may be rather too low, especially for people with an increased risk of cardiovascular disease.

This seems especially true of those individuals who have a common gene mutation MTGF-reductase. It is associated with a slightly reduced enzyme activity and a greater need for folate. Genetic variant is common, and the population of Europe, America and Asia has a predominant frequency of the homozygous mutation is 8-15%. Thus, a significant portion of the population, apparently, needs a higher level of folate than previously thought (R. Verhoef et over blood folic acid is below normal, as has long been known to be associated with depression, although it is unclear whether this relationship is causal or not (T. Bottiglieri, Nutrition Reviews, 1996; 54: 382-390: J. E. Alpert and M. Fava, Nutrition Reviews, 1997; 55: 145-9). Most people with depression have reduced appetite and eat enough and, thus, it is possible that depression in some individuals could cause folate deficiency. The possible mechanism by which folate deficiency could cause depression, is based on the effect of folate on the synthesis and secretion of neurotransmitters, particularly serotonin, but also include effects on norepinephrine and dopamine. In animals with deficiency of folate synthesis of serotonin in the brain is reduced (M. Botez et al. Nature 1979; 278: 182-3). In the same paper it is shown that there are limits to the consumption of folate within which the synthesis of serotonin is optimal. As increased amounts of folate and folate deficiency inhibit the formation of serotonin in the brain. Important data are the framework in which the person folic acid is effective but not toxic.

Based on some of the earlier works, the köppen suggested that folic acid supplementation could enhance effects of tricyclic compounds, MAOIS and lithium (A. J. Coppen, UK Patent Arriaval acid may be associated with depression. He also emphasized that one should not give too high a level of folic acid and, on this basis in his patent application he claimed combination of tricyclic compounds, MAOIS or lithium with folic acid, which amount was above 100 micrograms/day but less than 300 micrograms/day. The higher the number, were specifically excluded because of the possibility of adverse effects.

As far as we know, was published only two works, in which folic acid was investigated in a controlled placebo study as an adjunct to antidepressant treatment, as suggested by the köppen. In one of them, Koppen, compared the effects of 200 micrograms/day of folic acid, placebo and additives for lithium for prevention (not treatment) depression. There was a slight decrease on the scale Beck depression for folate, but not for the placebo group, although the difference between groups was not statistically significant (A. J. Coppen et al. Journal of Affective Disorders, 1986; 10: 9-13).

In another study looked at the effect MTHF, administered in very high doses (15000-90000 micrograms/day), with simultaneous introduction of any other antidepressant. In this work, 11 patients with depression, which was also treated with tricyclic soedienie or MAOIS, received placebo. After 3 and 6 months in the group with folic acid, the improvement was more noticeable than in the group with placebo. However, in the group with folic acid concentration of folate in serum and red blood cells was above the upper limit of detection, suggesting that this dose MTHF was excessive and possibly dangerous (P. S. A. Godfrey et al. Lancet, 1990; 336: 392-5).

The study of the literature has identified other works, in which MTHF at high dose levels tested in regard to its action on depression. Senile depression and MTHF (50,000 micrograms/day) and trazodone caused a small (about 15%) reduction in depression according to the measurement results using a rating scale Hamilton depression (HDRS). In an open study on elderly patients the dose 50,000 micrograms/day was associated with significant improvements in the current depression, but in the absence of a placebo is impossible to assess the validity of this effect (G. P. Guaraldi et al. Annals of Clinical Psychiatry, 1993; 5: 101-5). In alcoholics with depression 90000 micrograms/day MTHF also induced a decrease in depression in an open study (S. Di Palma et al., Current Therapeutic Research, 1994; 55: 559-568).

Thus, there is no experimental evidence that folic acid by itself is capable of privalite, tricyclic compounds and MAOIS and does not describe separately SFL or SYMPTOM. It is not specifically recommended the use of folic acid in excess of 300 micrograms/day. There is evidence that too much folic acid can inhibit the absorption of zinc, and in some individuals can cause epilepsy (D. A. Bender, Nutritional Biochemistry of the Vitamins, Cambridge University Press, 1992). In all other studies of treatment used MTHF in doses 15000 micrograms/day or more. Only one of them (P. S. A. Godfrey et al., quoted above) was used as tricyclic compounds, and MAOIS.

In light of recent work on the needs of folate, particularly in people with the usual form of the enzyme MTHFR, it seems that the köppen could be wrong in that he emphasized that consumption of folic acid in a quantity greater than 300 micrograms/day, not indicated as an adjunct to antidepressant therapy. Equally adverse effects of consumption of large quantities of folic acid in animals, as well as the fact that 15,000 micrograms/day MTHF in humans leads to the level of folate in the blood above the detection limits, indicate that very high levels, used in bolshinstve, can the consumption of folate in more than 300 micrograms/day and below 15000 micrograms/day to have beneficial effects in the treatment of depression and particularly in the treatment of depression using SFL. Due to its relative safety and acceptable performance SFL is now the "gold standard" for the treatment of depression in developed countries. There is some evidence that people with depression who do not respond to SFL, can have low levels of folate (M. Fava et al., American Journal of Psychiatry, 1997; 154: 426-8). However, only five of the 213 patients with depression showed a clear folate deficiency and all five of them responded to treatment with fluoxetine related to SFL, which indicates that there is no simple relationship between deficiency of folic acid and depression. The authors state, "our data on the relationship between low folate and as melancholic depression, and impaired response to antidepressant treatment does not mean, however, causality and to some extent limited by the possibility of a compromise in terms of design studies".

Now, the applicants have discovered that unlike paintings, arising on the basis of the prior art and razlichnykh joint introduction of folic acid and antidepressant choose from the SFL and the IPMS. These results include increased efficiency and reduced side effects.

Thus, in accordance with the first feature of the present invention proposes a method of treatment of depression, which includes the introduction of antidepressant selected from SFL classes and SYMPTOM, and is characterized by the addition of folic acid or other precursor of folate in an amount equivalent to from 300 to 5000 micrograms/day of folate, preferably between 300 and 2000 micrograms/day.

Source of folate may be folic acid, MTHF or other convenient, suitable for pharmaceutical administration source of folate.

As SFL or SYMPTOM can be any of the available inhibitors or inhibitors that may become available in the future, and they should be administered in accordance with the normal prescribed level doses. Can also apply a combination of SFL or SYMPTOM or one or more of each of them, although whether they can be particularly increased action, can be argued on the basis of results of clinical trials, if any, will be taken.

As an example, can be applied to any of the following SFL or SYMPTOM. They presticide daily dose and the size of the tablets are presented in milligrams (see table 1).

In accordance with the following characteristic of the invention features the pharmaceutical dosage form of antidepressant containing SFL or SYMPTOM and folic acid or other precursor of folate in such quantity that the introduction from 1 to 8 units, usually from 1 to 4 units of the dosage form, should ensure that the dose SYMPTOM or SFL equivalent assigned to their usual daily dose, and from 300 to 5000 micrograms of folate.

To put it another way, the present invention provides for the treatment of depression, the use of SYMPTOM or SFL, administered simultaneously with folate dose of from 300 to 5000 micrograms per day, and pharmaceuticals in any suitable pharmaceutically acceptable shape to provide such therapy. While the present invention is valuable in General to treat depression, it is particularly valuable in the case of treatment of depression in patients with cardiovascular disease or its risk. It is also particularly valuable in reducing the adverse effects associated with treatment.

Conducted a pilot study that clearly demonstrated the benefits of co-administration of folate and SFL/IPMS in accordance with the present invention. The details of the data, who met DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) for General depressive illness and who also scored at least 20 on the 17-point rating scale Hamilton depression (HDRS). All of them were treated with fluoxetine, the most widely prescribed SFL and all of them were randomized on the basis of double-blind method to receive either 500 micrograms/day of folic acid or identical in appearance to placebo. The point was giving folic acid in quantity, more than twice the recommended daily dose USA and 66% above the upper limit of the range (300 micrograms/day) recommended by the Köppen in 1980, All patients received fluoxetine at a dose of 20 mcg/day. For patients were followed for 10 weeks and assessed by the Hamilton depression rating scale before treatment and after 2, 4, 6 and 10 weeks. Before the study and after 10 weeks took blood samples for measurement of folic acid and homocysteine. The results of the study are shown in table 2.

You can see that the improvement in the estimation of Hamilton occurred in both groups, but after 4 weeks the improvement was always better in the group with folate and that the difference becomes significant at 10 weeks, when the average improvement in the estimated ball is lo, in particular, it was not epileptic seizures. As expected, the level of folic acid in the blood increased significantly, and homocysteine levels fell in the group with folate, whereas in the group with placebo, these levels did not change. After 10 weeks of differences in the changes of concentrations of folic acid and homocysteine between groups were statistically highly significant. Because now I know that elevated homocysteine is a major risk factor for cardiovascular disease, the results indicate that the combination of SFL with folic acid is especially valuable for patients with depression who have cardiovascular disease or its risk.

The results can be seen and on the other hand, comparing the two groups regarding the number of patients who showed after 10 weeks 50% improvement compared with baseline in HDRS, or comparing the number of those whose scores on the HDRS remained above 20, which indicates that they still meet the criteria of HDRS to conduct trials of antidepressants. These values are presented below.

The number of patients showing the percentage change in HDRS compared with baseline levels above and below 60% (table 3).

The number of patients with the patients, receiving folic acid, compared to only 66.7% of patients receiving placebo. After 10 weeks remained seriously repressirovannymi to such an extent that meet the criteria for the introduction of testing, 4.1% of patients treated with folic acid, compared with 19.6% in placebo-treated patients.

These results are both statistically significant and clinically important and show that 500 micrograms/day of folic acid can significantly improve the degree of response to fluoxetine, which is the most widely prescribed SFL. Since all SFL have similar mechanisms of action, responses to treatment all SFL should consider adding folic acid. The main currently known SFL above, but this effect should take place with any connection with the action of the SFL. The IPMS must also respond to folate as it is required for the synthesis of norepinephrine.

The dose of folic acid used in the present work, was 500 micrograms/day. Because the active form of folic acid in the body is MTHF may be interchangeably applied folic acid, MTHF or any predecessor of folic acid. Folic acid relative who are exposed to them, and can affect the absorption of zinc, and higher doses can affect the function of neurotransmitters. Doses of more than 5000 micrograms/day, apparently, do not have more favorable than found in the present work, and can also cause adverse effects.

Another feature identified in the pilot study, was a significant and unexpected decrease in reports of adverse reactions. In the group of 65 patients receiving fluoxetine + placebo recorded 98 adverse effects or 1,51 on one patient. In a group of 62 patients receiving fluoxetine + folic acid marked 53 adverse effect or 0.85 per patient. This difference was very significant at p<0,001. Adverse effects were typical of what was reported for SFL and consisted mostly of fatigue, nausea and dizziness. This is a 44% reduction in adverse effects has a very significant clinical advantage. It was completely unexpected result.

In accordance with the present invention supplements of folate or MTHF used as an aid to drugs with the action of SFL in the treatment of depression at a daily dose of folic € 300 to 2000 micrograms/day. In the treatment of all psychiatric disorders, including depression, the main problem is the observance of a prescribed mode of medical treatment. Patients too sluggish, forgetful or just resist therapy. For this reason, it is important to make the treatment as simple as possible. Therefore, the ideal is the inclusion of folic acid or MTHF in the same pill, capsule or liquid medication that contain SFL. One way of achieving this goal is the inclusion of 300-2000 micrograms of folate in the original full-time doses of medicine. Patients, therefore, should automatically receive the appropriate level of folate. If the medication dose should be increased, the maximum daily dose should generally not exceed more than 4 times the initial daily dose for this class of compounds. Apply the upper bound doses of folate should, therefore, also be in the range taken for safe. It is possible that treatment-resistant patients the level of folate unusually low or there is a variant of the enzyme MTHFR, meaning that they have an increased need for folate. These patients, therefore, should be automatically increased number of incoming focalise and depression, and heart disease associated with elevated levels of homocysteine and lower levels of folate in some patients, this combination of SFL with folate is especially valuable for many patients suffering from depression and cardiovascular diseases such as coronary insufficiency, peripheral artery, angina, myocardial infarction, transient ischemic attacks, stroke or hypertension, or for those who have increased levels of risk factors such as total cholesterol, LDL-cholesterol or triglycerides. Therefore, specific indications for the combination of folic acid/SFL depression is associated with cardiovascular disease or risk of cardiovascular disease of any type.

Below are typical examples of compounds in accordance with the present invention.

Example 1 20 mg fluoxetine prepared in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms, included in the 20 mg tablet or other dosage form.

Example 2 100 mg fluvoxamine made in the form of tablets, capsules or liquid medicine is up to 600 micrograms, included in the 100 mg tablet or other dosage form.

Example 3 20 mg paroxetine made in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms, included in the 20 mg tablet or other dosage form.

Example 4 50 mg of sertraline, are presented in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms included in the 50 mg tablet or other dosage form.

Example 5 to 10 mg of citalopram, is made in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms included in the 10 mg tablet or other dosage form.

Example 6 75 mg venlafaxine made in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms included in the 75 mg tablet or other dosage form.

Example 7 100 mg of nefazodone, the composition is of rogrammes folic acid, preferably from 400 to 600 micrograms, included in the 100 mg tablet or other dosage form.

Example 8 100 mg of trazodone made in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms, included in the 100 mg tablet or other dosage form.

Example 9
4 mg of reboxetine, made in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms included in the 4 mg tablet or other dosage form.

Example 10
The initial daily dose of any other SFL developed in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms included in the dosage form.

Example 11
The initial daily dose of any inhibitor of the reuptake of noradrenaline in the form of tablets, capsules, or liquid dosage forms, such as a solution or emulsion, with from 300 to 1000 micrograms of folic acid, preferably from 400 to 600 micrograms, in the dosage form of antidepressant, containing such a number of selective or partially selective inhibitors of serotonin uptake (SFL) or inhibitors of reuptake of norepinephrine (IPMS) and the amount of folic acid or other precursor of folate that the introduction 1-8 units of the dosage form should ensure that the dose SYMPTOM or SFL equivalent usually prescribed daily dose and 400-5000 mcg of folate.

2. A method for the treatment of depression, which includes the introduction of patient antidepressant selected from the class IFH or SYMPTOM, characterized by the introduction of additional folic acid or other precursor of folate in an amount equivalent to 400-5000 mcg/day of folate.

3. The method according to p. 2, in which the amount of folic acid or precursor of folate equivalent dose of 400-2000 mg/day of folate.

4. The method according to p. 2 or 3, wherein a source of folate is folic acid or MTHF.

5. The method according to any of paragraphs.2-4, in which SFL or SYMPTOM selected from fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine, nefazodone, trazodone, and reboxetine.

Priority items:

24.04.1983 on PP.1-5;

15.07.1998 - on the changes in PP.1-5.

 

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