Patent Description:
Major depressive disorder, MDD, (also known as clinical depression, major depression, endogenous depression, unipolar depression, unipolar disorder or recurrent depression, in the case of repeated episodes) is a psychiatric illness or mood disorder, characterised by depressed mood episodes, accompanied mainly by a low self-esteem and a loss of interest or pleasure in normally enjoyable activities (anhedonia). This group of symptoms (syndrome) has been identified, described and classified as one of the mood disorders in the <NPL>.

In the scientific field, it is believed that there is an involvement of inflammation in the pathogenesis of the major depressive disorder (DDM), in which inflammation plays a central role. Another orientation, instead, disputes the centrality of inflammation in the onset of DDM.

Notwithstanding the foregoing orientations, scientific research on the outcomes of the antidepressant treatments proposed to date has revealed that:.

The major depressive disorder is a chronic disturbance characterised by a high risk of relapse and a reduced percentage of remission. The response to conventional antidepressant drug treatments acting on monoaminergic systems is incomplete and often unsatisfactory due to the important side effects that sometimes lead to the need to suspend them, which is why the treatment of the major depressive disorder requires shifting attentional focus, on the one hand, to the identification of new mechanisms involved in the pathophysiology of the disorder and, on the other, to the introduction of new therapeutic strategies with antidepressant efficacy. In addition, the adoption of a new approach to the pathophysiology of DDM is indispensable, also in relation to the neuro-progression, which has been identified as a key feature of the disorder and which therefore requires attention addressing the various factors that may be involved in the neurodegeneration and reduction of the neuroplasticity which accompanies it.

The term mood disorder refers to the wide range of psycho-psychiatric disturbances and symptoms which consist in alterations or anomalies of the state of the individual's mood, which are such as to cause the person persistent or repeated problems or dysfunctions or marked discomfort, as well as malajustment to the environmental conditions of life with varying degrees of repercussions on inter-relational and/or work life. Mood disorders are known to compromise the good quality of life and may have consequences that also reflect on the state of health and mental health of an individual.

<CIT> discloses a method to treat major depressive disorder comprising administering magnesium orotate, one or more probiotic microorganisms (such as S. thermophilus, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium longum), coenzym Q10 and vitamins (B, C, D, E).

Therefore, the interest remains high from the operators in the sector for an effective solution for treating the patients suffering from a major depressive disorder or mood disturbances that presents itself as a valid and alternative solution to the existing drug treatments, in particular, with specific reference to the absence of side effects. Specifically, the need is felt to have products, compositions or formulations available which may reduce and relieve the symptoms deriving from or connected with the major depressive disorder, or mood disturbances, so as to allow an improvement in the quality of life, the physical and mental state of the patients, a reduction in the risk of relapse, and an increase in the rate of remission from the pathological state. The purpose of this invention is to provide an adequate response to the technical problem described above.

After an intensive and prolonged period of research and development activity, the Applicant has developed a composition to be administered to patients suffering from the major depressive disorder or from mood disturbances, which is able to overcome the limitations and drawbacks present in the prior art and to provide an effective response to the technical problem described above.

An object of this invention is formed by the pharmaceutical composition or composition for a medical device or a composition for food supplements, comprising a mixture and, optionally, technological additives and/or pharmaceutical or food grade excipients, for the use in the treatment of major depressive disorder, having the characteristics as reported in the independent claim hereto.

An object of this invention is formed by a pharmaceutical composition or composition for a medical device or a composition for food supplements, comprising a mixture and, optionally, technological additives and/or pharmaceutical or food grade excipients, for use in the treatment and/or improvement of mood disorders, said composition having the characteristics as reported in the independent claim hereto.

Preferred embodiments of this invention are reported in the dependent claims hereto.

The preferred embodiments of this invention are described in the following manifestation.

The Applicant has found it useful to study and examine in depth the therapeutic potential of intestinal microbiota in the treatment of major depressive disorder (endogenous).

The interaction between the immune system and the brain within the ambit of major depressive disorder focused attention primarily on the study of the role played by the innate immune response rather than the acquired one in the pathophysiology of depression. As a consequence, the potential alteration of T cells as a factor contributing to the development of major depressive disorder plays an important role. T-cell dysregulation, depending on their neuroprotective and anti-inflammatory properties, is capable of affecting the brain and behaviour, contributing to the onset and continuation of depressive symptoms.

Compared to healthy individuals, depressed patients have increased levels of proinflammatory cytokines such as IL-<NUM> beta and sIL-<NUM> RA, sIL2R, IL-<NUM> (and CPR), and TNF-alpha. In addition, there are findings which support the hypothesis that a T cell dysregulation, determined by a reduced Treg activity and increased Th17 activity, may contribute to the increase in the inflammatory state observed in said depressed patients. In depressed patients, there is an imbalance in the proportion of Th17 compared to Tregs, due to an increase in Th17 and a reduction in the Tregs. Intestinal permeability syndrome and bacterial translocation allow the release in circulation of LPS lipopolysaccharides of gram-negative bacteria which, due to their endo-toxic potential, cause the activation of the inflammatory response, not only at the peripheral level but also at the central level, influencing brain activity and behavioural response. The release in circulation of LPS stimulates the production of various proinflammatory cytokines including IL-1B, which in turn is a potent inducer of the expression of IL-<NUM> by the T cells. Due to increased permeability of the blood-brain barrier, the Th17 cells may then deposit the IL-<NUM> at CNS level, causing a progressive state of neuroinflammation and neurodegeneration, which are the constituent phenomena of clinical depression. Consequently, a therapeutic intervention is opportune, aimed at the treatment of depression, which not only results in the re-equilibrium of Th1-Th2 but also in the regulation of Th17, precisely because of their high pathogenic potential.

The Applicant has therefore come to develop a composition comprising a mixture which comprises or, alternatively, consists of:.

Said (a) comprises or, alternatively, consists of: (a-ii) a bacterial strain belonging to the species Lactobacillus fermentum, such as the bacterial strain Lactobacillus fermentum LF16 DSM <NUM>; and (a-iii) a bacterial strain belonging to the species Lactobacillus plantarum such as the bacterial strain Lactobacillus plantarum LP02 LMG P-<NUM>; and/or (a-iii-bis) a bacterial strain belonging to the species Lactobacillus plantarum, such as the bacterial strain Lactobacillus plantarum LP01 LMG P-<NUM>; and (a-iv) a bacterial strain belonging to the species Lactobacillus rhamnosus, such as the bacterial strain Lactobacillus rhamnosus LR06 DSM21981; and (a-v) a bacterial strain belonging to the species Bifidobacterium longum such as the bacterial strain Bifidobacterium longum BL04 DSM <NUM>.

Said second group of vitamins comprises or, alternatively, consists of: (b-i) group C vitamins; (b-ii) group E vitamins; (b-iii) group B vitamins; and (b-iv) group D vitamins.

In an embodiment, the mixture for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention provides that said (b-iii) group B vitamin is preferably vitamin B9, while said (b-iv) group D vitamin is preferably vitamin D3.

The composition for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention comprises a mixture which comprises or, alternatively, consists of:.

Said third group of organic and/or inorganic salts comprises or, alternatively, consists of: (c-i) organic and/or inorganic magnesium salts; (c-ii) organic and/or inorganic selenium salts; or (c-iii) organic and/or inorganic zinc salts.

In an embodiment, the mixture for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention provides that said (c-i) magnesium salt is preferably magnesium glycinate; said selenium salt (c-ii) is preferably selenium methionine and said zinc salt (c-iii) is preferably zinc gluconate.

Said fourth group of antioxidant substances comprises or, alternatively, consists of (d- i) N-acetyl cysteine (NAC), (d-ii) Co-enzyme Q10 (CoQ10) and (d-iii) acetyl-L-carnitine ALC.

CoQ10 exerts an antidepressant effect by reducing oxidative stress and promoting proper mitochondrial functioning also at neuron levels, with consequent impact on the regulation of serotonin.

Since fatigue and pain are two key aspects of depression that often remain as residual symptoms contributing to relapse and recurrence of the disorder, acetyl-L-carnitine ALC may thus be an effective solution to reduce the severity of said typically depressive symptomatic presentation.

In an embodiment, the mixture for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention provides the use of a combination consisting of (d-i) N-acetylcysteine (NAC), (d-ii) coenzyme Q10 (CoQ10) and (d-iii) acetyl-L-carnitine.

The composition for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention comprises, in addition to said mixture, also optionally, technological additives and/or pharmaceutical or food grade excipients.

All the strains described in this patent application have been filed, in accordance with the Treaty of Budapest as follows:.

Said mixture, contained in the composition for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention, provides that:.

The above-mentioned bacterial strains are present in the mixture for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention in an amount comprised from <NUM> % to <NUM>% by weight, preferably from <NUM>% to <NUM>% by weight and still more preferably from <NUM>% to <NUM>%, compared to the total weight of the mixture. However, said percentage depends on the desired embodiment for the type of pharmaceutical form. For example, in the case of capsules, the amount of said bacteria is greater than <NUM>%, for example greater than <NUM>%.

In an embodiment, the composition comprises bacterial strains in a concentration comprised from 1x10<NUM> to 1x10<NUM> CFU/dose, preferably from 1x10<NUM> CFU/dose to 1x10<NUM> CFU/dose. The dose may be comprised from <NUM> to <NUM>, for example, it may be <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. Bacterial strains may be present in the composition in solid form, for example, in powder form, dehydrated powder or lyophilised powder.

A preferred mixture embodiment for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention may be as follows:.

Another object of this invention is formed by a pharmaceutical composition or a composition for a medical device or a composition for food supplements (in brief, composition C) for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder, comprising a mixture that comprises or, alternatively, consists of a mixture of bacterial probiotics as described in claim <NUM> (in brief, composition M), said composition being also, optionally, comprising technological additives and/or pharmaceutical or food grade excipients; having the characteristics as reported in the independent claim hereto.

Said composition C being for use in the treatment and/or improvement of mood disorders (both in healthy individuals and pathological individuals (patients) who have been diagnosed with a disorder).

The mixture M (contained in said composition C, optionally, together with technological additives and/or pharmaceutical or food grade excipients) comprises or, alternatively, consists of:.

The above-mentioned bacterial strains are present in the mixture M for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention, in an amount comprised from <NUM> % to <NUM>% by weight, preferably from <NUM>% to <NUM>% by weight and still more preferably from <NUM>% to <NUM>%, compared to the total weight of the mixture. However, said percentage depends on the desired embodiment for the type of pharmaceutical form. For example, in the case of capsules, the amount of said bacteria is greater than <NUM>%, for example greater than <NUM>%.

In an embodiment, the composition C comprises bacterial strains in a concentration comprised from 1x10<NUM> to 1x10<NUM> CFU/dose, preferably from 1x10<NUM> CFU/dose to 1x10<NUM> CFU/dose. The dose may be comprised from <NUM> to <NUM>, for example, it may be <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. The bacterial strains may be present in the composition in solid form, for example, in powder form, dehydrated powder or lyophilised powder. Advantageously, the composition for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of the present invention provides an effective treatment for both healthy individuals and pathological individuals (patients) affected by the mood disorder (general emotional state, anxiety state and propensity to optimism), thanks to the use of a composition C, comprising a mixture that comprises or, alternately, consists of:.

An embodiment of this invention consists of a composition C for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder, which consists in a mixture of bacterial strains (a-ii), (a-iii-bis), (a-iv) and (a-v); all in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM> and having a concentration equal to 1x10<NUM> CFU/g. For example, said composition (daily dose) is <NUM>, where each of the <NUM> strains is <NUM> (4x0. <NUM> = <NUM> of mixture M) and <NUM> is represented by maltodextrin.

Advantageously the taking of the composition C for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention shows significant changes after the taking thereof, in particular, concerning mood, which is more positive and inclined to optimism. In addition, there are also, advantageously, significant decreases in the state of anxiety and a significant improvement in the general emotional state of individuals (decrease of dejection/depression, decrease in aggression/anger, decrease in fatigue/apathy and reduction in the stress-caused confusional state) treated with the composition for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder of this invention.

The Applicant conducted a study in vivo during which it undertook a psychological evaluation.

The following composition C was tested (daily amount) equal to <NUM> and comprising a mixture M as described:.

The sample under examination is composed of two groups of healthy male individuals aged between <NUM> and <NUM> years:.

Tension-Anxiety, Depression-Dejection, Aggressiveness-Anger, Energy-Activity, Fatigue-Apathy and Confusion-Bewilderment.

During the six weeks of treatment, the trial group took daily doses of the Composition C (<NUM> grams/sachet), comprising a mixture of probiotic strains M, with a concentration of 4x10<NUM> CFU/sachet-dose per day. The composition C comprises a mixture M of the following lyophilised probiotic strains:.

The mixture of probiotic strains has been supplemented with maltodextrin, as bulking agent to provide the composition. Maltodextrin is the only component (<NUM>) of the placebo doses administered to the control group. Three weeks of follow-up ensue.

Claim 1:
A mixture of bacterial strains for use in the treatment and/or improvement of a major depressive disorder or of a mood disorder comprising or, alternatively, consisting of:
- a bacterial strain belonging to the species Lactobacillus fermentum, such as the bacterial strain Lactobacillus fermentum LF16 DSM <NUM>; and
- a bacterial strain belonging to the species Lactobacillus plantarum, such as the bacterial strain Lactobacillus plantarum LP01 LMG P-<NUM>; and/or a bacterial strain belonging to the species Lactobacillus plantarum, such as the bacterial strain Lactobacillus plantarum LP02 LMG P-<NUM>; and
- a bacterial strain belonging to the species Lactobacillus rhamnosus, such as the bacterial strain Lactobacillus rhamnosus LR06 DSM <NUM>; and
- a bacterial strain belonging to the species Bifidobacterium longum, such as the bacterial strain Bifidobacterium longum BL04 DSM <NUM>.