JPH08283148A - Depressive symptom improver - Google Patents

Abstract

PURPOSE: To improve depressive symptom caused by stress and mental fatigue, etc., e.g., declined mood and lowering of desire in chronic fatigue syndrome. CONSTITUTION: This improver contains carnitines and vitamin B1 s. Inclined mood and lowering of desire in chronic fatigue syndrome are improved by administering the improver. The carnitines include, e.g., carnitine chloride. These vitamin B1 s include a thiol type thiamine derivative or its salt, e.g., a vitamin B1 derivative having disulfide bond such as fursulthiamine hydrochloride or its salt, an S-acyl type thiamine derivative or its salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a depressive symptom ameliorating agent having antidepressant-like action and useful for improving a depressed mood and a decrease in motivation.

[0002]

2. Description of the Related Art In recent years, chronic fatigue syndrome, in which chronic sleep insufficiency due to strong psychological stress is remarkably aside from physical fatigue, is regarded as one of social problems. In this chronic fatigue syndrome, weakness and malaise often cause a decrease in work motivation and a decrease in motivation for daily activities. Furthermore, the chronic fatigue syndrome has become younger, including the treatment of underlying diseases such as drug-induced depression caused by taking antihypertensive agents. From this point of view, the so-called “quality of life (quality of life)
The importance of "life)" is advocated.

Nourishing and tonic drugs are widely used to recover physical fatigue. However, it is difficult to improve psychological fatigue due to stress or the like, and mood stagnation or a decrease in motivation in a depressed state, by the above-mentioned nourishing tonic, instead of physical fatigue. In addition, although the chronic fatigue syndrome is originally a normal person, due to psychological stress and the like, a depression-like action, that is, a depressed mood (depression), decreased motivation, lack of concentration, etc. Is recognized. Therefore, the chronic fatigue syndrome is different from depression.

On the other hand, carnitine was discovered in the muscle extract of mammals at the beginning of this century, and it was later found that it exists widely in nature including microorganisms, and it is considered to play an important role in the living body. ing. Carnitine is used for chronic gastritis etc. as a digestive function improving drug such as appetite enhancement, gastrointestinal motility enhancement, and pancreatic secretion enhancement due to its pharmacological action, and it is considered to have a weak blood pressure lowering action and diuretic action in part. ing. Carnitine having such a pharmacological activity is widely used as a gastrointestinal drug and a nourishing tonic ingredient. Vitamin B ₁ is also widely used for treating beriberi, disorientation, and visual hallucinations. However, there is no report that carnitine and vitamin B ₁ are effective in improving depression-like symptoms.

[0005]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a depressive symptom ameliorating agent capable of ameliorating depression-like symptoms caused by stress, mental fatigue and the like. Another object of the present invention is to provide a depressive symptom ameliorating agent which can effectively improve the stagnation of mood and decrease of motivation in chronic fatigue syndrome.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that when carnitines and vitamin B ₁ are combined, carnitines alone or vitamin B ₁ alone are not expressed. The present invention has been completed by finding that the action, that is, the antidepressant-like action is effectively expressed. That is, the depressive symptom improving agent of the present invention contains carnitines and vitamin B ₁ . The carnitines include carnitine salts such as lunitine chloride.
In addition, vitamin B ₁ includes thiol-type thiamine derivatives or salts thereof, for example, vitamin B ₁ derivatives having a disulfide bond and salts thereof (fursultiamine hydrochloride, etc.),
S-acyl thiamine derivatives and salts thereof are included.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below. Carnitines include carnitine (eg, dl-carnitine, d-carnitine, 1-carnitine), carnitine salt (eg, carnitine chloride, carnitine sulfate, carnitine nitrate, etc.) and analogs thereof (eg, dicarnitine, acylcarnitine). , Propionylcarnitine, etc.) and the like. Preferred carnitines include:
Carnitine chloride, eg dl-carnitine chloride or l
-Includes carnitine chloride.

Examples of vitamin B ₁ include thiamine or a salt thereof (for example, thiamine hydrochloride, thiamine nitrate, etc.), thiol-type thiamine or a salt thereof (sodium salt,
Alkali metal salts such as potassium salts), thiamine derivatives or salts thereof (for example, thiol-type thiamine derivatives or salts thereof, O-acyl derivatives or salts thereof), and thiamine analogs. Vitamin B ₁ may be symmetrical or asymmetrical.

The thiol-type thiamine derivative or a salt thereof includes active vitamin B ₁ derivatives such as vitamin B ₁ derivatives having a disulfide bond [eg thiamine disulfide (TDS), prosultiamine (TPD),
Fursultiamine (TTFD), Octothiamine (TA
TD), bisbentamine (BTDS)], S-acyl thiamine derivative [for example, S-benzoylthiamine (bisibutyamine, DBT), S-benzoylthiamine phosphate (benfotiamine, BTMP), S-dicarbetate] Xithiamine hydrochloride (disetiamine, DC
ET), cocotiamine (CCT)] or salts thereof (for example, salts with acids such as hydrochlorides, sulfates and nitrates).

The O-acyl derivative or its salt includes, for example, a phosphoric acid ester such as thiamine diphosphate (TDP) and an organic acid ester such as thiamine acetate.

[0010] Preferred vitamin B ₁ class, vitamin B ₁ derivatives and S- acyl-type thiamine derivative having a disulfide bond is activated vitamin B ₁ derivatives. Particularly, in the vitamin B ₁ derivative having a disulfide bond, an alkyl group (for example, a C _1-10 alkyl group, particularly a C _1-8 alkyl group) has a substituent (for example, 2-
A 5- or 6-membered heterocyclic group such as tetrahydrofuranyl, a C _1-4 alkoxycarbonyl group such as methoxycarbonyl, a C _1-4 alkoxythiocarbonyl group such as methoxythiocarbonyl, etc.) Preferred are, for example, fursultiamine and fursultiamine hydrochloride.

A feature of the present invention is that the carnitines and the vitamin B ₁ are combined. That is,
Although carnitines alone and vitamin B ₁ alone have no significant antidepressant-like effects, when both active ingredients are used in combination, a considerably strong antidepressant-like effect is statistically significant. From this, it is considered that the antidepressant-like action by the combination of the above active ingredients is not due to the presence or absence of physical fatigue, but to an increase in mood and an increase in motivation.

The ratio of carnitines to vitamin B ₁ can be selected within a wide range in which antidepressant-like action is exhibited. The proportion of vitamin B ₁ is, for example, 1 to 500 parts by weight, preferably 5 to 30 parts by weight with respect to 100 parts by weight of carnitines.
0 parts by weight, more preferably about 10 to 250 parts by weight (for example, 20 to 250 parts by weight), and often about 25 to 250 parts by weight. When a salt of carnitine (for example, carnitine chloride) is combined with a vitamin B ₁ derivative having a disulfide bond or a salt thereof (for example, fursultiamine hydrochloride), the amount of the vitamin B ₁ derivative or its salt is carnitine. 5 to 300 parts by weight (for example, 20 to 200 parts by weight), preferably 25 to 150 parts by weight (for example, 30 to
It is often about 100 parts by weight).

The improving agent of the present invention is, in addition to carnitine and vitamin B ₁ , other active ingredients, for example, vitamins other than vitamin B ₁ and a nutritional tonic for enhancing the anti-fatigue action against physical fatigue. May be included.
Examples of vitamins other than vitamin B ₁ include vitamin B group such as vitamins B ₂ , B ₆ , and B ₁₂ , vitamin C, nicotinic acid and nicotinic acid amide, pantothenic acid, panthenol or salts thereof, biotin. , Water-soluble vitamins such as folic acid; vitamins A, vitamins D, vitamin E
Includes fat-soluble vitamins such as foods. These vitamins can be used alone or in combination of two or more. Of these vitamins, water-soluble vitamins are often added to solutions.

The nutritional tonic agent includes various components having a nutritional tonic activity, for example, pantethine, glucuronic acid, glucuronolactone, inositol, inositol hexanicotinate, ursodesoxycholic acid, orotic acid, gamma-oryzanol, chondroitin. Sulfuric acid, taurine,
Various amino acids (for example, aspartic acid or a salt thereof (potassium salt, magnesium salt, etc.), L-cystine or a salt thereof, lysine or a salt thereof (lysine hydrochloride, etc.), methionine, arginine or a salt thereof (arginine hydrochloride, etc.),
Includes crude drugs.

Examples of the crude drug containing the tonic component, for example, Chenopodium, angelica root, Epimedium, black nightshade, insect wax, nettle, In'youkaku, Acanthopanax, Siberian ginseng, Radix Astragali, royalism, Gastrodia elata, Euryale, Onji, Kaikujin, Asclepiadaceae, ground ivy, Kazarishida , Cucumber, kokushi, tenmondou, mulberry, ketsumei, kozo, gokahi, goshitu, fenugreek, sansonin, jiou, white jellyfish, seizoushi (nogatetou), ginkgo, burdock, taisan, taiso, kawarabi, chinensis, ginseng, senburi, senburi , Tsudukudami, Fuyu (denjisou),
Touki, Toujin, Touhou Kasou, Toshishi, Eucommia, Aconitum, Prickly wormwood, Piscus medusa, Carrot (Ginseng), Rattus cypristis, Prunus vulgaris, Yarrow, Bakumondou, Hamagou, Hamabishi, Bankouka (Saffron), Hiranpi, Hanpi, Hanpi, Hanpi, Hanpi
Fukubonshi, houkigi, okotsushi, hondawara, borei, makonbu, muirapuama, mistletoe (sousei), yokuinin, mugwort, ramashi, reishi, rangetsu (lotus), roquejo, royal jelly and the like. These crude drug components can be used alone or in combination of two or more. The crude drug component may be any of dry powder, dry extract, extract powder, flow extract, tincture, etc., depending on the form of the preparation.

In addition to the above components, various components,
For example, caffeine such as anhydrous caffeine, minerals (such as calcium and magnesium), and other galenical ingredients such as licorice, cinnamon, sycamore, psycho,
You may add ginger, bukuro, etc.

The form of the antidepressant symptom improving agent of the present invention is not particularly limited, and examples thereof include tablets, granules, fine granules, pills, powders, capsules, troches, and lozenges that can be licked and dissolved in the mouth. Oral solid preparations such as chewable preparations and oral liquid preparations such as elixir preparations and syrup preparations may be used. Further, the preparation, particularly the liquid preparation, may be a parenteral preparation, for example, a transdermal preparation such as an ointment or a poultice, an intravenous preparation such as an emulsion or an injection. Further, it may be a drink such as a drink.

For the preparation of the preparation, a conventional carrier component depending on the kind of the preparation, for example, in a solid preparation, an excipient, a binder, a disintegrating agent, a filler, a filler, a moisturizing agent, a surfactant,
Lubricants and the like can be used, and in the liquid preparation, solvents, solubilizing agents, suspending agents, isotonic agents, buffering agents, soothing agents and the like can be used. If necessary, preservatives, solubilizers, emulsifiers, dispersants, thickeners, plasticizers, adsorbents, fragrances, coloring agents, flavoring agents, sweeteners, preservatives, antioxidants, etc. are used. it can.

Examples of the excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gum arabic and the like. As the lubricant, for example,
Magnesium stearate, calcium stearate,
Examples thereof include talc and colloidal silica. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil,
Examples thereof include corn oil, and examples of the solubilizing agent include:
For example, ethanol, polyethylene glycol, propylene glycol, D-mannitol, cholesterol,
Examples include triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example,
Surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lecithin, glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. It can be illustrated. Examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like, and examples of the buffering agent include phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Preferable examples of soothing agents include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid and the like.

The improving agent of the present invention, depending on the form of the preparation,
For example, a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc. can be adopted. Regarding the production of the drug product, each section of the Japanese Pharmacopoeia General Regulations can be referred to.

The preparation of the present invention containing a combination of carnitines and vitamin B ₁ has a depressive symptom, for example,
It is useful for improving the depressed mood, motivation, and decreased motivation due to stress and psychological fatigue.

The doses of carnitines and vitamin B ₁ in the preparation of the present invention can be selected according to sex, age, degree of symptoms and the like. The dose of carnitines is, for example, 10 to 600 mg, preferably 50 per day for an adult.
~ 500 mg, more preferably about 100-300 mg. The dose of vitamin B ₁ is, for example, 1 adult
1 to 300 mg per day, preferably 5 to 200 m
g, more preferably 10 to 150 mg (eg, 30
~ 90 mg).

[0024] The carnitines and vitamin B ₁ may be administered as the present preparation in the above daily dose at a time,
It may be administered in multiple doses. When administered in a plurality of divided doses, the dose per administration is, for example, about 10 to 100 mg of carnitines (eg, 30 to 100 mg, preferably 50 to 100 mg), vitamins B _{1 to 1 to} 10.
00 mg (for example, 5 to 100 mg, preferably 10 to
It is often about 50 mg).

[0025]

The anti-depressive symptom improving agent of the present invention contains carnitines and vitamin B ₁ and is therefore useful for ameliorating the depression-like symptoms caused by stress, mental fatigue and the like. In particular, it has a mood enhancing effect, and can effectively improve the stagnation mood and the decrease in motivation in chronic fatigue syndrome.

[0026]

The present invention will be described in more detail based on the following examples and comparative examples, but the present invention is not limited to these examples. Examples, Comparative Examples 1 to 5 Male rats of 5 weeks of age (Sprague-Dawley rat (CLEA Japan, weight 130 to 170 g)) were mixed with a predetermined amount of d1-carnitine chloride (hereinafter simply referred to as carnitine) and a predetermined amount. Fursultiamine hydrochloride (hereinafter simply referred to as TTFD)
Was administered orally. In addition, carnitine and / or TT
FD was dissolved in distilled water or physiological saline and administered. The dose of each drug is as follows. Comparative Example 1: Carnitine 30 mg / kg Comparative Example 2: Carnitine 100 mg / kg Comparative Example 3: Carnitine 300 mg / kg Comparative Example 4: TTFD 10 mg / kg Comparative Example 5: TTFD 30 mg / kg Example: Carnitine 100 mg / kg and TTFD30
mg / kg The antidepressant action was examined by the following forced swimming method (Despair Test), rotating rod method and suspension method.

Forced swimming (day spare test, Desp
air Test) Porsolt's method (Porsolt, RD, et al;
Evaluation was performed according to Nature, 166 , 730-732, 1977). That is, a cylindrical glass beaker (height 4
(0 cm, diameter 19.5 cm), water of 25 ± 1 ° C. was added to a depth of 19.5 cm. The drug was orally administered, and after 1 hour, one rat was placed in each of the cylindrical glass beakers, and the immobility time (second) was measured at 5-minute intervals until 15 minutes later.

The effect of the drug was determined by comparing the immobility time (second) at each 5 minutes in the control untreated group (control) and the drug administration group. In addition, 1
The number of rats in the group was 7 to 8. The results are shown in Table 1 and FIG.
~ Shown in FIG.

[0029]

[Table 1] As is apparent from Table 1 and FIGS. 1 to 3, carnitine 1
In the 00 mg / kg alone group (Comparative Example 2), the immobility time tended to be shorter than that in the control untreated group, but carnitine 30
In the 0 mg / kg alone group (Comparative Example 3), the immobility time was hardly shortened, and neither was significant. For TTFD, 10 mg / kg administration group (Comparative Example 4) and 30 mg / kg
The immobility time was not significantly shortened in any of the kg alone groups (Comparative Example 5). On the other hand, in the example in which both drugs were used in combination, a remarkable shortening of the immobility time was significantly observed, and the immobility time was significantly shortened even in the TTFD 30 mg / kg administration group.

Rotating Rod Method Dunhan and Miya Method (Dunh
an, NW & Miya, TS; J, Am. Pharm. Ass. 46 , 208〜20
9, 1957) (Morimoto Shigeru, Kito Tsuyoshi; N. Pharmacol.,
104 , 39-49, 1994). That is, the rats were randomly placed on a wooden rod having a diameter of 1.2 cm rotating 6 times per minute 5 to 6 times per animal. After that, the time (seconds) until the rat falls from the rotating rod is measured, and 2-3
Rats whose reaction time was almost constant were selected and orally administered with the drug. 30 minutes, 1 hour, and 2 hours after drug administration, the time (seconds) until the rat fell from the rotating rod was measured. And the fall time before drug administration in rats is 100%
The effect of the drug was examined from the change rate between the control untreated group (control) and the drug administration group at each time. The maximum extension time was 180 seconds. In addition, 6 rats per group
Animals. The results are shown in Table 2 and FIGS.

[0031]

[Table 2] As is clear from Table 2 and FIGS. 4 to 6, TTFD 10 mg / kg compared to the control untreated group (control).
(Comparative Example 4) and 30 mg / kg alone group (Comparative Example 5)
In the carnitine alone group was dose-dependent, and in the 100 mg / kg administration group (Comparative Example 2) 3
Compared with the 0 mg / kg administration group (Comparative Example 1), the time of staying on the rod was slightly longer 30 minutes after administration, but no significant difference was observed thereafter. On the other hand, the formulation of the example in which both drugs were used in combination significantly prolonged the staying time on the rod even 1 hour after administration, as compared with the control untreated group.

Suspension method The method of Courvoisier et al. (Courvoisie)
r, S.et al, In "Psychotropic drugs" Ed. by Garattini,
S. and Ghetti, V., P373, Elsevier, Amsterdam. 1957)
It was evaluated according to. That is, a diameter of 2 mm stretched horizontally
The forelimb of the rat was grasped and suspended by the wire of 1., and the time (sec) until it dropped was measured. The drug was administered orally. 30 minutes before drug administration, 1 hour and 2 hours later, the time from when each rat gripped and suspended on the wire to the drop was measured. The drop time before drug administration of the rat was taken as 100%, and no control was performed at each time. The effect of the drug was investigated from the rate of change between the treatment group and the drug administration group. The number of animals in one group was 6. The results are shown in Table 3.

[0033]

[Table 3] As is clear from Table 3, carnitine 100 mg / kg
No prolongation of the gripping time was observed in any of the single group, the TTFD 30 mg / kg single group, and the both drug combination group.

As described above, the carnitine alone administration group and the TTFD alone administration group were not so effective as the control group. However, by administering carnitine in combination with TTFD, the forced swimming test and the rotating rod were performed. A significant effect was observed in the test. In the rotating rod method,
It is known that even when a drug showing only an anti-fatigue action is used, the time staying on the rotating rod does not show an increasing tendency. Also, in the suspension test, the motility enhancing action due to mere muscle fatigue greatly affects the extension of the grip time. From this, the formulation in which carnitine and TTFD are combined has an antidepressant-like action for improving a mentally depressed state caused by stress and anxiety, unlike an anti-fatigue action, and with mood elevation, It is useful in improving motivation in daily activities.

Formulation Example 1 (Prescription) Adult daily dose (in 2 tablets) [Uncoated tablet] dl-carnitine chloride 100 mg Flusultiamine hydrochloride 30 mg Lactose 141 mg Starch 58 mg Hydroxypropyl cellulose 10 mg Magnesium stearate 1 mg Total 340 mg [Film coating] Tablet] Uncoated tablet 340 mg Hydroxypropylmethylcellulose 11.6 mg Macrogol 2 mg Titanium oxide 2.4 mg Total 356 mg Taking the above ingredients and amounts, a film-coated tablet is produced according to the General Rules for Pharmaceutical Formulation of Japan, Tablets.

Formulation Example 2 (Prescription) Adult daily dose (in 3 capsules) [T granules] dl-carnitine chloride 100 mg Flusultiamine hydrochloride 100 mg Vitamin B ₁₂ (hydroxocobalamin acetate) 1.5 mg Crystalline cellulose 96 mg Starch 48 mg Hydroxy Propyl cellulose 15 mg Lactose 112.5 mg Subtotal 483 mg [E grain] Vitamin B ₆ (pyridoxine hydrochloride) 100 mg Vitamin E (dl-α-tocopherol succinate) 100 mg Gamma-oryzanol 9.9 mg Crystalline cellulose 96 mg Starch 60 mg Hydroxypropyl cellulose 21 mg Lactose 96. 1 mg Subtotal 483 mg [Mixed powder] T granules 483 mg E granules 483 mg Talc 9 mg Total 975 mg To stabilize the mixability, the above components and amounts are taken, and T
Granules are divided into two groups, ie, granules and E granules, and the granules are manufactured according to a conventional method, and a mixed powder is prepared and filled into hard capsules according to the Japanese Pharmacopoeia General Rules, Capsule, to manufacture capsules.

Formulation Example 3 (prescription) Adult daily dose dl-carnitine chloride 100 mg Flusultiamine hydrochloride 30 mg Royal jelly 150 mg Carrot flow extract 1 ml Eucommia flow extract 1 ml Rokujo tincture 1.1 ml L-aspartate 125 mg Sucrose 10 g citric acid 150 mg Sodium benzoate 40 mg Methyl paraoxybenzoate 2 mg Purified water (additional total amount) 50 ml The above ingredients and their amounts are taken to prepare an oral liquid preparation according to the Japanese Pharmacopoeia General Rules for Preparations, Liquid Solution. If desired, filter and sterilize and fill colored glass bottles.

Formulation Example 4 (Formulation) Adult daily dose (in 3 tablets) [Uncoated tablet] dl-carnitine chloride 100 mg Flusultiamine hydrochloride 100 mg Precipitated calcium carbonate 81.5 mg Anhydrous calcium hydrogen phosphate 85 mg Magnesium carbonate 120.2 mg Vitamin D ₂ (Ergocalciferol) 200 international units Vitamin B ₂ (riboflavin) 10 mg Vitamin B ₆ (pyridoxine hydrochloride) 10 mg Vitamin B ₁₂ (cyanocobalamin) 20 μg Lactose 135.3 mg Crystalline cellulose 84 mg Starch 84 mg Hydroxypropyl cellulose 27 mg Magnesium stearate 3 mg Subtotal 840 mg [sugar-coated tablet] Uncoated tablet 840 mg Talc 309 mg Gum arabic 21 mg Titanium oxide 13.5 mg White sugar 301.5 mg Total 1500 mg The above composition Take the amount and the amount, and manufacture plain tablets and sugar-coated tablets according to the General Rules for Japanese Pharmacopoeia Preparation, Granules. Colorants, fragrances, corrigents, and the like can be added if necessary.

[Brief description of drawings]

FIG. 1 is a view showing the results of a carnitine single administration group in a forced swimming method.

FIG. 2 is a diagram showing the results of the TTFD single administration group in the forced swimming method.

FIG. 3 is a diagram showing a result of a forced swimming method.

FIG. 4 is a diagram showing the results of a carnitine single administration group in a rotating rod method.

FIG. 5 is a view showing the results of the TTFD single administration group in the rotating rod method.

FIG. 6 is a diagram showing a result in the rotating rod method.

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Claims (6)

[Claims] 1. A depression symptoms improving agent comprising carnitines and vitamin B ₁ class. 2. The depressive symptom ameliorating agent according to claim 1, wherein the carnitine is carnitine chloride. 3. The agent for improving depressive symptoms according to claim ₁ , wherein the vitamin B ₁ is a thiol-type thiamine derivative or a salt thereof. 4. depressive symptoms improving agent according to claim 1, wherein vitamin B ₁ class is vitamin B ₁ derivative or a salt thereof having a disulfide bond. 5. The depressive symptom improving agent according to claim ₁ , wherein the vitamin B ₁ is an S-acyl type thiamine derivative or a salt thereof. 6. The depressive symptom improving agent according to claim ₁ , wherein the vitamin B ₁ is fursultiamine hydrochloride.