Depression has been a major social problem. A survey in the United States of America estimates that the lifetime prevalence rate of depressive disorders is 26% for women and 12% for men (Non-patent Document 1). An extensive survey was also carried out in Japan, and it was reported that the lifetime prevalence rate was 14%. It was also reported that 84% of the patients with depression have complication, 61% of the patients have other mental diseases, 30% of the patients have personality disorders, and 58% of the patients have complication of physical diseases (Non-patent Document 2).
Common symptoms of depression include a wide variety of symptoms, such as depressive mood, lethargy, depressive attitudes, suicidal ideation, impatience, insomnia, anorexia, decreased sexual impulse, and physical ailments. Pathologically-severe depression is called major depression. With regard to major depression, there is reported experimental data showing that in many cases, a rapid recovery is observed during the first 40 weeks, but the recovery plateaus thereafter. It is reported that results of a 20-year follow-up survey on patients having major depression show that 15 to 19% of the patients had chronic residual symptoms such as working difficulty (Non-patent Document 3).
With regard to causes of depression, various theories are suggested. A hypothesis that was suggested in the early days and is still popular is a theory stating that a decrease in the function of monoamines in the brain is responsible for depression (this hypothesis is called “intracerebral monoamine hypothesis”). This theory is suggested on the basis of the fact that a tricyclic antidepressive agent having an action to enhance the function of monoamines in the brain by blocking the reuptake of monoamines in cells is effective for remission of depression.
Currently, especially the function of serotonin, which is an intracerebral monoamine, attracts great attention, and there is a popular hypothesis suggesting that the antidepressive action can be produced by sensitizing serotonin-1 receptors present in the serotonin nerve cell body to increase the amount of free serotonin from presynaptic cells (Non-patent Document 4). This idea is basically the same as that of the classical intracerebral monoamine hypothesis. In any cases, it is considered that depression is caused by a decrease in the intracerebral serotonin function.
With regard to medications for depression, first, a tricyclic antidepressive agent, imipramine, and monoamine oxidase inhibitors were developed about 40 years ago. On the basis of the idea that the action to increase serotonin and noradrenaline in the synaptic cleft, which is one of the features the above drugs, is the core of the antidepressant effect, many antidepressive agents have been developed following imipramine and monoamine oxidase inhibitors. In recent years, use of selective serotonin reuptake inhibitors (SSRI) and serotonin/norepinephrine reuptake inhibitors (SNRI), which more selectively inhibit the reuptake of the monoamines by serotonin transporters, have been used in clinical practice. There are as many as 17 antidepressive agents that are approved in Japan at this time, including tricyclic/tetracyclic antidepressive agents, SSRI, and SNRI (Non-patent Document 5).
These antidepressive agents are effective against various diseases besides depression. According to package inserts of the pharmaceutical agents presented by the Pharmaceuticals and Medical Devices Agency, for example, fluvoxamine maleate, which is an SSRI, is effective against obsessive-compulsive and social anxiety disorders; paroxetine hydrochloride, which is an SSRI, is effective against panic and obsessive-compulsive disorders; and sertraline hydrochloride, which is an SSRI, is effective against a panic disorder. Further, amitriptyline hydrochloride, which is a tricyclic SNRI, is effective against nocturnal enuresis.
However, it is reported that these antidepressive agents have side effects. For example, nausea, headache, hypersensitivity and the like are reported as side effects of SSRI, and tremor, tachycardia, erection/ejaculation disorders and the like are reported as side effects of SNRI. There are several reports that side effects are increased in the case of administration of multiple antidepressive agents, compared with administration of a single antidepressive agent (Non-patent Document 6).
It is also reported that when administration of an antidepressive agent is discontinued, withdrawal symptoms may occur. Withdrawal symptoms of tricyclic/tetracyclic antidepressive agents that are reported include: digestive symptoms and physical discomfort accompanied by anxiety and irritability, such as lethargy, emesis, and headache; sleep disorders such as insomnia and multi-dream; motility disorders such as akathisia and Parkinsonian symptoms; activation of behavior that leads to a transition to a manic state; and arrhythmia. These symptoms, except for arrhythmia, are also observed in withdrawal symptoms of SSRI (Non-patent Document 7). Disturbance to the sense of equilibrium, paresthesia, aggressive/impulsive behavior and the like are reported as withdrawal symptoms characteristic of SSRI (Non-patent Document 8).
As described above, it is reported that the antidepressive agents that are widely used at this time have side effects, and the development of safe food ingredients and components, which have ever been eaten and are applicable in place of the above antidepressive agents, are expected. Royal jelly-derived compositions (Patent Document 1) and compositions comprising a hop extract as a main component (Patent Document 2) are reported as food-derived compositions having antidepressive action.
1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) is a compound contained in fruits, such as lemon, grapefruit, orange, and mandarin (Non-patent Document 9), beer, wine (Non-patent Document 10), soy sauce (Non-patent Document 11) and the like, and two types of diastereomers, (1S,3S) and (1R,3S), are known. It is known that MTCA is produced nonfermentatively in the presence of tryptophan and acetaldehyde; especially, it is known that (1S,3S)-MTCA (also called (1S,3S)-2,3,4,9-tetrahydro-1-methyl-1H-pyrido[3,4-b]-indole-3-carboxylic acid) is produced through fermentation by S. cerevisiae (Non-patent Document 12). Further, it is known that (1S,3S)-MTCA has antioxidation action, prevents self-polymerization reaction of γ-crystallin by the Fenton reaction using FeCl3, and prevents photopolymerization reaction of γ-crystallin (Non-patent Document 13). Further, there is a description that pinoline (6-methoxy-1,2,3,4-tetrahydro-β-carboline), which is a carboline compound, inhibits the activity of monoamine oxidase A, and also inhibits the uptake of serotonin in the brain (Non-patent Document 14). Further, it is reported that pinoline reduces immobility time in forced-swimming tests using rats, and that this is the same action as that of a tricyclic antidepressive agent (Non-patent Document 15).
However, inhibitory action of serotonin uptake, antidepressive effect, and improvement of learning motivation by MTCA have completely been unknown.