A traditional Chinese medicine composition for preventing and / or treating five types of stagnation and its application.

Abstract

This invention relates to the field of biomedical technology, and more particularly to a traditional Chinese medicine composition for the prevention and / or treatment of the five types of stagnation (wood, fire, earth, metal, and water) and its application. The traditional Chinese medicine composition of this invention comprises the following components in parts by weight: 8-16 parts of Platycladus orientalis leaves, 5-14 parts of cinnamon, 8-16 parts of mulberry leaves, 8-16 parts of chrysanthemum, 5-14 parts of dried ginger, 5-14 parts of patchouli, 5-14 parts of saposhnikovia divaricata, 10-20 parts of Ilex chinensis root, 10-20 parts of Bidens pilosa, 10-20 parts of Cyperus rotundus, 8-16 parts of Perilla frutescens, and 5-14 parts of turmeric. When prepared as an external medicated bath, this traditional Chinese medicine composition can effectively regulate neuroendocrine function and simultaneously improve the complex five types of stagnation (wood, fire, earth, metal, and water), with significantly better efficacy than existing antidepressant drugs. It is non-toxic, non-irritating to the skin, and has strong pharmacological stability. It provides broad application prospects for the prevention and treatment of the five types of stagnation.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a traditional Chinese medicine composition for the prevention and / or treatment of five types of stagnation and its application. Background Technology

[0002] The Five Stagnations in Traditional Chinese Medicine (TCM) originate from the *Huangdi Neijing* (Yellow Emperor's Inner Classic). These stagnations are categorized as Wood Stagnation, Fire Stagnation, Earth Stagnation, Metal Stagnation, and Water Stagnation, corresponding to stagnation of Qi in the five internal organs: liver, heart, spleen, lungs, and kidneys. They represent the core pathogenesis of contemporary emotional and psychosomatic illnesses. Wood Stagnation refers to liver Qi stagnation, manifesting as chest tightness, hypochondriac pain, irritability, insomnia, and excessive dreaming. Fire Stagnation refers to stagnation of heart fire and internal heat, manifesting as mouth ulcers, irritability, hot flashes, and facial acne. Earth Stagnation refers to spleen and stomach Qi stagnation and dampness obstruction, manifesting as abdominal distension, heaviness in the limbs, and poor appetite. Metal Stagnation refers to lung Qi stagnation and disharmony of the exterior Qi, manifesting as chest tightness, cough, wheezing, sadness, and susceptibility to external pathogens. Water Stagnation refers to kidney Qi stagnation and cold stagnation, manifesting as aversion to cold, fatigue, lower back pain, cold limbs, and emotional apathy.

[0003] Current clinical treatment methods are as follows: 1. Psychotherapy: long cycle, minimal efficacy, many influencing factors, and limited applicability to individuals; 2. Drug therapy: mostly uses oral medications such as Xiaoyao San, Shugan Jieyu capsules, Xiexin Tang, and Yueju pills, which have a slow onset of action, large individual differences in efficacy, significant side effects, and most require long-term medication with a high relapse rate; 3. Physical therapy: high potential risk, large differences in risk, and significant side effects.

[0004] Therefore, there is an urgent need for safe, side-effect-free drugs with shorter treatment cycles that are suitable for various population groups to address the shortcomings of existing technologies. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a traditional Chinese medicine composition for the prevention and / or treatment of five types of stagnation and its application.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a traditional Chinese medicine composition for preventing and / or treating five types of stagnation, comprising the following components in parts by weight: 8-16 parts of arborvitae leaves, 5-14 parts of cinnamon, 8-16 parts of mulberry leaves, 8-16 parts of chrysanthemum, 5-14 parts of dried ginger, 5-14 parts of patchouli, 5-14 parts of saposhnikovia root, 10-20 parts of Ilex chinensis root, 10-20 parts of Bidens pilosa, 10-20 parts of Cyperus rotundus, 8-16 parts of perilla, and 5-14 parts of turmeric.

[0007] Preferably, the components include the following parts by mass: 10-14 parts of arborvitae leaves, 8-11 parts of cinnamon, 10-14 parts of mulberry leaves, 10-14 parts of chrysanthemum, 8-11 parts of dried ginger, 8-11 parts of patchouli, 8-11 parts of saposhnikovia root, 12-18 parts of Ilex chinensis root, 12-18 parts of Bidens pilosa, 12-18 parts of Cyperus rotundus, 10-14 parts of perilla, and 8-11 parts of turmeric.

[0008] Preferably, the components include the following parts by mass: 12 parts of arborvitae leaves, 9 parts of cinnamon, 12 parts of mulberry leaves, 12 parts of chrysanthemum, 9 parts of dried ginger, 9 parts of agastache, 9 parts of saposhnikovia root, 15 parts of Ilex chinensis root, 15 parts of Bidens pilosa, 15 parts of Cyperus rotundus, 12 parts of perilla, and 9 parts of turmeric.

[0009] The present invention also provides the application of the aforementioned traditional Chinese medicine composition in the preparation of medicines for preventing and / or treating five types of stagnation; The medication is for external use only. The external medication mentioned is a topical medicated bath.

[0010] The present invention also provides an external medicated bath for treating five types of stagnation, wherein the external medicated bath is prepared using the aforementioned traditional Chinese medicine composition; The external medicated bath includes external medicated bath packs or external medicated bath solutions.

[0011] Preferably, the preparation method of the external medicated bath pack is as follows: The Chinese herbal composition is pulverized, passed through a 20-40 mesh sieve, sterilized, and packaged to obtain an external medicated bath pack. The sterilization method is ethylene oxide low-temperature sterilization.

[0012] Preferably, the preparation method of the external medicated bath solution is as follows: The herbal composition is mixed with water, soaked for 40-50 minutes, decocted for 30-40 minutes, filtered, and the filtrate is collected to obtain the first medicinal liquid; the dregs are mixed with water, decocted for 15-20 minutes, filtered, and the filtrate is collected to obtain the second medicinal liquid; the first and second medicinal liquids are combined to obtain a mixed liquid; the mixed liquid is concentrated to a relative density of 1.1-1.2 at 55-65℃, filtered through a microporous membrane, and the filtrate is collected to obtain an external medicated bath solution.

[0013] Preferably, the mass ratio of the traditional Chinese medicine composition to water is 1:4~6; The microporous filter membrane has a pore size of 0.2~0.3µm.

[0014] The present invention also provides the use of the aforementioned topical medicated bath in the preparation of medicaments for the prevention and / or treatment of depression.

[0015] The solution of the present invention has the following beneficial effects: In this invention, the herbal composition contains cinnamon to warm the yang and reduce heat, arborvitae leaf and chrysanthemum to clear heat and purge fire, cyperus and turmeric to regulate qi and relieve stagnation, iris root and beggar-ticks to drain turbidity and promote diuresis, saposhnikovia root, perilla leaf and mulberry leaf to open the pores and relieve external stagnation, agastache to aromatically resolve dampness, invigorate the spleen and harmonize the middle jiao, and ginger to warm the middle jiao and dispel cold, and promote the clear qi of the spleen and stomach. It treats the five internal organs separately while taking into account the harmony of qi, relieves stagnation without harming yin, clears heat without harming yang, and warms yang without promoting fire, thus curing the complex five types of stagnation. The traditional Chinese medicine composition of the present invention is prepared into an external medicated bath, which delivers medicine directly to the meridians through the skin. The medicine penetrates quickly and has a shorter onset period compared to traditional medicated baths.

[0016] The traditional Chinese medicine composition of the present invention contains no toxic or mineral-irritating components, and all drugs are safe and non-allergenic.

[0017] The traditional Chinese medicine composition of this invention treats the complex five types of depression caused by emotional distress, including irritability, insomnia, chest tightness, fatigue, aversion to cold, and lower back pain. It can also improve skin dullness, acne, and aversion to cold limbs caused by stagnant heat. It takes into account both physical and mental conditioning and skin care, and has a wide range of indications. Detailed Implementation

[0018] In this invention, the herbal composition uses Cyperus rotundus and Cinnamomum cassia as the principal herbs, which are warming and cooling in nature, to harmonize the body's Qi. The secondary herbs, corresponding to the five internal organs and their corresponding pathogenesis, address the five types of stagnation: wood, fire, earth, metal, and water. These include Curcuma longa and Perilla frutescens, which soothe the liver, regulate Qi, disperse blood stasis, and treat wood stagnation; Chrysanthemum morifolium and Platycladus orientalis, which clear heat and purge fire without harming Yang, and treat fire stagnation; Pogostemon cablin and Zingiber officinale, which resolve dampness, invigorate the spleen, and break up stagnation in the middle Jiao, and treat earth stagnation; Morus alba and Saposhnikovia divaricata, which disperse lung heat, relieve lung Qi stagnation, and treat metal stagnation; and Ilex chinensis and Bidens pilosa, which clear stagnation in the lower Jiao, disperse dampness, and promote circulation, and treat water stagnation. Zingiber officinale also acts as an adjuvant, harmonizing the warming and cooling properties of the herbs, opening the skin pores, and guiding the medicinal power into the collaterals. The combination of these components effectively regulates the neuroendocrine system, improves damage to the Qi of the internal organs, harmonizes warming and cooling in both directions, and simultaneously improves the complex five types of stagnation (wood, fire, earth, metal, and water).

[0019] The traditional Chinese medicine composition of the present invention is safe, non-toxic, non-irritating to the skin, and has strong pharmacological stability.

[0020] The following detailed description of the solutions provided by the present invention, in conjunction with the embodiments, should not be construed as limiting the scope of protection of the present invention.

[0021] Example 1

[0022] External medicated bath pack for treating five types of stagnation

[0023] (1) Raw material pretreatment: Weigh 10kg of arborvitae leaves, 5kg of cinnamon, 12kg of mulberry leaves, 16kg of chrysanthemum, 12kg of dried ginger, 14kg of patchouli, 10kg of saposhnikovia root, 15kg of Ilex chinensis root, 20kg of Bidens pilosa, 10kg of Cyperus rotundus, 12kg of Perilla frutescens and 10kg of turmeric, mix them, remove impurities, wash them, and dry them at 50℃ until the moisture content is 6% to obtain the Chinese herbal composition.

[0024] (2) Crushing and sieving: Crush the Chinese medicine composition and pass it through a 30-mesh sieve to remove the residue.

[0025] (3) Sterilization and packaging: The traditional Chinese medicine composition after removing the residue is sterilized by ethylene oxide at low temperature for 2 hours, packaged in non-woven bags, and vacuum sealed to obtain external medicine bath packs. Each pack contains 200g of sterilized traditional Chinese medicine composition.

[0026] Example 2

[0027] External medicated bath solution for treating five types of stagnation

[0028] (1) Raw material pretreatment: Weigh 8kg of arborvitae leaves, 14kg of cinnamon, 8kg of mulberry leaves, 8kg of chrysanthemum, 14kg of dried ginger, 10kg of patchouli, 14kg of saposhnikovia root, 10kg of Ilex chinensis root, 15kg of Bidens pilosa, 20kg of Cyperus rotundus, 8kg of Perilla frutescens, and 14kg of turmeric, mix them, remove impurities, wash them, and dry them at 50℃ until the moisture content is 6% to obtain the Chinese herbal composition.

[0029] (2) Water decoction extraction: Add 6 times the mass of water to the Chinese herbal composition, soak for 50 min, decoct for 35 min, filter with 5 layers of gauze, and collect the filtrate to obtain the first decoction. Add 4 times the mass of water to the residue, decoct for 20 min, filter with 5 layers of gauze, and collect the filtrate to obtain the second decoction; combine the first and second decoctions to obtain a mixed solution. Concentrate the mixed solution under reduced pressure to a relative density of 1.12 at 60℃, filter with a 0.22µm microporous membrane, collect the filtrate, and obtain the external bath solution.

[0030] Example 3

[0031] External medicated bath pack for treating five types of stagnation

[0032] (1) Raw material pretreatment: Weigh 16kg of arborvitae leaves, 10kg of cinnamon, 16kg of mulberry leaves, 12kg of chrysanthemum, 5kg of dried ginger, 5kg of agastache, 5kg of saposhnikovia root, 20kg of Ilex chinensis root, 10kg of Bidens pilosa, 15kg of Cyperus rotundus, 16kg of perilla, and 5kg of turmeric, mix them, remove impurities, wash them, and dry them at 50℃ until the moisture content is 6% to obtain the Chinese herbal composition.

[0033] (2) Crushing and sieving: Crush the Chinese medicine composition and pass it through a 30-mesh sieve to remove the residue.

[0034] (3) Sterilization and packaging: The traditional Chinese medicine composition after removing the residue is sterilized by ethylene oxide at low temperature for 2 hours, packaged in non-woven bags, and vacuum sealed to obtain external medicine bath packs. Each pack contains 200g of sterilized traditional Chinese medicine composition.

[0035] Experimental Example 1

[0036] 1. Preparation of the Five-Depression Mouse Model

[0037] SPF-grade healthy Kunming mice, half male and half female, weighing 20-22g, were selected and kept in an environment with a temperature of 22±2℃ and a humidity of 50%±5%, with a 12-hour light-dark cycle, and free access to food and water. The experiment was conducted after 7 days of acclimatization.

[0038] A combined model of chronic, unpredictable emotional stress and cold-dampness stimulation was used, with a modeling period of 21 days. (1) Emotional stress modeling (inducing liver qi stagnation, fire qi stagnation, and metal qi stagnation): Any two of the following stimuli were randomly applied daily: ① fasting for 24 hours; ② day-night reversal; ③ tilting the cage at 45°; ④ swimming in ice water for 5 minutes; ⑤ tail clamping stimulation for 5 minutes. The purpose was to induce liver qi stagnation, heart fire stagnation, and lung qi stagnation in mice.

[0039] (2) Cold and dampness intervention model (inducing earth stagnation and water stagnation): blow cold wind at 12℃ for 30 minutes every day and humidify the bedding (bedding and water in a 1:2 ratio) to damage spleen yang, stagnate kidney qi, and induce spleen deficiency and dampness stagnation and lower jiao water stagnation.

[0040] Model establishment criteria: The five-eighths complex model was successfully established when mice showed decreased food intake, slowed weight gain, reduced activity, cold intolerance and curling up, dry fur, and decreased sugar water preference.

[0041] 2. Administration of drugs to mice with five stagnations

[0042] Sixteen mice that successfully established the model were randomly divided into four groups: Example 1 group, Example 2 group, control group, and model control group, with four mice in each group. Normal mice that did not undergo modeling or drug administration served as blank controls.

[0043] Blank control: Normal feeding, daily immersion in 39℃ warm water for 15 minutes for 14 consecutive days; Model control group: bathed in 39℃ warm water for 15 minutes daily, with no drug intervention, and all other feeding conditions were the same for 14 consecutive days; Control group: Daily gavage with 0.4g / kg of liver-soothing and mood-lifting capsules, followed by a 15-minute bath in 39°C warm water after half an hour, with all other feeding conditions being the same, for 14 consecutive days; Example 1 group: 200g of the external medicated bath pack prepared in Example 1 was placed in 40L of 39℃ warm water for 15min to allow the drug to penetrate into the water. Then the mice were immersed in the medicated water for 15min. All other feeding conditions were the same for 14 consecutive days. Example 2 group: 220 mL of the external medicated bath solution prepared in Example 2 was placed in 40 L of 39℃ warm water, stirred evenly, and the mice were immersed in the medicated bath for 15 min. All other feeding conditions were the same for 14 consecutive days.

[0044] 3. Indicator Testing

[0045] (1) Behavioral testing

[0046] After the experiment, the mice in each group underwent the following behavioral tests: ① Sugar water consumption experiment: After fasting and depriving mice of water for 24 hours, each mouse was given two bottles (100 mL each) containing water and 1% sucrose solution. After 2 hours, the water and sucrose solution consumed by each group of mice were recorded, and the sugar water preference was calculated.

[0047] Sugar solution preference percentage % = Sucrose solution consumption / (Sucrose solution consumption + Water consumption) × 100%.

[0048] ② Tail suspension test: The tails of mice in each group were fixed, and their heads were suspended downwards. The immobility time of each group of mice was recorded within 5 minutes using the TST-100 tail suspension video analysis system.

[0049] ③ Forced swimming experiment: The mouse fully automated forced swimming experiment system was used to record the swimming still time of each group of mice within 5 minutes.

[0050] ④ Open field activity test: The horizontal activity distance of each group of mice within 5 minutes was recorded using the OFT-100D rat and mouse open field activity test system.

[0051] (2) Biochemical index detection

[0052] The ELISA kit was used to detect the levels of inflammatory factors TNF-α, IL-1β and IL-4 in the serum of mice in each group.

[0053] (3) Safety Experiment

[0054] Observe the skin on the back and abdomen of mice daily for redness, swelling, desquamation, and ulceration, and record the sensitization status.

[0055] 4. Experimental Results

[0056] (1) The behavioral results are shown in Table 1.

[0057] Table 1. Behavioral results of mice in different groups

[0058] Table 1 shows that, compared with the blank control, the model control mice consumed significantly less sucrose, had significantly increased time spent in forced swimming and tail suspension, and significantly shortened movement distance. Compared with the model control, the mice in Examples 1, 2, and the control mice showed increased sucrose preference, decreased time spent in tail suspension and forced swimming, and increased movement distance. The topical medicated bath solution in Example 2 group showed the best effect.

[0059] (2) The results of physiological and biochemical indicators are shown in Table 2.

[0060] Table 2. Physiological and biochemical results of mice in different groups

[0061] Table 2 shows that, compared with the blank control group, the levels of TNF-α, IL-1β, and IL-4 in the model control mice were significantly increased; compared with the model control group, the levels of TNF-α, IL-1β, and IL-4 in mice from Examples 1, 2, and the control group were reduced, with Example 2 showing the best reduction effect. This indicates that the external medicated bath solution prepared using the traditional Chinese medicine composition of the present invention can effectively treat mice with five stagnations.

[0062] (3) Safety Experiment

[0063] All experimental mice had smooth skin, without redness, swelling, scaling, or allergic reactions, and their fur was smooth. This demonstrates that the traditional Chinese medicine composition of this invention is safe and effective.

[0064] Application Example 1

[0065] high Qiong, female, 16 years old, from Huilai County, Jieyang City, Guangdong Province, was diagnosed with schizophrenia in 2019 by a psychiatric hospital in Huilai County. Her main symptoms included talking to herself, silly laughter, and a two-year history of believing she had been framed, accompanied by a six-month history of hearing voices from afar. She was admitted to the hospital and treated with risperidone, quetiapine, and olanzapine for 30 days, but the treatment was only moderately effective, and she was subsequently discharged.

[0066] After discharge, the patient used the external medicated bath solution of Example 2 of this invention, adding 220mL of the solution to 40L of water for 30 minutes of bathing daily. After 21 days of treatment, the symptoms of talking to oneself and giggling significantly decreased. After another 21 days of treatment, the symptoms of talking to oneself and giggling disappeared. Occasionally, the patient experienced being framed or hearing voices from afar. After 3 months of continued treatment, the patient's mental state returned to normal, and the phenomena of being framed or hearing voices from afar ceased. No recurrence was observed during the 6-month and 1-year follow-ups.

[0067] Application Example 2

[0068] List Xu, male, 18 years old, underwent examination at a neurology hospital in Guangzhou due to recurrent head shaking. The diagnosis was undifferentiated schizophrenia and epilepsy. Upon admission, the following psychiatric examination revealed: clear consciousness, age-appropriate appearance, passive interaction, accurate orientation, denial of hallucinations, responsive to forced feeding, reports recurring thoughts with varying content but no pain, enjoyment of the feeling, as if imposed upon him by an external force, difficult to describe specifically, responsive to associations, feeling that passersby are watching him and pointing at him, but unsure if it is related to him, anxiety, tension, occasional crying, described as insecurity, reduced willpower, fear of social contact, reluctance to interact with others, poor concentration, poor cooperation during memory and intelligence tests, and unclear description of the illness.

[0069] After admission, the patient was treated with olanzapine, fluvoxamine, tandospirone, oxazepam, trihexyphenidyl, and hepatoprotective capsules. After 25 days of treatment, the condition stabilized, and the patient was discharged. Six months after discharge, the patient experienced the same symptoms again and was treated with the external medicated bath pack described in Example 1.

[0070] Add 200g of the external medicated bath pack prepared in Example 1 to 40L of water daily, soak the medicated bath pack for 20 minutes, and then take a bath for 20 minutes. Do this once a day for 10 consecutive days. After that, the patient's condition improved significantly. Continue using the product for 1 month and the condition completely improved. There was no recurrence during a 6-month follow-up.

[0071] As can be seen from the above embodiments, the present invention provides a traditional Chinese medicine composition for the prevention and / or treatment of five types of stagnation and its application. When the traditional Chinese medicine composition of the present invention is prepared into a topical medication, it can effectively regulate the neuroendocrine system and simultaneously improve the complex five types of stagnation (wood, fire, earth, metal, and water), with significantly better efficacy than existing antidepressant drugs. It is non-toxic, non-irritating to the skin, and has strong pharmacological stability, providing a basis for the safe prevention and treatment of five types of stagnation.

[0072] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine composition for preventing and / or treating five types of stagnation, characterized in that, The components include the following parts by mass: 8-16 parts of arborvitae leaves, 5-14 parts of cinnamon, 8-16 parts of mulberry leaves, 8-16 parts of chrysanthemum, 5-14 parts of dried ginger, 5-14 parts of patchouli, 5-14 parts of saposhnikovia root, 10-20 parts of Ilex chinensis root, 10-20 parts of Bidens pilosa, 10-20 parts of Cyperus rotundus, 8-16 parts of perilla, and 5-14 parts of turmeric.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The components include the following parts by mass: 10-14 parts of arborvitae leaves, 8-11 parts of cinnamon, 10-14 parts of mulberry leaves, 10-14 parts of chrysanthemum, 8-11 parts of dried ginger, 8-11 parts of patchouli, 8-11 parts of saposhnikovia root, 12-18 parts of Ilex chinensis root, 12-18 parts of Bidens pilosa, 12-18 parts of Cyperus rotundus, 10-14 parts of perilla, and 8-11 parts of turmeric.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The components include the following parts by mass: 12 parts of arborvitae leaves, 9 parts of cinnamon, 12 parts of mulberry leaves, 12 parts of chrysanthemum, 9 parts of dried ginger, 9 parts of agastache, 9 parts of saposhnikovia root, 15 parts of Ilex chinensis root, 15 parts of Bidens pilosa, 15 parts of Cyperus rotundus, 12 parts of perilla, and 9 parts of turmeric.

4. The use of the traditional Chinese medicine composition according to any one of claims 1 to 3 in the preparation of a medicament for preventing and / or treating five types of stagnation; The medication is for external use only. The external medication mentioned is a topical medicated bath.

5. A topical medicated bath for treating five types of stagnation, characterized in that, The external medicated bath is prepared using the traditional Chinese medicine composition according to any one of claims 1 to 3; The external medicated bath includes external medicated bath packs or external medicated bath solutions.

6. The external medicated bath according to claim 5, characterized in that, The preparation method of the external medicated bath pack is as follows: The traditional Chinese medicine composition according to any one of claims 1 to 3 is pulverized, passed through a 20 to 40 mesh sieve, sterilized, and packaged to obtain an external medicated bath pack. The sterilization method is ethylene oxide low-temperature sterilization.

7. The external medicated bath according to claim 5, characterized in that, The preparation method of the external medicated bath solution is as follows: Mix the traditional Chinese medicine composition according to any one of claims 1 to 3 with water, soak for 40 to 50 minutes, decoct for 30 to 40 minutes, filter, collect the filtrate, and obtain the first medicinal liquid; Mix the dregs with water, decoct for 15-20 minutes, filter, collect the filtrate to obtain the second medicinal solution; combine the first and second medicinal solutions to obtain a mixed solution; concentrate the mixed solution to a relative density of 1.1-1.2 at 55-65℃, filter through a microporous membrane, collect the filtrate to obtain an external medicated bath solution.

8. The external medicated bath according to claim 7, characterized in that, The mass ratio of the traditional Chinese medicine composition to water is 1:4~6; The microporous filter membrane has a pore size of 0.2~0.3µm.

9. The use of the external medicated bath according to any one of claims 5 to 8 in the preparation of a medicament for the prevention and / or treatment of depression.

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