Core prescription pattern of Chinese herbal medicine for depressive disorders in Taiwan: a nationwide population-based study.

BACKGROUND: Depressive disorders (DD) affect not only mood and behavior but also various physical functions. Traditional Chinese medicine (TCM) has been shown to have some benefits in treating DD. However, one formula or one single herb might be not show high efficacy when used to treat depression. Thus, this study aimed to examine the core prescription pattern of Chinese herbal medicine (CHM) among patients with DD in Taiwan as a reference for related research and clinical applications.
METHODS: All patients, who had been diagnosed with major depressive disorder or minor depression or dysthymia without any other baseline diseases and had at least one CHM outpatient clinical visit from 2002 to 2011, were extracted from three randomly sampled cohorts, namely the 2000, 2005 and 2010 cohorts of the National Health Insurance Research Database (NHIRD) of Taiwan. The collected data was analyzed to explore the patterns of herbal products.
RESULTS: There were 197,146 patients with a diagnosis of DD and of these 1806 subjects had only a diagnosis of DD and utilized CHM. The most common formula was Gan-Mai-Da-Zao-Tang (12.19%), while Suan-Zao-Ren (3.99%) was the most commonly prescribed single herb. The core pattern of prescriptions consisted of a combination of Gan-Mai-Da-Zao-Tang, Jia-Wei-Xiao-Yao-San, Chai-Hu-Jia-Long-Gu-Mu-Li-Tang, He-Huan-Pi, Yuan-Zhi and Shi-Chang-Pu.
CONCLUSIONS: This study describes the CHM core prescription pattern used to treat patients in Taiwan with DD and it is a potential candidate for study in future pharmacological or clinical trials targeting DD.

Introduction

According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5), depressive disorders (DD) include several mood disorders (major depressive disorder, dysthymia, and so on) that not only affect emotions (anxiety, sadness), mind (slow thinking, indecisiveness) and behaviors (irritability, suicide attempts), but also affect various bodily functions (eating changes, sleeping problems) and causes disability (social isolation, trouble with interpersonal relationship). As reported by Global Burden Disease study in 2016, DD were ranked among top ten leading causes of years lived with disability in Taiwan. Many studies have shown that patients with DD have a relatively poor quality of life, have increased medical use, and are at risk of suicide. Moreover, when DD are associated with chronic diseases, such as hypertension, diabetes, heart diseases, cancer, and so on, there are higher rates of morbidity and mortality compared to similar patients without DD.

Many studies are been carried with the aim of discovering the underlying mechanisms behind DD. Until the present it has been suggested that several related factors are involved such as monoaminergic systems, brain-derived neurotrophic factor (BDNF), the hypothalamic-pituitary-adrenal axis, and neuroinflammation. The treatment of DD is based on the use of antidepressants and/or various psychological treatments. Antidepressants are effective when treating moderate and severe depression, although they are not recommended as a first line of treatment for either mild depression in adults or depression in adolescents. However, many of the side effects of antidepressants, including nausea, headache, insomnia, anxiety, weight gain, sexual dysfunction and so on, often make patients reluctant to continue to use them. On the other hand, the use of psychological treatments is limited by factors such as time-consuming process, high cost (in many countries, the fee of psychological treatments is not covered by insurance), and lack of professionals (psychiatrists, psychologists, and so on).

Because of the reasons mentioned above, patients with DD have looked for other treatments. In Taiwan, because Traditional Chinese Medicine (TCM) has been incorporated into health insurance system, many people use TCM to promote their health or to treat various diseases., A study has shown that more than 40% of depression patients in Taiwan used TCM in 2003, and that younger age individuals, women, individuals with other chronic diseases, and individuals with less exposure to psychiatric treatment are likely to use TCM frequently.

Chinese herbal medicine (CHM) has been demonstrated to show benefits when used to treat depression. To investigate the effects, safety, and types of CHM for depression, Yeung and his collaborators conducted a meta-analysis. This showed that three most common formulae used in clinical trials were Xiao-Yao-Tang or its modifications, Chai-Hu-Shu-Gan-Tang and Gan-Mai-Da-Zao-Tang; and CHM had a better efficacy than the placebo control group. The effects were equal to those of antidepressants, and, furthermore, the integration of CHM and antidepressants resulted fewer side effects when treating depressive disorders. However, due to the low methodological quality of most the included studies, more randomized and better controlled trials using internationally accepted methods and standards are required to confirm the benefits of CHM for the treatment of DD.

As mentioned above, DD has been suggested to develop via a number of different possible mechanisms. One formula or one single herb might be not able to regulate all the pathways relevant to depression. Thus, it is necessary to examine if combination of different formulae or single herbs are able to enhance the treatment's effectiveness. In 1995 Taiwan established its National Health Insurance program, and 99.9% of Taiwan's population were enrolled in the system by the end of 2014. National Health Insurance Research Database (NHIRD) provides a platform for understanding the core pattern of prescribed CHM among the depressed patient population in Taiwan. Therefore, the purpose of this study was to analyze three randomly extracted cohort samples from the NHIRD database in order to investigate the core pattern of CHM prescriptions for patients with DD in Taiwan; this can then be used as a reference for related research and for specific clinical applications.

Methods

Data sources

NHIRD is a nationwide population-based claims database with long-term follow-up. Annually, data has been collected from National Health Insurance program and de-identified before being sent to the National Health Research Institutes to form NHIRD. The NHIRD's data includes patients’ gender, age, dates of clinical visits, major disease diagnosis codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) format, and details of any prescription provided to the patient. All identity information of the beneficiaries and the medical facilities used are encoded in order to protect the patients' and hospitals' privacy. This study used a retrospective observational population-based design to analyze three random cohort samples from the Longitudinal Health Insurance Database (LHID2000, LHID2005, and LHID2010) to survey the patterns of prescribed CHM among patients with only a diagnosis of depressive disorder between January 1, 2002 and December 31, 2011. LHID 2000, LHID2005, and LHID2010 are three datasets which include one million beneficiaries randomly extracted from NHIRD in 2000, 2005, and 2010, respectively. The random sampling method is to assign all people in the insured population to serial numbers, and use a random number generator to generate at least one million random values, after that take the same serial numbers as one million random values to randomly select the required sample. There are no differences in demographic factors between the randomly selected sample and the entire datasets; thus, these samples could be regarded as representative of the general population. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (VGHIRB-2018–03–010CC).

Study subjects

The flowchart of subject extraction from the 3 million random samples forming the Taiwan NHIRDs is presented in Fig. 1. First, all patients diagnosed with major depressive disorder (ICD-9 234.2x or 234.3x), with minor depression (ICD-9 300.4) or with dysthymia (ICD-9 311) were extracted. From 2002 to 2011 in Taiwan, there were 76,425 depressed patients within LHID2000, 68,142 within LHID2005, and 52,579 within LHID2010. Second, within these DD cohorts, patients were separated into either CHM users, who had received at least one CHM prescription between 2002 to 2011 (n = 877 within LHID2000, n = 859 within LHID2005, and n = 780 within LHID2010, respectively), and non-CHM users, who has received no CHM prescription based on these outpatient records. Finally, only CHM users with only a diagnosis of DD were included. Claims with only one of the diagnosis codes for DD, and without any other baseline diseases, were defined as subjects with only a diagnosis of depression. The use of only a diagnosis of DD, in terms of CHM visits, should diminish measurement bias caused by CHM visits for non-depressive disorders treatments. Among the CHM users, a total of 1806 subjects (622 in LHID2000, 627 in LHIDD2005, 557 in LHID2010, respectively) achieved this criterion.

Fig. 1

Flowchart of recruitment of patients with depressive disorders from the 3 million random samples.

Statistical analysis

Data analysis comprised of descriptive statistics, including the basic characteristics of patients, the most common formulae used to treat DD and the most common single herbs used to treat DD. This study used SAS software, version 9.4 (SAS Institute Inc., Cary, NC, U.S.A.) to analyze the data. In addition, an open-sourced freeware NodeXL was used to discover the core pattern of CHM used when treating patients with DD, and the most frequent combinations of two formulae/single herbs were then utilized for the network analysis. Within the network, formulae and single herbs were connected via lines. The number of combinations between a certain CHM and co-prescribed CHM was used to determine the width of the line connecting them, and the thicker the width of a given line connections is used to identify important prescription patterns. For example, if CHM-A and CHM-B are more frequently co-prescribed than CHM-A and CHM-C, the width of the line between CHM-A and CHM-B will be thicker than the one between CHM-A and CHM-C. The above approach allows the core pattern of CHM utilization to be clearly detected. This approach to identifying core prescription pattern analysis has been used in previous study.

Results

Characteristics of DD patients

From 2002 to 2011 in Taiwan, there were 1806 subjects with only a diagnosis of DD used CHM. Table 1 presents the demographic characteristics of the CHM users. Females had a higher tendency to use CHM than males. Among the various age groups, the group with the highest percentage utilization was the 35–49 years old group (37.3%) and the mean±SD overall age was 44.88±14.34. Patients with diagnosis of dysthymia used CHM more frequently than two other groups. In addition, almost three quarters of the patients (72.3%) used CHM 1–3 times.

Table 1

Demographic characteristics of Chinese herbal medicine users among patients with depressive disorders from 2002 to 2011.

Characteristics	Chinese herbal medicine users
	N	%
Gender
Male	555	30.73
Female	1251	69.27
Age
<20	58	3.21
20–34	411	22.76
35–49	674	37.32
50–64	493	27.30
65–79	158	8.75
>=80	12	0.66
Mean±SD	44.88±14.34
Max	88
Min	7
Depression diagnosis at index visit
Major depression	254	14.06
Minor depression	622	34.44
Dysthymia	930	51.50
Number of visits for Chinese herbal products
1–3	1306	72.31
4–6	234	12.97
>6	266	14.72
Total	1806	100

Top ten CHM formulae and single herbs for DD patients

The top ten CHM formulae for treating DD from 2002 to 2011 are listed in Table 2. Gan-Mai-Da-Zao-Tang was the most commonly prescribed formula (12.19%), with an average dose of 4.36 g, followed by Jia-Wei-Xiao-Yao-San (10.08%), Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (6.83%).

Table 2

Ten most commonly prescribed formulae for depressive disorders (total prescription number=12,748).

Herbal formulas	Ingredients/Scientific name	Therapeutic actions	Average dose (g)	Frequency of prescription N (%)
Gan-Mai-Da-Zao-Tang	Gan-Cao (Glycyrrhiza uralensis Fisch), Xiao-Mai (Triticum aestivum L.), Da-Zao (Ziziphus jujuba Mill.)	Nourishes the Heart and calms the Shen	4.36	1555 (12.19%)
Jia-Wei-Xiao-Yao-San	Dang-Gui (Angelica sinensis (Oliv.) Diels), Bai-Shao (Paeonia lactiflora Pall.), Chai-Hu (Bupleurum abchasicum Manden.), Fu-Ling (Poria cocos (Schw.) Wolf.), Bai-Zhu (Atractylodes macrocephala Koidz.), Gan-Cao (Glycyrrhiza uralensis Fisch.), Mu-Dan-Pi (Moutan officinalis (L.) Lindl. & Paxton.), Wei-Jiang (Zingiber officinale Roscoe.), Bo-He (Mentha haplocalyx Briq.), Zhi-Zi (Gardenia jasminoides J.Ellis)	Courses the Liver and resolves depression	4.64	1286 (10.08%)
Chai-Hu-Jia-Long-Gu-Mu-Li-Tang	Chai-Hu (Bupleurum abchasicum Manden.), Sheng-Jiang (Zingiber officinale Roscoe), Huang-Qin (Scutellaria baicalensis Georgi.), Da-Zao (Ziziphus jujuba Mill.), Fu-Ling (Poria cocos (Schw.) Wolf.), Ren-Shen (Panax ginseng C.A.Mey), Da-Huang (Rheum palmatum L.), Zhi-Ban-Xia (Pinellia ternata (Thunb.) Makino.), Mu-Li (Ostrea gigas Thunb.), Gui-Zhi (Cinnamomum cassia Presl.), Long-Gu (Fossilia Ossia Mastodi)	Sedates and calms the Spirit	4.2	871 (6.83%)
Tian-Wang-Bu-Xin-Wan	Sheng-Di-Huang (Rehmannia glutinosa (Gaertn.) Libosch. Ex Fisch. & C.A. Mey.), Dang-Gui (Angelica sinensis (Oliv.) Diels), Suan-Zao-Ren (Ziziphus jujuba Mill.), Mai-Men-Dong (Ophiopogon japonicus (Thunb.) Ker Gawl.), Yuan-Zhi (Polygala tenuifolia Willd.). Tian-Men-Dong (Asparagus cochinchinensis (Lour.) Merr.), Bai-Zi-Ren (Platycladus orientalis (L.) Franco.), Wu-Wei-Zi (Schisandra chinensis (Turcz.) Baill.), Fu-Ling (Poria cocos (Schw.) Wolf.), Jie-Geng (Platycodon grandiflorus (Jacq.) A. DC.), Ren-Shen (Panax ginseng C.A.Mey), Dan-Shen (Salvia miltiorrhiza Bunge.), Xuan-Shen (Scrophularia ningpoensis Hemsl.)	Enriches Yin and calms the Shen	5.36	798 (6.26%)
Suan-Zao-Ren-Tang	Suan-Zao-Ren (Ziziphus jujuba Mill.Sclerotium), Fu-Ling (Poria cocos (Schw.) Wolf.), Zhi-Mu (Anemarrhena asphodeloides Bge.), Chuan-Xiong (Laserpitium striatum Wall.), Gan-Cao (Glycyrrhiza uralensis Fisch.)	Clears heat in Liver and Heart, calms the Shen	4.12	405 (3.17%)
Wen-Dan-Tang	Zhi-Ban-Xia (Pinellia ternata (Thunb.) Makino.), Zhu-Ru (Bambusa tuldoides Munro.), Zhi-Shi (Citrus aurantium L.), Chen-Pi (Citrus reticulata Blanco.), Fu-Ling (Poria cocos (Schw.) Wolf.), Gan-Cao (Glycyrrhiza uralensis Fisch.), Sheng-Jiang (Zingiber officinale Roscoe.), Da-Zao (Ziziphus jujuba Mill.)	Regulates the Qi and transforms Phlegm	4.12	402 (3.15%)
Wu-Zhu-Yu-Tang	Wu-Zhu-Yu (Evodia rutaecarpa (Juss) Benth.), Ren-Shen (Panax ginseng C.A.Mey), Sheng-Jiang (Zingiber officinale Roscoe.), Da-Zao (Ziziphus jujuba Mill.)	Warms and tonifies the Spleen, Stomach, Liver and Kidneys and descends Rebellious Qi	3.64	307 (2.41%)
Gui-Pi-Tang	Ren-Shen (Panax ginseng C.A.Mey), Bai-Zhu (Atractylodes macrocephala Koidz.), Fu-Ling (Poria cocos (Schw.) Wolf.), Suan-Zao-Ren (Ziziphus jujuba Mill.), Long-Yan-Rou (Arillus Longan (Lour.) Steud.), Huang-Qi (Astragalus membranaceus (Fisch) Bge), Dang-Gui (Angelica sinensis (Oliv.) Diels), Mu-Xiang (Auklandia lappa Clarke.), Zhi-Yuan-Zhi (Polygala tenuifolia Willd.), Gan-Cao (Glycyrrhiza uralensis Fisch.), Sheng-Jiang (Zingiber officinale Roscoe.), Da-Zao (Ziziphus jujuba Mill.)	Augments Qi, nourishes the Blood, strengthens the Spleen, nourishes the Heart	4.56	283 (2.22%)
Yi-Gan-San	Chao-Bai-Zhu (Atractylodes macrocephala Koidz.), Fu-Ling (Poria cocos (Schw.) Wolf.), Dang-Gui (Angelica sinensis (Oliv.) Diels), Chuan-Xiong (Laserpitium striatum Wall.), Gou-Teng (Uncaria rhynchophyllia (Miq.) Jacks.), Chai-Hu (Bupleurum abchasicum Manden.), Gan-Cao (Glycyrrhiza uralensis Fisch.)	Calms the Liver andregulates the Liver Qi and Blood	4.4	251 (1.97%)
Ban-Xia-Hou-Po-Tang	Ban-Xia (Pinellia ternata (Thunb.) Makino.), Hou-Po (Magnolia officinalis Rehder & E.H.Wilson.), Fu-Ling (Poria cocos (Schw.) Wolf.), Sheng-Jiang (Zingiber officinale Roscoe.), Zi-Su-Ye (Perilla frutescens (L.) Britton.)	Activates Qi, descends Rebellious Qi, eliminates Phlegm, and relieves Stagnation	5.16	199 (1.56%)

The top ten single herbs for treating DD are also listed and the most frequently used single herb is Suan-Zao-Ren (3.99%) with an average dose was 1.36 g (Table 3). The next common single herbs were Da-Huang (3.07%), Yuan-Zhi (2.89%).

Table 3

Ten most commonly prescribed single herbs for depressive disorders (total prescription number = 19,343).

Single herbs	Scientific name	Therapeutics Actions	Average dose (g)	Frequency of prescription N (%)
Suan-Zao-Ren	Ziziphi Spinosae Semen Ziziphus jujuba Mill.	Nourishes Heart Yin, tonifies Liver Blood andcalms the Spirit	1.36	772 (3.99%)
Da-Huang	Rhei Radix et Rhizoma Rheum palmatum L.	Clears heat and drains fire	0.64	595 (3.07%)
Yuan-Zhi	Polygalae Radix Polygala tenuifolia Willd.	Calms the Spirit, sedatesthe Heart	0.68	559 (2.89%)
Ye-Jiao-Teng	Polygoni Multiflori Caulis Polygonum multiflorum Thunb	Nourishes the Heart Yin and Blood and calms the Spirit	1.16	546 (2.82%)
Bai-He	Bulbus Lili Lilium brownii F.F. Br. var. colchesteri Wils	Clears the Heart and calms the Spirit	1.12	542 (2.80%)
Dan-Shen	Salviae Miltiorrhizae Radix Salvia miltiorrhiza Bunge.	Clears Heat and soothes irritability; nourishes theBlood and calms the Spirit	0.96	538 (2.78%)
He-Huan-Pi	Cortex Albiziae Albizia julibrissin sensu Baker.	Calms the Spirit and relieves constraint	1.16	525 (2.71%)
Mu-Li	Ostreae Testa Ostrea gigas Thunb.	Heavily settles and calms the Spirit	0.92	510 (2.63%)
Yu-Jin	Curcumae Radix Curcuma aromatica Salisb. Curcuma longa L.	Invigorates the Blood, dispels Blood Stasis, regulates Qi flow	1.04	492 (2.54%)
Fu-Shen	Scierotium Pararadicis Poriae Cocos Poria cocos (Schw). Wolf	Calms the Spirit	0.92	492 (2.54%)

The prescription patterns between formulae and single herbs

The most common prescription patterns with regard to formula/single herb associations are shown in Table 4. The most common association of two formulae/single herbs was Jia-Wei-Xiao-Yao-San plus Gan-Mai-Da-Zao-Tang. The other identified patterns were Gan-Mai-Da-Zao-Tang plus Chai-Hu-Jia-Long-Gu-Mu-Li-Tang, and Gan-Mai-Da-Zao-Tang plus He-Huan-Pi. Furthermore, Long-Gu, plus Suan-Zao-Ren, plus Bai-He was the most common association of three formulae/single herbs, followed by Suan-Zao-Ren, plus Ye-Jiao-Teng, plus Bai-He, and Suan-Zao-Ren, plus Bai-He, plus Wu-Wei-Zi.

Table 4

The most common prescription patterns for two and triple drug combinations in a single prescription of depressive disorders.

	Name			Number of prescription
Two combination
1	Jia-Wei-Xiao-Yao-San	Gan-Mai-Da-Zao-Tang		580
2	Gan-Mai-Da-Zao-Tang	Chai-Hu-Jia-Long-Gu-Mu-Li-Tang		440
3	Gan-Mai-Da-Zao-Tang	He-Huan-Pi		307
4	Shi-Chang-Pu	Yuan-Zhi		288
5	Bai-He	Suan-Zao-Ren		272
6	Jia-Wei-Xiao-Yao-San	Suan-Zao-Ren		265
7	Mu-Li	Long-Gu		260
8	Jia-Wei-Xiao-Yao-San	He-Huan-Pi		256
9	Ye-Jiao-Teng	Suan-Zao-Ren		249
10	Gan-Mai-Da-Zao-Tang	Suan-Zao-Ren		240
Triple combination
1	Long-Gu	Suan-Zao-Ren	Bai-He	166
2	Suan-Zao-Ren	Ye-Jiao-Teng	Bai-He	144
3	Suan-Zao-Ren	Bai-He	Wu-Wei-Zi	138
4	Suan-Zao-Ren	Bai-Zi-Ren	Ye-Jiao-Teng	132
	Fu-Shen	Suan-Zao-Ren	Ye-Jiao-Teng	132
5	Bai-Zi-Ren	Ye-Jiao-Teng	Bai-He	129
	Suan-Zao-Ren	Bai-Zi-Ren	Bai-He	129
6	Fu-Shen	Bai-Zi-Ren	Ye-Jiao-Teng	127
7	Fu-Shen	Ye-Jiao-Teng	Bai-He	125
	Fu-Shen	Suan-Zao-Ren	Bai-Zi-Ren	125
	Fu-Shen	Suan-Zao-Ren	Bai-He	125
8	Yuan-Zhi	Bai-He	Shi-Chang-Pu	124
9	Fu-Shen	Bai-Zi-Ren	Bai-He	123
10	Long-Gu	Bai-Zi-Ren	Ye-Jiao-Teng	114

The software NodeXL analyzed the top 100 common combinations of two formulae/single herb for patients with DD to identify the core pattern of the prescriptions, and the result was a combination of three formulae and three single herbs, Gan-Mai-Da-Zao-Tang, Jia-Wei-Xiao-Yao-San, Chai-Hu-Jia-Long-Gu-Mu-Li-Tang, He-Huan-Pi, Yuan-Zhi and Shi-Chang-Pu (Fig. 2).

Fig. 2

The core pattern of Chinese formulae and single herbs usage for depressive disorders. The number of combinations between a certain CHM and co-prescribed CHM was used to determine the width of the line connecting them, and the thicker and darker line showed the more frequently co-prescribed between CHMs in the network.

Discussion

This study investigated the most common formulae and single herbs, as well as the core pattern of the prescriptions for patients with only a diagnosis of DD in Taiwan. As presented in Table 2, the most commonly prescribed formula for DD was Gan-Mai-Da-Zao-Tang. A previous study has reported that Gan-Mai-Da-Zao-Tang decoction was able to ameliorate depressive-like behaviors, attenuate glutamate levels, and enhance expression of N-methyl-D-aspartate receptors in the frontal cortex and hippocampus of unpredictable chronic mildly stressed rats, as well as decreasing immobility times and regulating the concentration of monoamines using a forced swimming test model. In other animal studies, this formula has been shown to have a sedative effect and lengthen the hexobarbital sleeping time, as well as inhibiting sodium, calcium and potassium currents in neurons, in associated with a local anesthetic action using a nerve fiber model. A meta-analysis found that Gan-Mai-Da-Zao-Tang was as efficient as antidepressants; furthermore, when combined with antidepressants, Gan-Mai-Da-Zao decoction showed an increased effectiveness, as well as a reduction in side effects, both compared to antidepressants alone.

The next most commonly prescribed formula was Jia-Wei-Xiao-Yao-San, which has been widely used in TCM to treat psychological disorders including depression, sleep disturbances, and anxiety disorder. Reportedly, Jia-Wei-Xiao-Yao-San has an antidepressant-like effect when animal models of depression are used via a hippocampal neurogenesis mechanism. In addition, other experimental studies have identified anxiolytic, antioxidant, neuroprotective, anti-inflammatory effects of Jia-Wei-Xiao-Yao-San. In clinical trial studies, the formula has been shown to effectively improve the quality of sleep in peri- menopausal and post-menopausal women, to improve depression in patients with premenstrual dysphoric disorder, and to reduce vasomotor and psychological symptoms in climacteric patients.

The third most commonly used formula was Chai-Hu-Jia-Long-Gu-Mu-Li-Tang. This formula was shown by Kazushige Mizoguchi et al. to attenuate chronic stress-induced abnormalities of the hypothalamic-pituitary-adrenal axis, which has been shown to be related to depression. In another study by the same authors, the results indicated that Chai-Hu-Jia-Long-Gu-Mu-Li-Tang is able to relieve chronic stress-induced depressive state via preventing dysfunction of the prefrontal cortex. Additionally, this formula has been shown to decrease corticosterone levels during psychological stress and conditioned-fear stress using a mouse model. which implies that this formula could be useful when treating stress that involves emotional factors.

In Taiwan, TCM physicians frequently use Tian-Wang-Bu-Xin-Wan, Suan-Zao-Ren-Tang, and Wen-Dan-Tang for the treatment of sleep disorders. Experimental studies have suggested that Tian-Wang-Bu-Xin-Wan is able to promote sleeping using hyposomnia models. In human study, Tian-Wang-Bu-Xin-Wan showed a significant effect when combined with dormancy hygiene education when it was used to treat insomnia patients. Suan-Zao-Ren-Tang would appear to have a sedative effect when tested in pharmacological and clinical studies., When Wen-Dan-Tang is examined, several clinical and case studies have revealed that it is able to relieve the symptoms of somatic disorders and melancholia. The next formula, Yi-Gan-San, has been demonstrated to prevent an accumulation of cerebral Aβ while bringing about a reduction in anxiety-like behaviors; these were preclinical studies. Other recent studies have found that this formula improves the quality of sleep when psychological insomnia is present, as well as being able to ameliorate the psychiatric symptoms of both dementia and borderline personality disorder, including low mood, anxiety, and irritability., A meta-analysis found that a combination of Gui-Pi-Tang and antidepressants was able to ameliorate the depressed symptoms better than antidepressants alone. Finally, Ban-Xia-Hou-Po-Tang in a number of current studies and case reports has been shown to be effective when treating depression, anxiety, and insomnia.

Most of the common formulae in this study are frequently used by TCM practioners to treat insomnia, depression, and anxiety, the exception being Wu-Zhu-Yu-Tang. By way of contrast, the latter formula is widely used to treat headache and migraine. Experimental studies and randomized controlled trials have reported that it is useful when treating headache., This formula also has an anti-emetic effect when tested using animal models. Thus, TCM physicians may be using Wu-Zhu-Yu-Tang to treat the physical symptoms of DD, including headache and nausea, rather than the depression itself.

Table 3 presented the top ten most frequent single herbs used for DD in Taiwan. The most commonly prescribed single herb for DD from 2002 to 2011 was Suan-Zao-Ren. Sanjoinine A, one of Suan-Zao-Ren active compounds, has been shown to have an anti-anxiety effect using a mouse model; it seems to act increasing chloride influx, activating GAD65/67 expression, and thus increasing GABA transmission. Another main constituent of this herb is jujuboside, and this has been reported to have a sedative-hypnotic effect.

Da-Huang is used as a purgative medicine in TCM and is often used to treat constipation. Modern experimental studies have proven that rhubarb, the main component of Da-Huang, increases the contractile frequency of gastric body circular muscle and improves gut motility., According to the study of Haug et al., depression is often associated with constipation. Lifestyle and diet changes during depression such as a decrease in physical activity, the consumption of a lot of foods that are high in sugar or fat, and/or a loss in appetite, might be the reasons for constipation in depressive patients. In addition to the above, one of the side effects of antidepressants is constipation and therefore it seems likely that TCM physicians might be using Da-Huang to relieve these symptoms/side-effects in depressive patients.

Yuan-Zhi has been shown to have antidepressant, anti-stress, anxiolytic, sleep-enhancing, and anti-inflammatory activities. The underlying mechanisms would seem to include increasing the expression of CAM-L1, pCREB and BDNF in the hippocampus, protecting and bring about the proliferation of neurons, inhibiting norepinephrine in locus coeruleus, stimulating various GABAergic systems, suppressing various noradrenergic systems, and restraining the NF-κB/MAPK pathways. Moreover, several main chemicals in Yuan-Zhi, including polygalasaponin XXXII and onjisaponin B, have been shown to ameliorate cognitive impairments using in vivo studies.,

Studies about TCM for the treatment of insomnia have indicated that Ye-Jiao-Teng is one of the most frequently used herbs used to treat sleep disorders. In TCM terms, its action is related to the nourishment of the Heart Yin and Blood, as well as calming the Spirit; thus, it could be affecting the Heart Yin Deficiency or Heart Blood Deficiency that are associated with insomnia and irritability. In addition, Ye-Jiao-Teng has shown to have a sedative-hypnotic effect using mouse and rat models as well as showing anti-oxidant activity in an in vitro study.

The major constituents of Bai-He and He-Huan-Pi have been reported to have antidepressant effects., Two recent in vivo studies have revealed that He-Huan-Pi had an anti-anxiety effect via the regulation of neurotransmitters and the serotonergic nervous system. Additionally, a study used a Chinese formula that consisted of He-Huan-Pi, Suan-Zao-Ren, Bai-Shao and Bai-Zi-Ren using a depressed mice model indicated that this formula was able to reduce the immobility time of depressed mice by inhibiting the monoamine oxidase enzyme system, as well as by increasing serotonin and noradrenaline levels.

If we examine research available on Dan-Shen, a pharmacological study has shown that it has a sedative-hypnotic effect when combined with Suan-Zao-Ren; the results suggest that a combination of these two herbs prolongs sleeping time, as well as reducing sleep latency. Magnesium lithospermate B, the active compound extracted from Dan-Shen, has been reported to have an antidepressant-like effect using a rat model. Furthermore, curcumin, which is the main component of Yu-Jin has been shown to reduce depression and anxiety symptoms. The possible mechanisms behind this antidepressant activity of curcumin seem to be a promotion of hippocampal BDNF and ERK levels. In this context curcumin also has anti-inflammatory effects, enhances neurotransmitters, and suppresses monoamine oxidase. Finally, Fu-Shen has a long history in TCM of being used for the treatment of insomnia and memory disorders.

In TCM, one disease can include various TCM syndromes and these are used to guide the practitioner toward a treatment principle and whereby to specific herbs and herbal formulae that can be used for treatment. However, one formula or one single herb alone may not alleviate all the symptoms or signs with different severity the patients have because there are differences in the effects and targets of each formula or each single herb. In addition, as mentioned above, DD is through to involve various mechanisms. Therefore, TCM physicians often combine different formulae and single herbs to enhance the treatment depending on a specific patient's symptoms and signs. In this study, we aimed to investigate in clinical practice which formulae and single herbs TCM physicians usually combine together to treat DD; thus, the hundred most common combinations found in formulae and single herbs were analyzed to examine the core prescription pattern used to treat DD. The results showed that the core pattern was the association of Gan-Mai-Da-Zao-Tang, Jia-Wei-Xiao-Yao-San, Chai-Hu-Jia-Long-Gu-Tang, He-Huan-Pi, Yuan-Zhi and Shi-Chang-Pu (Fig. 2). In the famous classic TCM book “Essentials from the Golden Cabinet” Gan-Mai-Da-Zao-Tang is mentioned as a treatment for “Zang Zao” one of the traditional terms for DD. On the other hand, Jia-Wei-Xiao-Yao-San has been used to treat Liver Qi stagnation by turning it towards Heat when there is underlying Spleen and Blood Deficiency, which is also related to depressive disorders. The clinical manifestations associated with Chai-Hu-Jia-Long-Gu-Mu-Li-Tang include anxiety, insomnia, irritability, agitation, depression, fatigue and so on. In modern studies, these three formulae have been found to have anti-depressant as well as sedative effects via a variety of mechanisms. As discussed above, He-Huan-Pi and Yuan-Zhi seem to alleviate depression-like or anxiety-related behaviors, as well as reduce inflammatory activity, when tested using animal models. In addition, Yuan-Zhi gas been shown to ameliorate cognitive impairment, which ought to be helpful when treating DD. Rhizoma Acori Tatarinowii, used in TCM as Shi-Chang-Pu, has been shown to have antidepressant activity both in vivo and in vitro. Moreover, Yuan-Zhi and Shi-Chang-Pu together have been demonstrated to have an anti-amnestic effect on memory impairment. In summary, because DD involve many different biological mechanisms and no single formula or single herb is able to affect all the pathways involved in a given disease, a combination of a number of different TCM medicines is necessary. Moreover, several previous studies in Taiwan have shown that a combination of several formulae and single herbs could improve some diseases., Therefore, the core pattern described in Fig. 2 provides a significant number of potential candidates that can be used in the future in new pharmacological/clinical trials targeting DD.

There are some limitations to this study. Firstly, this study did not include folk medicines or herbal diets that may have been directly purchased by patients from TCM herbal pharmacies; thus, the use of CHM among depressed patients might have been underestimated. Secondly, this study has only focused on the utilization of CHM in patients with DD; specifically, the utilization of acupuncture, and/or various other TCM treatments, which may also have been offered by TCM practitioners, at the same time as the TCM, in order to treat depression, are not included in this study and have not investigated.

In conclusion, this study describes the Chinese herbal medicine prescription patterns of patients with DD. Gan-Mai-Da-Zao-Tang is the most commonly prescribed formula, and Suan-Zao-Ren is the most commonly prescribed single herb. The core prescription pattern comprises Gan-Mai-Da-Zao-Tang, Jia-Wei-Xiao-Yao-San, He-Huan-Pi, Yuan-Zhi, Shi-Chang-Pu, and Chai-Hu-Jia-Long-Gu-Mu-Li-Tang. Although previous studies have shown that CHM can be efficacious in relieving the symptoms of DD, there have been only a limited number of such studies, and often their quality is low. Therefore, further pharmacological studies, as well as clinical trials, need to be conducted to examine the mechanisms, the efficacy and the safety of this CHM core prescription pattern in depression treatments.