Journal of Affective Disorders 170 (2015) 71–77

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Research report

Herbal medicine for hospitalized patients with severe depressive episode: A retrospective controlled study Lan-Ying Liu a, Bin Feng a,n, Jiong Chen a, Qing-Rong Tan b, Zheng-Xin Chen a, Wen-Song Chen a, Pei-Rong Wang a, Zhang-Jin Zhang c,nn a

Department of Psychosomatics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang, China Department of Psychiatry, Fourth Military Medical University, Xi'an 710032, Shaanxi, China c School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China b

art ic l e i nf o

a b s t r a c t

Article history: Received 24 March 2014 Received in revised form 8 August 2014 Accepted 12 August 2014 Available online 27 August 2014

Herbal medicine is increasingly used in depressed patients. The purpose of this retrospective controlled study was to evaluate the efficacy and safety of herbal medicine treatment of severe depressive episode. A total of 146 severely depressed subjects were selected from patients who were admitted to the Department of Psychosomatics of Tongde Hospital at Hangzhou, China between 1st September 2009 and 30th November 2013. While all were medicated with psychotropic drugs, 78 received additional individualized herbal medicine. The severity of depressive symptoms was measured using 24-item Hamilton Rating Scale for Depression (HAMD-24) at admission and thereafter once weekly during hospital stay. The proportion of patients achieving clinical response and remission and incidence of adverse events were compared. The two groups had similar average length of hospital stay for approximately 28 days and were not different in the use of psychotropic medications. Survival analysis revealed that patients with herbal medicine had significantly higher chance of achieving clinical response [relative risk (RR)¼ 2.179, P o0.001] and remission (RR¼5.866, P o 0.001) compared to those without herbal medicine. Patients with herbal medicine experienced remarkably fewer incidences of physical tiredness, headache, palpitation, dry mouth and constipation, but had a significantly higher incidence of digestive discomfort compared to patients without herbal medicine. These results indicate that additional treatment with individualized herbal medicine enhances antidepressant response and reduces certain side effects associated with psychotropic medications. Herbal medicine is an effective and relatively safe therapy for severe depressive episode (Trial Registration: ChiCTR-OCH-13003864). & 2014 Elsevier B.V. All rights reserved.

Keywords: Herbal medicine Severe depressive episode Psychotherapeutic agents Clinical trial

1. Introduction Depression is a serious mental illness that affects 8–20% of the worldwide population (Ferrari et al., 2012). Although a variety of antidepressant drugs have been developed for the treatment of depressive episode, there still remains a large portion of depressed patients who do not make a full response and experience relapse, often resulting in the worsening and hospitalization (Arroll et al., 2005). A high incidence of adverse side effects has largely hampered the clinical use of conventional agents (Arroll et al., 2005). These limitations have led to a search of alternative treatment strategies.

n

Corresponding author. Tel.: þ 86 571 8997 2003; fax: þ86 571 8885 3199. Corresponding author. Tel.: þ 852 2589 0445; fax: þ 852 2872 5476. E-mail addresses: [email protected] (B. Feng), [email protected] (Z.-J. Zhang). nn

http://dx.doi.org/10.1016/j.jad.2014.08.027 0165-0327/& 2014 Elsevier B.V. All rights reserved.

Over the past two decades, herbal medicine has been increasingly introduced into psychiatry practice (Zhang, 2004). This is particularly apparent in China where Chinese medicine has become an important component in public mental healthcare. For instance, Chinese herbal medicine is often recommended as an adjuvant to depressed patients in order to augment antidepressant efficacy, reduce side effects and comorbid symptoms while they are treated with conventional psychotropic medications (Butler and Pilkington, 2013). Indeed, empirical and experimental evidence suggests that there are numerous herbal medicines possessing the antidepressant potential (Zhang, 2004). There are a large number of clinical studies showing the benefits of herbal medicine in the treatment of various depressive disorders (Butler and Pilkington, 2013). Our controlled trials have demonstrated the clinical efficacy of one herbal preparation called Free and Easy Wanderer Plus (FEWP) in reducing bipolar and unipolar depression and adverse event rates (Zhang et al., 2007a, b). Despite these, the effectiveness and safety of herbal medicine for depression are

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not yet fully delineated, as most published clinical trials lacked rigorous protocol design with significant methodological flaws (Butler and Pilkington, 2013). Tongde Hospital is a leading specialty psychiatric hospital in Zhejiang Province of China. It has long been dedicated to integrating Chinese medicine and conventional medication for individuals with complex mental illness (http://www.zjtongde.com/cms/Default.aspx). Since 2009, the Department of Psychosomatics of this Hospital has developed an herbal medicine treatment protocol for depressed patients. In this retrospective controlled study, we sought to evaluate the efficacy and safety of additional treatment with herbal medicine in severely depressed patients in comparison with conventional psychotropic treatment alone.

admitted to the Hospital due to a severe depressive episode between September 1, 2009 and November 30, 2013. Subjects were excluded from the study if they had: (1) herbal medicine treatment for over 7 days prior to admission; (2) herbal medicine treatment, but the compliance was less than 75% within the designated schedules during hospital stay; (3) received brain stimulation therapy, such as electroconvulsive therapy (ECT), psychotherapy or acupuncture treatment during hospital stay; (4) severe comorbid cardiac, hepatic or renal condition, brain tumors or intracranial spaceoccupying lesions; (5) a history of alcohol or substance abuse within the previous 12 months; or (6) an investigational drug treatment within the previous 6 months.

2.2. Psychotropic and herbal medicine treatment 2. Methods 2.1. Settings and selection of subjects This retrospective controlled study was conducted in Department of Psychosomatics of Tongde Hospital at Hangzhou, China. Subjects were selected from patients who were admitted to the Department between 1st September 2009 and 30th November 2013, on the basis of electronic database. The study protocol was approved by the Medical Ethical Committee of Tongde Hospital and retrospectively registered in www.chictr.org (Trial Registration: ChiCTR-OCH-13003864). All patients and/or their guardians were required to give voluntary, written, informed consent when they were admitted to the Hospital. Subjects were selected for this study if they: (1) were either gender aged 16–75 years; (2) had a diagnosis of severe depressive episode based on the International Classification of Diseases (10th version) (ICD-10), as evidenced by a score of Z35 on the 24-item Hamilton Rating Scale for Depression (HAMD-24) (Hamilton, 1960) or having depression-associated suicidal attempts; and (3) were

Patients who were not medicated at admission immediately received orally administered venlafaxine (VLX), a dual serotonin– norepinephrine reuptake inhibitor (SNRI). VLX dose was initiated at 75 mg/day and escalated to an optimal dose (150–225 mg/day in most cases) within 1 week, depending upon individual patient response, but the maximum dose could not exceed 300 mg/day. This dosing regimen has been widely used for depressive episodes in China (Fang et al., 2010). Patients who were already taking VLX would continue his/her VLX regimen. Those who were taking other psychotropic medications, including other antidepressants, were otherwise required to continue, rearrange or remove certain drugs, depending on patients' condition and psychiatrists' discretion. During hospital stay, most patients were prescribed a combination of VLX and other psychotropic medications for comorbid psychiatric symptoms, such as sleep disturbance, anxiousness and hallucination. Other psychotropic medications included other antidepressants, hypnotics, anxiolytics, antipsychotics and mood stabilizers. The determination of dose, frequency and time of day

Table 1 Herbal medicine formulae for various TCM subtypes of patients with depressive episode. TCM subtypes

Formula name

Liver stagnation with spleenqi deficiency

A combination of Free Wanderer Powder Bupleurum chinense DC. [Chai-Hu, 12], Angelica sinensis (Oliv.) Diels. [Dang-Gui, 9], Paeonia and Pinellia–Magnolia Decoction lactiflora Pall. [Shao-Yao, 12], Glycyrrhiza uralensis Fisch. [Gan-Cao, 6], Pinellia ternata (Thunb) Breit. [Fa-Ban-Xia, 9], Magnolia officinalis Rehd. et Wils [Hou-Po, 12], Poria cocos (Schw.) Wolf. [Fu-Ling, 12], Zingiber officinale Rosc. [Sheng-Jiang, 10], Perilla frutescens (Linn.) Brito. [Zi-SuYe, 12]. Bupleuri-improved Mood Powder Bupleurum chinense DC. [Chai-Hu, 12], Poria cocos (Schw.) Wolf. [Fu-Ling, 12], Cyperus rotundus L. [Xiang-Fu, 12], Citrus aurantium L. [Zhi-Ke, 12], Bupleurum chinense DC. [Chai-Hu, 9], Citrus reticulata Blanco. [Chen-Pi, 9], Prunus mume (Sieb.) Sieb. et Zucc. [Lv-E-Mei, 12], Lilium pumilum DC. [Bai-He, 12], Albizia julibrissin Durazz [He-Huan-Hua, 12], Cynanchum paniculatum (Bge.) Kitag. [Xu-Chang-Qing, 12], Citrus medica L. var. sarcodacylis Swingle [FoShou, 12], Ligusticum chuanxiong Hort. [Chuan-Xiong, 10], Glycyrrhiza uralensis Fisch. [GanCao, 6]. Digestion and Mind invigorated Codonopsis tangshen Oliv. [Dang-Shen, 12], Poria cocos (Schw.) Wolf. [Fu-Ling, 12], Atractylodes Decoction macrocephala Koidz [Bai-Zhu, 12], Astragalus membranaceus (Fisch.) Bunge. [Huang-Qi, 20], Angelica sinensis (Oliv.) Diels. [Dang-Gui, 9], Polygala tenuifolia Willd. [Yuan-Zhi, 12], Curcuma longa L. [Yu-Jin, 12], Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H.F. Chow [Suan-Zao-Ren, 20], Aucklandia lappa Decne. [Mu-Xiang, 6], Ziziphus jujuba Mill. [Da-Zao, 15], Glycyrrhiza uralensis Fisch. [Gan-Cao, 6]. A combination of Six-herb Plus Rehmannia glutinosa Libosch [Sheng-Di-Huang, 12], Ophiopogon japonicus (L.f.) Ker-Gawl. Rehmannia Pill and Yi-Guan Decoction [Mai-Dong, 12], Rehmannia glutinosa Libosch [Shu-Di-Huang, 12], Cornus officinalis Sieb. Et Zucc. [Shan-Zhu-Yu, 12], Dioscorea opposita Thunb. [Shan-Yao, 12], Angelica sinensis (Oliv.) Diels. [Dang-Gui, 9], Lycium barbarum L. [Gou-Ji-Zi, 15], Paeonia suffruticosa Andr. [Mu-Dan-Pi, 12], Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H.F. Chow [Suan-Zao-Ren, 20], Polygala tenuifolia Willd. [Yuan-Zhi, 12], Acorus tatarinowii Schott [Shi-Chang-Pu, 12], Melia toosendan Sieb. et Zucc. [Chuan-Jian-Zi, 6]. Decoction of Gentian Root for Purging the Gentiana manshurica Kitag. [Long-Dan-Cao, 12], Scutellaria baicalensis Georgi [Huang-Qin, 6], liver-heat Gardenia jasminoides Ellis [Zhi-Zi, 12], Alisma orientale (Sam.) Juz. [Ze-Xie, 12], Angelica sinensis (Oliv.) Diels. [Dang-Gui, 9], Rehmannia glutinosa Libosch [Sheng-Di-Huang, 12], Bupleurum chinense DC. [Chai-Hu, 12], Glycyrrhiza uralensis Fisch. [Gan-Cao, 6], Plantago asiatica L. [Che-Qian-Zi, 10], Cristaria plicata (Leach) [Zhen-Zhu-Mu, 30], Apatite [Long-Chi, 20].

Liver stagnation with qi stagnancy

Deficiency of both heart and spleen

Deficiency of Yin (vital essence) of the liver and kidney

Dampness and heat in the liver and gallbladder

Latin binomial and Chinese names of herbs and dosage (g)

L.-Y. Liu et al. / Journal of Affective Disorders 170 (2015) 71–77

of the prescribed medications was based on individual patient's condition and response. Whether patients were additionally treated with herbal medicine was determined by Chinese medicine practitioners, psychiatrists and patients' acceptance in a nonrandomized manner. Five herbal medicine formulas were specifically designed based on traditional Chinese medicine (TCM) diagnostic subtypes of depressive disorders (Table 1). These formulae were derived from classic TCM formulae (Maciocia, 1994), including Free and Easy Wanderer Powder (Xiao-Yao-San in Chinese and Shoyoh-San in Japanese), Pinellia–Magnolia Decoction (Banxia-Houpo Tang in Chinese and Hange Koboku-To in Japanese), Bupleuri-improved Mood Powder (Chaihu-Shugan-San in Chinese and Saiko-Keishi-To in Japanese), Digestion and Mind invigorated Decoction (Gui-Pi-Tang in Chinese and Kihi-To in Japanese), Six-herb Plus Rehmannia Pill (LiuweiDihuang-Wan in Chinese and Rokumi-Gan in Japanese), Yi-Guan Decoction (Yi-Guan-Jian in Chinese) and Decoction of Gentian Root for Purging the Liver-heat (Longdan-Xiegan-Tang in Chinese). Herbs and dosages were adjusted to better meet individual patient's manifestations on a weekly basis. All raw herbal materials were purchased from government authorized Chinese medicine suppliers. Potential hazardous substances, including heavy metals and pesticides, had been tested by suppliers to ensure the quality and safety of herbal materials. The authentication was further done by senior Chinese medicine pharmacists in the Hospital. The herbal medicine was prepared as decoction in an automatic boiling machine. Briefly, raw herbal materials were immersed in a 3-fold volume of distilled water for 30 min and then boiled for 45 min. This process was repeated twice. The extractive solution was pooled and concentrated to a volume equivalent to 300 ml each dose. The resulting decoction was packed in a 150-ml, vacuum-sealed plastic bag (2 bags each dose per day), without adding any other liquids, buffers, stabilizers, or flavorings. The decoction was stored at 4 1C and would be used within 14 days.

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7 days. Assessment for discharge was carried out by at least two psychiatrists. Hospital stay days were counted as a clinical outcome variable. The clinical response is defined as a Z 50% reduction from baseline on HAMD-24. The remission is defined as an HAMD-24 score of r7. The proportion of patients who had achieved the clinical response or remission was compared over the period of hospital stay between the two groups using survival analysis (see below). Safety and tolerability were assessed using the Treatment Emergent Symptom Scale (TESS) (Guy, 1976) and Åsbergs's Side Effects Rating Scale (SERS) (Asberg et al., 1970). Clinical assessments were conducted by a psychiatrist (L.Y.L.) who was blind to herbal medicine treatment. 2.4. Data analysis Our previous studies have shown that additional herbal medicine produced an 84.8% of clinical response, significantly higher than a 63.8% of conventional treatment in patients with major depression (Zhang et al., 2007a, b). In the present study, a sample size of 146 of the two groups (n¼ 68 for conventional treatment and n ¼78 for additional herbal medicine treatment) could provide a greater than 80% power to detect a 21% difference in the clinical response between the two groups at a significant level of 0.01. Kaplan–Meier survival analysis with log-rank test and relative risk (RR) was used to detect longitudinal effects of herbal medicine by comparing the proportion of patients who achieved the clinical response and remission over time between the two groups. Categorical variables, including categorical baseline data, proportion of psychotropic treatment, and incidence of adverse events were analyzed using Chi-square (χ2) test. Continuous baseline data and hospital stay days were analyzed using Student t-test. Statistical significance was defined as a two-sided P value of o0.05. The analyses were performed using SPSS version 16 software (Chicago, IL, USA).

3. Results 2.3. Clinical assessments 3.1. Baseline characteristics of patients Clinical assessment was regularly conducted in the Department. The severity of depressive symptoms was assessed using HAMD-24 at admission (baseline) and thereafter once weekly during hospital stay. The endpoint of the study was discharge from hospital. The criteria for discharge are near or complete remission of depressive symptoms, as evidenced by an HAMD-24 score of r7, or the patients' condition had been stable for at least

Of 1672 patients who were admitted to the Department of Psychosomatics between 1st September 2009 and 30th November 2013, 146 met the inclusion criteria and were included in the study. While all were treated with conventional psychotherapeutic agents, 85 received additional herbal medicine during hospital stay; 7 of them were excluded due to unmet compliance (Fig. 1).

Admitted patients (n = 1672)

Excluded in initial screening (n = 1519): • Did not meet the inclusion criteria (1495). • The diagnosis was undetermined (13). • Had herbal medicine treatment for more than 7 days when admitted (2). • Had brain stimulation and acupuncture treatment (5). • Had severe hepatic and renal diseases (4). Conventional psychotropic treatment only (n = 68)

Additional herbal medicine treatment (n = 85) Herbal medicine compliance less than 75% (n = 7)

Included in analysis (n = 68)

Included in analysis (n = 78)

Fig. 1. Flowchart of selection of study subjects from patients who were admitted to Department of Psychosomatics of Tongde Hospital at Hangzhou, China, between 1st September 2009 and 30th November 2013.

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Baseline characteristics are summarized in Table 2. The proportion of females in the additional herbal treatment group was significantly higher than in the conventional treatment group (P o0.042). Other baseline variables were not different in the two groups. The majority of patients had experienced one depressive episode (78.8%, 115/146) and had psychotherapeutic treatment (78.1%, 114/146) when admitted. Psychotropic medications used included selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants (TCAs), antipsychotics, mood stabilizers and anxiolytics. The baseline severity of depressive symptoms was 43.5 76.7 (mean 7SD).

3.2. Psychotropic treatment during hospitalization The average dose of VLX taken during hospitalization was similar between conventional treatment group (139.1734.1 mg/day, mean7SD) and additional herbal treatment group (134.6741.2 mg/day, P¼0.482). The proportion of patients treated with VLX alone and in combination with other psychotropic medications was not significantly different in the two groups (P¼0.242). The proportion of patients treated with various classes of psychotropic medications was also not different in the two groups (Table 3).

3.3. Clinical efficacy The overall average hospital stay days were similar in the conventional treatment group (27.6 718.2) and the additional herbal medicine-treated group (27.7721.5, P ¼0.969). Survival analysis revealed that the herbal medicine-treated group had a significantly greater chance of achieving a clinical response (RR ¼2.179, P o0.001) and remission (RR ¼ 5.866, P o0.001) compared to that without herbal medicine (Fig. 2).

3.4. Adverse events The adverse events occurred in both groups are summarized in Table 4. Herbal medicine-treated patients experienced significantly fewer incidents of physical tiredness, headache, palpitation, dry mouth and constipation, but had significantly higher incidents

Table 3 The use of psychotropic medications at admission to hospital. Psychotherapeutic agent

Conventional treatment (n¼ 68)

Additional herbal treatment (n ¼78)

P values (χ2 test)

Anxiolytics/hypnoticsa β-blockersb Antipsychoticsc SSRIsd TCAse Mood stabilizersf No. (%) of patients treated withg venlafaxine only venlafaxine and another agent venlafaxine and other two or more agents

51 12 50 14 23 13

66 14 60 13 19 13

(84.6) (17.9) (76.9) (16.7) (24.4) (16.7)

0.213 0.866 0.778 0.693 0.282 0.866

5 (7.4) 23 (33.8)

8 (10.3) 35 (44.9)

0.242

40 (58.8)

35 (44.9)

(75.9) (17.6) (73.5) (20.6) (33.8) (19.1)

a Anxiolytics/hypnotics were principally used for insomnia, including benzodiazepines (alprazolam, clonazepam, estazolam, and lorazepam) and non-benzodiazepines (buspirone, tandospirone, and zolpidem). b The β-blockers, metoprolol and propranolol, were mainly used for arrhythmias. c Antipsychotics included atypical (aripiprazole, quetiapine, olanzapine, sulpiride, and ziprasidone) and typical (chlorprothixene and perphenazine) agents. d Selective serotonin reuptake inhibitors (SSRIs): paroxetine, fluoxetine, citalopram, sertraline and escitalopram. e Tricyclic and tetracyclic antidepressants (TCAs): chlorimipramine and mirtazapine. f Mood stabilizers: lamotrigine, lithium, topiramate and valproate. g Anxiolytics/hypnotics and β-blockers were not accounted in combination treatment.

Table 2 Demographic and clinical characteristics of hospitalized patients with severe depressive episode. Variables

Conventional treatment only (n¼ 68)

Additional herbal treatment (n¼ 78)

P values (t or χ2 test)

Female, n (%) Age (y) Duration of the illness (months)a No. (%) of patients previously experiencing at least one depressive episode, # of episode 1 2–4 Z5 No. (%) of patients having suicidal attempts when hospitalized No. (%) of patients with family members having mental illnesses No. (%) of patients previously hospitalized due to psychiatric diseases, # of hospitalization 1 2 Z3 No. (%) of patients having psychotherapeutic treatment at hospitalizationb SSRIs SNRIs TCAs Antipsychotics Anxiolytics/hypnotics Mood stabilizers Baseline HAMD-24 scorea,c

47 (69.1) 40.1 714.4 65.1 796.8 50 (73.5)

66 (84.6) 44.17 16.1 75.2 7 91.9 65 (83.3)

0.042 0.126 0.521 0.214

11 (22.0) 35 (70.0) 4 (8.0) 4 (5.9) 17 (25.0) 36 (52.9)

15 (23.1) 38 (58.5) 12 (18.4) 2 (2.6) 17 (21.8) 46 (59.0)

12 (33.3) 13 (36.1) 11 (30.6) 45 (66.2)

20 (43.5) 9 (19.5) 17 (37.0) 69 (88.5)

0.209

25 (36.8) 21 (30.9) 10 (14.7) 13 (19.1) 11 (16.2) 5 (7.4) 43.3 7 6.9

30 (38.5) 21 (26.9) 10 (14.7) 22 (28.2) 22 (28.2) 2 (2.6) 43.7 7 6.5

0.968 0.731 0.929 0.276 0.050 0.336 0.729

a

0.243 0.555 0.794 0.576

0.242

Continuous data are expressed mean7 SD. SSRIs, selective serotonin reuptake inhibitors: paroxetine, fluoxetine, citalopram, sertraline, escitalopram, and fluvoxamine; SNRIs, serotonin–norepinephrine reuptake inhibitors: venlafaxine and duloxetine; TCAs, tricyclic/tetracyclic antidepressants: clomipramine, mirtazapine; antipsychotics: aripiprazole, quetiapine, olanzapine, and sulpiride; mood stabilizers: valproate, lamotrigine, and topiramate; anxiolytics: alprazolam, clonazepam, estazolam, tandospirone, and zolpidem. c HAMD-24, 24-item Hamilton Rating Scale for Depression. b

L.-Y. Liu et al. / Journal of Affective Disorders 170 (2015) 71–77

This retrospective controlled study represents a systematic evaluation of the effectiveness and safety of herbal medicine as an additional treatment in depressed patients. Several classic herbal medicine formulae were used in the present study, including Bupleuri-improved Mood Powder and Free and Easy Wanderer Powder, two most commonly prescribed formulae for depressed patients in clinical practice (Butler and Pilkington, 2013). All subjects included in this study were hospitalized due to severe depressive episode. The majority of them had experienced at least one relapse and were taking various psychotropic medications, indicating that most patients' condition was refractory and exacerbated. Although the hospital stay length and the use of psychotropic drugs were similar in patients treated with and without herbal medicine, those receiving herbal medicine showed an approximately 2–5 fold greater chance of achieving a clinical response and remission over the course of hospitalization compared to those without herbal medicine. These results indicate that additional treatment with herbal medicine can enhance the antidepressant response and particularly supports findings of previous studies of Bupleuri-improved Mood Powder (Qin et al., 2013; Wang et al., 2012b) and Free and Easy Wanderer Powder (Qin et al., 2011). However, unlike most previous studies in which a fixed herbal medicine formula was used (Butler and Pilkington, 2013), the present study proposed several specific herbal medicine formulae based on TCM diagnostic subtypes. Certain herbs and dosages were further adjusted in order to better meet individual patient's manifestations and different stages of the development of the disease. This therapeutic pattern represents the important TCM philosophy of individualized or personalized medicine. Individualized treatment is believed to be particularly beneficial for depression which is a highly symptomatic, multi-system heterogeneous disorder (Ward and Irazoqui, 2010). In addition to central serotonin (5-HT) deficiency, neuroendocrine and visceral-autonomic nervous system dysfunction, hypothalamic-pituitary-adrenal axis, cardiac and digestive systems are also heavily involved in the pathogenesis of depressive disorders (Ward and Irazoqui, 2010). TCM diagnostic subtypes somehow reflect such highly heterogeneous symptomatic, multi-system disorder. Therefore, there is reason to expect that herbal mixtures targeting specific symptoms and pathogenesis could produce better treatment outcomes. The superior antidepressant effects achieved in the present study are likely to be related to multiple psychotherapeutic and psychopharmacological properties of herbal medicine. While a large number of studies in animal models have shown the antidepressant effects, anxiolytic and anti-stress effects also have been extensively observed with Bupleuri-improved Mood Powder (Kim et al., 2005; Chen et al., 2013; Xie et al., 2013; Qiu et al., 2014), Free and Easy Wanderer Powder (Mizowaki et al., 2001; Wang et al., 2009; Dai et al., 2010; Yin et al., 2012), Pinellia–Magnolia Decoction (Luo et al., 2000; Li et al., 2003; Guo et al., 2004; Zhang et al., 2004; Wang et al., 2005; Yi et al., 2009) and Digestion and Mind Invigorated Decoction (Nishizawa et al., 1990). Furthermore, Bupleuri-improved Mood Powder shortens pentobarbital-induced sleeping time in mice (Nose et al., 2003) and reduces trigeminal neuralgia in rats (Sunagawa et al., 2001). On the other hand, angelica sinensis, peony root, liquorice root, rehmannia root, polygala root, radix bupleuri and semen zizyphi spinosae are principal herbs constituting the herbal formulae. Extractions and preparations from these herbs not only exhibit competitive binding

Conventional treatment (n = 68)

% of patients achieving clinical response

4. Discussion

affinity at 5-HT1A, 5-HT2, 5-HT3A and 5-HT7 of serotonin (5-HT) receptor subtypes (Hong et al., 2003; Deng et al., 2006b; Yi et al., 2007; Lee et al., 2009), but also modulate other transmitter receptors, including γ-aminobutyric acid (GABA) and dopamine receptors (Liao et al., 1995; Sugiyama et al., 1996; Chung et al., 2002; Deng et al., 2006a; Han et al., 2009; Wang et al., 2012a, b; Jin et al., 2013; Fu et al., 2014). Multi-acting receptor-targeted herbal medicine may provide a novel therapeutic approach for multi-system involved depressive disorders. The present study further revealed that herbal medicinetreated patients experienced remarkably fewer incidences of physical tiredness, headache, palpitation, dry mouth and constipation; all these adverse events are often reported in psychotropic treatment. These results provide direct evidence in support of the

Additional herbal treatment (n = 78)

100 80 60 RR = 2.179 P < 0.0001

40 20 0

100 % of patients achieving remission

of digestive discomfort compared to patients without herbal medicine. No patients discontinued herbal treatment because of digestive problems as they were reportedly mild.

75

80 60

RR = 5.866 P < 0.0001

40 20 0 0

1

2

3

4

5

6

7

8

9

10

Week of treatment Fig. 2. Differences in the proportion of patients achieving the clinical response (A) and remission (B) between the two groups over the course of hospitalization were examined using Kaplan–Meier survival analysis with log-rank test. Clinical assessment was conducted at admission (baseline) and thereafter once weekly during hospital stay. The clinical response is defined as a Z 50% reduction from baseline on total HAMD-24 score. The remission is defined as r7 of an HAMD-24 score. Patients receiving additional herbal medicine had an approximately 2- and 5-fold greater chance of achieving the clinical response and remission, respectively, compared to those without herbal medicine. RR, relative risk.

Table 4 Incidence of adverse events occurred during hospitalization. Adverse event

Conventional treatment (n¼ 68)

Additional herbal treatment (n¼ 78)

Physical tiredness Headache Sleep disturbance Vertigo Palpitations Dry mouth Constipation Somnolence Tremor sweating Digestive discomforta

11 6 2 7 23 26 25 2 4 2 1

3 (3.8) 0 0 8 (10.3) 12 (15.4) 7 (9.0) 15 (19.2) 3 (3.8) 6 (7.7) 7 (9.0) 9 (11.5)

(16.2) (8.8) (2.9) (10.3) (33.8) (38.2) (36.8) (2.9) (5.9) (2.9) (1.5)

P values (χ2 test)

0.025 0.024 0.417 0.790 0.016 o0.001 0.029 0.876 0.918 0.243 0.036

a Digestive discomfort symptoms included abdominal pain and fullness, nausea, vomiting and diarrhea.

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empirical view that herbal medicine can reduce adverse side effects caused by conventional medications. In addition to psychotherapeutic effects, most herbal formulae used in the present study possess immunomodulatory and cytoprotective effects (Yamaguchi et al., 1993; Naito et al., 2003; Lee and Chang, 2010; Gou et al., 2013). Many herbs contained in the formulae have strength- and endurance-improving potentials (Zhang, 2004), including angelica sinensis lily bulb, ophiopogon root, radix astragali, radix ligusticum, poria, radix tangshen and wolfberry fruit. These herbs are often prescribed to treat tiredness and fatigue in clinical practice. Moreover, Bupleuri-improved Mood Powder and Yi-Guan Decoction can protect against liver injury and pancreatic inflammation (Motoo et al., 2000; Su et al., 2001; Horie et al., 2004; Gou et al., 2013) and reduce trigeminal neuralgia (Sunagawa et al., 2001). Bupleuri-improved Mood Powder, Free Easy Wanderer Powder and Pinellia–Magnolia Decoction are effective in treating functional dyspepsia and chronic gastritis (Oikawa et al., 2009; Qin et al., 2009, 2013; Yang et al., 2013). Thus, alleviation of tiredness, headache, palpitation, dry mouth and constipation observed appear to be derived from the broad modulation of immune, digestive and autonomic nervous system functions. However, we also noticed that herbal medicine-treated patients had higher incidence of digestive discomfort symptoms, such as adnominal pain and fullness, nausea, vomiting and diarrhea. Empirical evidence suggests that digestive discomfort is a common adverse event observed in herbal medicine treatment (Dunnick and Nyska, 2013). The use of herbal medicine in patients with digestive dysfunction should be more carefully evaluated. Several limitations of the present study should be considered. First, this was a retrospective study in which investigators and patients were not blind to treatment conditions. Doctor and patient expectation bias on treatment outcomes could not be excluded in the study. We implemented the International Classification of Diseases (ICD) rather than the Diagnostic and Statistical Manual (DSM) for diagnostic criteria. These two instruments may have discrepancies in the diagnosis of depressive disorders (Saito et al., 2010). There was a significantly higher proportion of female subjects in the herbal medicine-treated group than the group without herbal medicine. This may result in gender-associated bias as women have a higher degree of confidence in complementary and alternative medicine efficacy and safety (Barnes et al., 2004). Both TESS (Guy, 1976) and SERS (Asberg et al., 1970) were introduced into assessing adverse events in the 1970s before SSRIs. Not all SSRIs-related side effects could be monitored and recorded with these two instruments. Second, there were 26% of the patients with a first episode of major depression. It may be difficult to differentiate between unipolar and bipolar depression in these first-episode patients. Our previous study has revealed that herbal medicine was effective in treating depression but not mania (Zhang et al., 2007a). Whether there are differences in the clinical response to herbal medicine between patients with bipolar and unipolar depression may need further evaluation. Third, although the present study did not compare dosage and time of days of other psychotropic medications taken due to large variations, the average dose of VLX and the proportion of patients taking VLX alone and in combination with other psychotropic medication were similar in the two groups. Therefore, the better outcomes observed in patients treated with herbal medicine are unlikely to be related to therapeutic effects of other drugs. Whether herbal medicine could reduce adverse side effects of other drugs deserves further investigation. Finally, individualized TCM treatment regimes of the present study were basically developed from TCM doctrine and empirical evidence, rather than modern pharmacological rationales. It is unclear whether the better treatment outcomes were achieved via either pharmacokinetic or pharmacodynamic pathways or both as

herb–drug interactions have been suggested in patients with various psychiatric disorders (Kales et al., 2004; Zhang et al., 2011). It seems difficult to characterize the therapeutic mechanisms, as herbal mixtures contain complex chemical components with diverse biological and pharmacological actions (Zhang, 2004). In addition, although herbal materials used in the present study had been tested for potential hazardous substances, including heavy metals and pesticides, we did not evaluate the quality of the prepared herbal decoctions and batch-to-batch consistency using phytochemical measurement. This is because of large variation of herbal formulae used in individual patients. How to balance individualized treatment regimes and “standardized” herbal preparations needs further investigation. In summary, the present study suggests that additional herbal medicine not only enhances the antidepressant response, but also reduces adverse side effects associated with conventional psychotherapeutic agents in hospitalized patients with severe depressive episode. Herbal medicine can be considered as an effective and relatively safe therapy for depressive disorders. The study also warrants a prospective, randomized controlled trial.

Role of funding source This study was supported by General Research Fund (GRF) of HK Research Grant Council (RGC) (785813, 786611, Z.J.Z.) and HMRF (10111381, Z.J.Z.). These funding agents had no role in this study.

Conflict of interest None has conflict of interest in this research work.

Acknowledgments This study was supported by General Research Fund (GRF) of Research Grant Council (RGC) of Hong Kong (785813 and 786611, Z.J.Z.) and HMRF (10111381, Z.J.Z.).

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