Clinical Study on Fuzi Lizhong Pill in Treating Salivation after Taking Clozapine for Schizophrenia

Tiancheng JIA, Zhe HONG, Zhilian PI, Chunhe MA

Department of Psychiatry, Fourth People’s Hospital of Jiande City, Jiande 311612, China

Abstract [Objectives] To observe the clinical effect of Fuzi Lizhong pills for salivation after taking clozapine in schizophrenia. [Methods] A total of 45 cases of schizophrenia patients with salivation after taking clozapine only were selected as the study subjects and randomly divided into two groups according to enrollment order. The control group (22 cases) was treated with propantheline bromide tablets and the treatment group (23 cases) were treated with Fuzi Lizhong pills combined with propantheline bromide tablets. Clinical effects and adverse reactions were compared between the two groups. Chinese medicine syndrome scores, scores of severe degree of salivation and levels of serum cholinesterase were compared between the two groups before treatment, after one-week treatment and after two-week treatment. [Results] The total clinical effective rate was 86.96% in the treatment group，higher than that of 59.09% in the control group (P<0.05). When compared with those before treatment, Chinese medicine syndrome scores of short breath and lack of strength, lassitude of spirit and somnolence, poor appetite, spontaneous sweating and dyspnea, and salivation as well as scores of salivation in Rating Scale for Extrapyramdal Side Effects (RSESE) and the severe degree of salivation in the two groups were decreased after 1 week and 2 weeks treatment (P<0.05), and levels of serum cholinesterase were increased (P<0.05). When compared with those in the control group after one-week and two-week treatment, Chinese medicine syndrome scores of short breath and lack of strength, lassitude of spirit and somnolence, poor appetite, spontaneous sweating and dyspnea, and salivation as well as scores of salivation in RSESE and the severe degree of salivation in the treatment group at the same period were lower (P<0.05), and level of serum cholinesterase was higher (P<0.05). There was no significant difference in the comparison of incidence of adverse reactions between the two groups (P>0.05). [Conclusions] Fuzi Lizhong pills combined with propantheline bromide tablets can improve clinical symptoms of schizophrenia patients with salivation after taking clozapine, and enhance level of serum cholinesterase and clinical effect.

Key words Schizophrenia, Clozapine, Salivation, Fuzi Lizhong pill, TCM syndrome score, Safety

1 Introduction

Clozapine is one of the most effective drugs for refractory schizophrenia. Clozapine is often used in schizophrenic patients for which other antipsychotics are ineffective. However, the adverse reactions of clozapine occupy the top 5 of antipsychotics, in which salivation is a common adverse reactions of clozapine in nervous system, accounting for 30.23% of all adverse reaction of nervous system[1]. Salivation affects patients’ self-esteem and social interaction, and in serious cases, it can cause aspiration pneumonia or even asphyxia at night[2]. It is very important and necessary to take effective measures to treat salivation. At present, there is a lack of effective methods in the treatment of salivation in western medicine, and the adverse reaction of western medicine in the treatment of salivation is large. Traditional Chinese medicine has a far-reaching understanding of salivation, and it is recorded inPlainQuestions:ClarificationofFive-Qithat the viscera change into liquid, spleen for saliva, kidney for spit. Yang deficiency of spleen and kidney can lead to excessive salivation. In the treatment of salivation, warming the kidney and invigorating the spleen, replenishing qi and invigorating body fluid should be used. Fuzi Lizhong pill evolved from Lizhong pill and mankshood, which has the effect of warming the spleen and stomach to dispel cold, replenishing qi and invigorating spleen and kidney[4], and is used in clinical treatment of vomiting, diarrhea and salivation[5]. However, there are few reports on the application of Fuzi Lizhong pill in the adverse reactions of salivation caused by clozapine. therefore, we observed the efficacy and safety of Fuzi Lizhong pill in the treatment of salivation caused by clozapine for schizophrenia.

2 Clinical data

2.1 Diagnostic criteriaWe refer to the diagnostic criteria of schizophrenia in theAmericanDiagnosticandStatisticalManualofMentalDisorders[6]. One of the first three (delusions, hallucinations, speech disorder, abnormal behavior or apathy, hypobulia) and any other one, lasting for more than one month; social or professional dysfunction; excluding the physiological effects caused by mental, material and physical diseases, emotional and mental disorders.

2.2 Standard of syndrome differentiationWe refer to the syndrome differentiation standard on deficiency of heart and spleen in theGuidingPrinciplesofClinicalResearchofNewDrugsofTraditionalChineseMedicine(Trial)[7]. Main symptoms: shortness of breath, fatigue, loss of appetite. Secondary symptoms: spontaneous sweating, asthma, salivation, fat white tongue, deep pulse.

2.3 Inclusion criteriaPatients meeting the above diagnostic and syndrome differentiation criteria. After taking clozapine alone, RSESE (Rating Scale for Extrapyramidal Side Effects)[8]score (for saliva) ≥ 3 points; all the patients’ immediate family members know and agree to this study and sign the consent form.

2.4 Exclusion criteriaPregnant or lactating women; patients with chronic basic diseases such as hypertension, heart disease, liver disease and diabetes; patients with acute and chronic infections such as colds, upper respiratory tract infections, and pneumonia; patients with allergies.

2.5 General information45 patients with schizophrenia who had salivation after taking clozapine alone in the Department of Psychiatry of the Fourth People’s Hospital of Jiande City from January 2019 to December 2019 were randomly divided into two groups according to the order of enrollment. There were 23 cases in the treatment group, including 14 males and 9 females; the age ranged from 35 to 62 years, with an average of (49.35 ±8.59) years; the course of disease ranged from 3 to 10 d, with an average of (6.02 ±2.59) d; the RSESE score was 3-4 points, with an average of (3.42±0.39)points. There were 22 cases in the control group, including 13 males and 9 females; the age ranged from 39 to 65 years old, with an average of (50.24 ±5.77) years; the course of disease ranged from 1 to 9 d, with an average of (6.52 ±2.41) d; the RSESE score was 3-4 points, with an average of (3.36±0.37) points. There was no significant difference in the above baseline data between the two groups (P>0.05).

3 Methods of treatment

The use of clozapine was stopped in both groups, and the food not digested easily was prohibited during the treatment period.

3.1 Control groupBromopropylamine Tailin tablets (trade name Probenxin, Xinjiang Pharmaceutical Co., Ltd., Sinopharm Group Co. Ltd., OTC H65020311) were given orally, 15 mg each time, once a day for 2 weeks.

3.2 Treatment groupOn the basis of the control group, Fuzi Lizhong pills were taken orally (Beijing Tongrentang Science and Technology Development Co., Ltd., OTC Z11020053), 9 g each time, twice a day for 2 weeks.

4 Observation index and statistical method

4.1 Observation index(i) The TCM syndrome scores of the two groups before treatment, 1 week after treatment and 2 weeks after treatment were evaluated according to theGuidingPrinciplesofClinicalResearchofNewDrugsofTraditionalChineseMedicine(Trial)[7]. According to the level of the symptoms, the patients were divided into four grades: none, mild, moderate and severe. The main symptoms (shortness of breath, fatigue and anorexia) were assigned with 0, 2, 4 and 6 points respectively, and the secondary symptoms (spontaneous sweating, asthma and salivation) were assigned with 0, 1, 2 and 3 points respectively. The total score was 0-24 points.

(ii) RSESE salivation score and salivation severity score were assessed before treatment, 1 week after treatment and 2 weeks after treatment. RSESE saliva was scored by 0-4 scale, with 0 for normal, 1 for mild, 2 for moderate, 3 for severe and 4 for extremely severe. The salivation degree was evaluated from the time of salivation, the extent of pillowcase saturation in the morning, or oral condition. 0 point for no salivation, 1 point for saturation diameter<10 cm, saliva volume<10 mL; 2 points for saturation diameter<10-20 cm, saliva volume=10-20 mL; 3 points for saturation diameter >20 cm, saliva volume >20 mL[9].

(iii) 3 mL of venous blood (two groups) was collected before treatment, 1 week after treatment and 2 weeks after treatment. The supernatant was collected after 3 000 r/min, 10 cm and 5 min centrifugation. The level of cholinesterase was detected by BS-380 automatic biochemical analyzer (Mindray Medical).

(iv) The drug-related adverse reactions during treatment were recorded, including digestive tract reactions, allergic reactions, liver and kidney function damage,etc.

5 Criteria of curative effect and results of treatment

5.1 Evaluation of curative effectIt was evaluated with reference to theGuidingPrinciplesofClinicalResearchofNewDrugsofTraditionalChineseMedicine(Trial)[7]. Cured: RSESE score dropped to 0; marked: RSESE score decreased by more than 2 points; effective: RSESE score decreased by 1 point; ineffective: RSESE score did not decrease or increase. Total effective rate = number of (cured+marked+effective) cases/total number of cases × 100%.

5.2 Comparison of clinical efficacy between two groupsAs can be seen from Table 1, the total effective rate of the treatment group was 86.96%, which was higher than that of the control group (59.09%) (P<0.05).

Table 1 Comparison of clinical efficacy between two groups (case, %)

5.3 Comparison of TCM syndrome scores before treatment, 1 week after treatment and 2 weeks after treatment between two groupsAs can be seen from Table 2, compared with those before treatment in the same group, the scores of TCM syndromes such as shortness of breath, fatigue, anorexia, spontaneous sweating and asthma and salivation in the two groups decreased 1 week after treatment and 2 weeks after treatment (P<0.05). Compared with the control group at the end of 1 week and 2 weeks, the scores of TCM syndromes such as shortness of breath, fatigue, loss of appetite, spontaneous sweating and asthma and salivation in the treatment group were lower than those in the control group (P<0.05).

Table 2 Comparison of TCM syndrome scores before treatment, 1 week after treatment and 2 weeks after treatment between two groups points)

5.4 Comparison of TCM syndrome scores before treatment, 1 week after treatment and 2 weeks after treatment between two groupsAs can be seen from Table 3, RSESE salivation score and salivation degree decreased in both groups at the end of 1 week and 2 weeks after treatment as compared with those before treatment in the same group (P<0.05); the RSESE salivation score and salivation degree in the treatment group were lower than those in the control group at the end of 1 week and 2 weeks after treatment (P<0.05).

Table 3 Comparison of TCM syndrome scores before treatment, 1 week after treatment and 2 weeks after treatment between two groups points)

5.5 Comparison of serum cholinesterase level before treatment, 1 week after treatment and 2 weeks after treatment between two groupsAs can be seen from Table 4, compared with that before treatment in the same group, the level of serum cholinesterase in both groups increased at the end of 1 week and 2 weeks after treatment (P<0.05); compared with the control group at the end of 1 week and 2 weeks of treatment, the average level of serum cholinesterase in the treatment group was higher than that in the control group (P<0.05).

Table 4 Comparison of serum cholinesterase level before treatment, 1 week after treatment and 2 weeks after treatment between two groups U/L)

5.6 Comparison of the incidence of adverse reactions between two groupsAs can be seen from Table 5, there was no drug allergy or injury of liver and kidney function in both groups. There were 1 case of xerostomia and 1 case of constipation in the treatment group, 1 case of xerostomia, 1 case of blurred vision, 1 case of palpitation and 1 case of headache in the control group. There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05).

Table 5 Comparison of the incidence of adverse reactions between two groups (case, %)

6 Discussion

The mechanism of salivation induced by clozapine is not clear, which may be related to partial activation of M1 receptor, weakening of swallowing function caused by cerebral cortical inhibition, sensitization caused by clozapine, abnormal immunomodulatory mechanism and so on[10]. Bromopropylamine Tailin tablet is one of the anti-salivation drugs, which has a similar effect as atropine. It can control salivation by blocking the acid secretion of M-receptor transplanted stomach. However, Bromopropylamine Tailin tablet can cause adverse reactions such as xerostomia, blurred vision, palpitation, constipation, headache and even similar atropine poisoning, which greatly reduces the clinical efficacy and treatment compliance[11]. According to traditional Chinese medicine, saliva belongs to one of the "five fluids", and the survival of human body fluid is closely related to the five internal organs, in which saliva is closely related to spleen and kidney. Salivation is the oral fluid, which is the essence of the spleen, and the saliva is the essence of the kidney driven by the kidney qi under the tongue. If the movement of the spleen and fixation effect is normal, salivation will not overflow outside the mouth, and if it can not turn into fluid due to spleen Yang deficiency, spleen and stomach deficiency, it will condense into salivation. Salivation belongs to yin, so it is common to salivate at night. Yang deficiency of spleen and stomach, loss of transportation and transformation, and loss of descending and unobstruction will hurt kidney in the long run. Kidney yang is lost in warmth, and water and fluid are lost and overflow in the mouth, causing salivation. Fuzi Lizhong pill originated fromPrescriptionofPeacefulBenevolentDispensaryand was derived from Lizhong pill inTreatiseonFebrileDiseasesby doctors of later generations. In the prescription, mankshood tastes pungent, sweet and hot, returning to the heart, spleen and kidney meridians, which has the effect of returning Yang to save adversity, replenishing fire and soil, invigorating spleen and transportation, dispelling cold and relieving pain; dried ginger tastes pungent and is hot in nature, returning to the spleen, stomach, kidney, heart, lung meridians, which has the functions of warming and dispelling cold, restoring yang and dredging pulse, warming lung and transforming fluid, and is often used for the treatment of abdominal pain, vomiting and diarrhea;C.pilosulagreatly increases the vital energy, tonifies the spleen and stomach, and is used for the treatment of weakness of the spleen and stomach, deficiency of qi and blood, fatigue and weakness of the body, and lack of appetite; white atractylodes rhizome can invigorate the spleen and replenish qi, promote dryness and diuresis, and stop sweating, and is used for the treatment of spleen deficiency, loss of appetite, indigestion, diarrhea, edema and spontaneous sweating. The combined use of various medicines can give full play to the effect of tonifying kidney, warming Yang and invigorating spleen, replenishing qi and essence to stop salivation[12].

The results of this study showed that the score of TCM syndrome and the score of salivation level in the treatment group were significantly lower than those in the control group, indicating that Fuzi Lizhong pill combined with Bromopropylamine Tailin tablets can improve the clinical curative effect and control clinical symptoms. Clozapine has obvious pseudo-choline effect and can affect the level of serum cholinesterase in patients with schizophrenia. Clozapine can increase the level of acetylcholine, maintain the high level of dopamine/acetylcholine, inhibit the activity of cholinesterase and stimulate the cholinergic nerve, resulting in a series of adverse reactions[13-14]. The results of this study showed that the content of serum cholinesterase in the treatment group was higher than that in the control group after treatment. On the one hand, this explains the mechanism of Fuzi Lizhong pill in the treatment of salivation caused by clozapine, on the other hand, it verifies that Fuzi Lizhong pill has unique advantages in the treatment of salivation. Modern studies have shown that white atractylodes rhizome can regulate the level of serum cholinesterase in the rat model of spleen deficiency induced by reserpine[15], indicating that Fuzi Lizhong pill may reduce the symptoms of salivation caused by clozapine by regulating the activity of cholinesterase. The results of this study showed that the total effective rate of the treatment group was higher than that of the control group, which verified the synergistic effect of Fuzi Lizhong pill combined with Bromopropylamine Tailin tablets in the treatment of salivation in patients with schizophrenia caused by clozapine.

To sum up, Fuzi Lizhong pill can improve the salivation symptoms caused by clozapine, improve the level of serum cholinesterase and clinical effect. Adding Fuzi Lizhong pill on the basis of western medicine treatment is one of the ideal schemes for the treatment of salivation in patients with schizophrenia caused by clozapine.