Malignant syndrome or withdrawal reaction?

Wenzheng WANG, Hui WEN, Jianhua SHENG*

·Case report·

Malignant syndrome or withdrawal reaction?

Wenzheng WANG, Hui WEN, Jianhua SHENG*

clozapine, schizophrenia, malignant syndrome, withdrawal reaction

1. Case history

The female patient was 45 years old. Her onset age was 17 years old and the course of her disease has been 28 years. She has been hospitalized for 6 times,and was diagnosed as schizophrenia for several times.She was also once diagnosed as affective disorder 27 years ago. Since 2000, the patient has started to take the treatment of clozapine (75 mg Bid), chlorpromazine(100 mg Bid), lithium carbonate (0.5 g Qd), and trihexyphenidyl (2 mg Tid). Her disease was controlled stably. Before the onset in this report, the patient had not taken medicine regularly for one and a half months.She appeared out of thin air dialogue, suspected tracking, excited talk, and messy speech 4 days before the admission to hospital. So she was hospitalized for the seventh time in February 17th, 2016.

After the ward round in three levels, the patient was diagnosed as “undifferentiated schizophrenia”.Clozapine (dose was added from 150 mg/d to 350 mg/d in 14 days), risperidone (dose was added from 2 mg/d to 5 mg/D in 11 days), and modified electroconvulsive therapy (MECT, 12 times in 25 days) were used to control psychiatric symptoms, but the curative effects were poor. The patient was always in an excited status with incongruous spirit athletic, and appeared delusion,excited talk too much, love nosy, and extreme lack of coordination on emotional reaction (sometimes laugh,sometimes cry). Therefore, the treatment prescription was adjusted to stop using risperidone and increase the dose of clozapine. The dose of risperidone reduced from 5 mg/d to zero in 11 days, and the dose of clozapine increased from 350mg/d to 450 mg/d in 2 days.However, the effect was not obvious, and the patient was always restrained because of her words and deeds disorder. Then the treatment prescription was adjusted one more time which clozapine was used to combine with chlorpromazine (double chlorine treatment): the dose of clozapine was reduced to 400 mg/d, and the dose of chlorpromazine was added from 250 mg/d from 100 mg/d in 5 days. After the treatment of double chlorine, the patient’s mental symptoms were improved 33 days after admission to hospital which she did not appear any delusion and excited talk relieved.

At the 37thday (March 25) after admission, the patient suddenly appeared soft spirit, dull eyes, and high tension of upper extremity muscle. We decreased the dosage of the medicine and used Trihexyphenidyl therapy at the same time. One day after the patient’s condition change, she began to appear silent, so we reduced the dose of clozapine from 400 mg/d to 325 mg/d. Thereafter, patient was still in the status of silence, so we continued to adjust the dosage of drugs.Two days after the patient’s condition change, the dosage of clozapine has been reduced from 325 mg/d to 250 mg/d and chlorpromazine from 250 mg/d to 200 mg/d. Since the patient was still in a status of tense and silence, we gradually reduced the dose of chlorpromazine from 200 mg/d to withdrawal in 5 days. Eleven days after the patient’s condition change, the patient began to appear sweat, contact noncooperation, no answer to question, difficult understand the thinking. Body check: normal vital signs (body temperature 36.5oC, heart rate 86 beats/min, respiratory 20 times/min, blood pressure 110/80 mmHg), deep reflection existing, muscle tension increased but not tonic. Secondary check: white blood cells increased, neutrophile granulocyte count and proportion increased (WBC: 13.5*109, neutral cells:12.32*109, neutrophil proportion: 91.1%), normal creatine kinase (93 IU/L, normal range is 26-140 IU/L),and the CT results of brain at that day showed no obvious abnormalities. Therefore, we suspected that the patient might have atypical malignant syndrome,and immediately withdrew clozapine (250 mg/d).Thereafter, the patient appeared obvious sweating,swallowing difficult, and creatine kinase slightly elevated condition changes after 12 days of condition changes.At the 14thday after condition changed, the report of drug concentrations in blood indicated that clozapine concentration was 917.7 ng/ml↑ (normal range 350-600 ng/ml) and chlorpromazine concentration was 26.5 ng/ml (normal range 22-246 ng/ml). At the 17thday, the patient appeared urinary retention. During those days, we kept to withdraw the antipsychotic drugs and provided nutrition supplement and anti-infection treatment. At the 18thday after condition changed, the director made the rounds of the wards and considered patients had a withdrawal reaction. So we treated her with clozapine from 50 mg/d to 125 mg/d in 8 days. The patient’s body symptoms improved obviously, sweating relieved, myocardial enzyme spectrum gradually declined, and white blood cell approaching below 10*109/L. Since the patient did not get significantly improvement in silence, we provided MECT treatment combined with aripiprazole at the 26thday after the condition changed. The dosage of aripiprazole was from 10 mg/d to 15 mg/d within 2 days. Twenty nine days after the condition changed, the patient had improvement in silence and could make simple talk but lack of thinking expression. Thirty nine days after the condition changed, the patient’s silent condition became remission, and admitted the existence of some verbal hallucination. Since she was in stable mood, the patient moved in the ward class II (clozapine 150 mg/d,aripiprazole 15 mg/d). When we asked the patient if she had verbal hallucination when she was in the status of silence, the patient said she did not remember. This might be associated with modified electroconvulsive which resulted in memory disorders. The patient’s body temperature was in the normal range (36.6oC-37oC)during the process of condition changed.

2. Discussion

Neuroleptic malignant syndrome (NMS) is a rare but serious adverse drug reaction associated with antipsychotic drug treatment, which can be fatal. It usually happened during a large increase in the number and dosage of antipsychotic drugs in short time,especially for the drug with high effectiveness. Patients will appear high fever, muscle rigidity, swallowing difficulties, and obvious symptoms of autonomic nervous system. Severe patients will appear disturbance of consciousness, sweat, exhaustion, breathing difficulties, and even death. The results of laboratory examination found increased leukocyte and muscle creatine kinase[1].

Reaction of drug withdrawal is a series of psychiatric symptoms and somatic symptoms, which appear in a sudden stop the using of antipsychotic drugs.Especially clozapine has a complex mechanism and its anti cholinergic action is strong, so the probability of the effect of clozapine withdrawal is high. The withdrawal effects include many serious symptoms of mental activity disorder, including cognition, mood,behavior, and consciousness, and of autonomic nerve dysfunction, including insomnia, restlessness, behavior disorders, gastrointestinal tract symptoms, disturbance of consciousness, abnormal muscle tone, insomnia, and hallucinations[2]. Withdrawal reaction mostly occurred at the 1st- 2ndday (the 5thday is the longest) after stopping drugs. The peak time is usually in the first week, and then the effects gradually dropped. There is a limit in the withdrawal reaction[3]. It usually disappears within 2 weeks, and few cases take longer than 3 weeks.

The patient with refractory schizophrenia was treated with clozapine combined with risperidone and MECT. Since the treatment obtained poor curative effect, we changed to treat her with double chlorine.The patient’s condition changed during the double chlorine treatment. The director concluded that the patient’s symptoms changed processed two stages. The first of all was soft spirit, silence, no fever, sweating,normal level of white blood cells and creatine kinase in the results of laboratory examination. We considered the stage as the side effects of high level of the diclofenac concentration in the blood. The other stage was that the patient was still in a status of silence,sweating, urinary retention, increased white blood cells and creatine kinase in the results of laboratory examination. We considered it should be the withdrawal reaction of the discontinuation of clozapine (250 mg/d). The deterioration of the condition is easy to be confused with the malignant syndrome. The patient appeared the symptoms of spirit soft, sweating, urinary retention, and swallowing difficulty. In addition, the laboratory examination showed that the white blood cells and myocardial enzyme spectrum increased.Therefore, we could not exclude malignant syndrome.Although the patient did not have significantly increased body temperature and myotonia, there were several studies mentioned that early symptoms of malignant syndrome could be not typical[4]. In some cases,malignant syndrome even does not appear myotonia or fever, and the level of muscle enzymes does not increase greatly, either. In our case, after we stopped using clozapine on the patient, the symptoms did not improve significantly, while the white blood cell and creatine phosphate kinase increased which was contrary to the symptoms of malignant syndrome. In addition,the symptoms changed during the process of stopping the use of antipsychotic drugs, not of adding drugs, so we considered it as withdrawal reactions because of sudden discontinuation of clozapine (250 mg/d).

The common dosage of clozapine is 300-450 mg,and chlorpromazine in the treatment of acute dose is 200-600 mg. The highest dose of clozapine used on the patient was 450mg, and chlorpromazine was 250mg. Why did those doses cause a high blood drug concentration? This may be related to the metabolism of the two drugs. We conducted clozapine gene detection on the patients. The results showed that 06CYP2D6（2850C ＞T）: CC, 08CYP2D6（100C ＞T）TT,10CYP2D6（1758G ＞A）: GG, which indicated that the patient was CYP2D6 intermediate metabolizes (IM) with decreased activity enzyme. Since chlorpromazine is also the metabolic substrates of CYP2D6D, double chlorine treatment leaded to a high drug concentration which resulted in the serious adverse reactions. This suggested that we should combine the monitoring of drug concentration with the conditional gene detection in the future clinical work, so that the adjustment of drug dosage will be more effective and safe. Clozapine and chlorpromazine usually have more adverse reactions,so we should be careful to use them and strengthen the monitoring.

Whatever it is malignant syndrome or clozapine withdrawal reactions, the consequences are extremely dangerous. Clinicians should identify the two kinds of syndrome. From the view of treatment, malignant syndrome and withdrawal reaction caused by clozapine is completely different. Once malignant syndrome occurs, all antipsychotic medications need to stop immediately, while withdrawal reactions of clozapine occurs, low dose of clozapine need to be applied,especially the symptom of delirium can quickly relieve after continually using small dose of clozapine[5].Therefore, in order to avoid the appearance of malignant syndrome, we should pay attention to the speed and dosage in the process of anti psychotic drugs adding, especially for the first generation of the antipsychotic drugs with highly effectiveness. On the other hand, in order to avoid the drug withdrawal reaction, withdrawal process of clozapine has to be slow which can be completed withdrew after the dosage decreased at 12.5-25 mg/d.

In addition, there is another issue that needs to be discussed. The common diseases of silent state include organic disease, schizophrenia, and depression. Why did not we consider the case as depression? Silent state caused by depression usually does not appear disobeying and has normal muscle tension. Depressed patient could give slight answer when asked. However,the patient in this case had not only silent state, but also increased muscle tension, urine retention, no talk,motionless, no eat, and no drink. Therefore, we did not consider her as depressive episode.

Since clozapine may cause lack of agranulocytosis,and other atypical antipsychotic drugs have been widely used in clinical, clozapine is not the first choice of antipsychotic drugs. A lot of patients who used to be treated with clozapine may consider changing the drugs.Therefore, the withdrawal reaction of clozapine needs more clinical attention.

Conflict of interest statement

The authors declare that they have no conflict of interest related to this manuscript.

Funding

No funding support was obtained for preparing this case report.

Informed consent

The patient signed an informed consent form and agreed to the publication of this case report.

Authors’ contribution

WWZ was in charge of article writing. WH and SJH were in charge of article proofing.

Reference

1. Jiang KD. [Psychiatry]. Beijing: People’s Medical Publishing House; 2005. P. 342. Chinese

2. Wang ZL. [Withdrawal of clozapine]. Shanghai Arch Psychiatry. 2009; 21: 58-59. Chinese. doi: http://doi.med.wanfang.com.cn/10.3969/j.issn.1002-0829.2009.01.019

3. Wu GJ, Yi ZH, Zhu LP. [A survey on withdrawal symptoms of clozapine]. Lin Chuang Jing Shen Yi Xue Za Zhi. 2004; 14(5):284-285. Chinese. doi: http://dx.chinadoi.cn/10.3969/j.issn.1005-3220.2004.05.012

4. Guo YE, Jia JJ, Tan JP, Shi XB, Guan JP. [A case report of atypical neuroleptic malignant syndrome and review of the literature]. Xian Dai Sheng Wu Yi Xue Jin Zhan. 2012; 12(5):925-926. Chinese

5. Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases.J Clin Psychiatry. 1997; 58(6): 252-255

Dr. Wenzheng Wang graduated from Shanghai Jiaotong University in 2014 with a doctor’s degree in clinical medicine. Since 2009, she has worked at the Shanghai Mental Health Center as a resident physician. Her research interest is substance abuse, especially alcohol and tobacco abuse.

恶性综合征还是撤药反应？

王文政，闻晖，盛建华

氯氮平，精神分裂症，恶性综合征，撤药反应

We reported that a female patient occurred serious side effects in the treatment of antipsychotic drug, clozapine and chlorpromazine, and then appeared withdrawal reactions after she suddenly withdrew clozapine. During the treatment process, she was misdiagnosed as malignant syndrome, so clinicians need to identify the malignant syndrome and withdrawal reaction, and be familiar with the methods of treatment and prevention.

[Shanghai Arch Psychiatry. 2016; 28(4): 227-229.

http://dx.doi.org/10.11919j.issn.1002-0829.216048]

Shanghai Key Laboratory of Major Mental Health Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University Medical College, Shanghai, China

*Correspondence: Dr. Sheng Jianhua. Mailing address: RD Wanping 600, Shanghai Mental Health Center. Postcode: 200030. E-mail: sjh-lyl@263.net

概述：我们报告一名女性患者在抗精神病药物过程中使用氯氮平和氯丙嗪出现严重的不良反应，随后患者氯氮平的突然停药后出现撤药反应。在处理过程中曾误诊为恶性综合征，因此临床医生需要识别恶性综合征及撤药反应，熟悉处理及预防方法。