Malignant Syndrome or Withdrawal Reaction?

We report on a case of a female patient who had serious side effects from treatment with clozapine and chlorpromazine and the appeared to have a withdrawal reaction from cessation of clozapine. During the treatment process she was misdiagnosed as having malignant syndrome. This case highlights the importance of clinicians being able to distinguish malignant syndrome from withdrawal reactions, and to be familiar with treatment and prevention methods for both.

1. Case history

The patient was a 45 year old female. Age of onset disease was 17 years old and the course of illness had been 28 years. She had been hospitalized 6 times, and was given a diagnosis of ‘schizophrenia’ several times. The patient had also been previously diagnosed with an affective disorder 27 years ago. Since 2000, the patient received clozapine (75mg Bid), chlorpromazine (100mg Bid), lithium carbonate (0.5g Qd), and trihexyphenidyl (2mg Tid) and her condition had been stable since then. Prior to the episode reported here the patient had not taken medicine regularly for approximately 6 weeks. She was found dialoguing with non-existent persons, suspected that she was being followed, and for 4 days had pressured and chaotic speech. She was hospitalized for the seventh time on February 17th, 2016.

Upon examination and clinical interview the client was given a diagnosis of “undifferentiated schizophrenia”. Clozapine (dose was increased from 150mg/d to 350mg/d in 14 days), risperidone (dose was increased from 2mg/d to 5mg/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 extremely agitated, delusional, and affect was extremely labile (laughing at times, crying at times). Therefore, risperidone was stopped and the dosage of clozapine was increased. The dosage of risperidone was reduced from 5mg/d to 0mg/d over the course of 11 days and the dose of clozapine was increased from 350mg/d to 450mg/d in 2 days. However, the increase in dosage was not effective and eventually the patient had to be restrained due to her disordered behavior. Medication was adjusted again this time clozapine was combined with chlorpromazine (double chlorine treatment): the dose of clozapine was reduced to 400 mg/d and the dosage of chlorpromazine was added starting at 250 mg/d going down to 100 mg/d over the course of 5 days. After double chlorine treatment the patient’s symptoms improved around the 33rd day after admission – she did not present with any delusions and her pressured speech stopped.

At the 37th day (March 25) after admission, the patient suddenly appeared with low energy, dull eyes, and high tension in upper extremity muscles. 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 grow silent, so we reduced the dose of clozapine from 400 mg/d to 325 mg/d. Thereafter, patient was still in the state of silence, so we continued to adjust the dosage. Two days after the patient’s condition change, the dosage of clozapine was further reduced from 325 mg/d to 250 mg/d and chlorpromazine was reduced from 250 mg/d to 200 mg/d. Since the patient was still in a state of tension and silence, we gradually reduced the dose of chlorpromazine from 200 mg/d to complete withdrawal in 5 days. Eleven days after the patient’s condition change, the patient began sweating, was non-cooperative, and had difficulty answering questions. Physical examination results showed: normal vital signs (body temperature 36.5 °C, heart rate 86 beats/min, respiratoration 20 times/ min, blood pressure 110/80 mmHg), muscle tension increased but not catatonic. Secondary physical examination: white blood cells were increased, neutrophile granulocyte count and proportion were increased (WBC: 13.5*10^9, neutral cells: 12.32*10^9, neutrophil proportion: 91.1%), normal creatine kinase (93 IU/L, normal range is 26-140 IU/L), and the CT results of a brain scan showed no obvious abnormalities. Therefore, we suspected that the patient might have an atypical malignant syndrome, and immediately withdrew clozapine (250 mg/d). Thereafter, the patient appeared with obvious sweating, difficulty swallowing, and creatine kinase was slightly elevated after 12 days of condition changes. At the 14th day after her condition changed, blood drug concentration results showed 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). On the 17th day, the patient presented with urinary retention. During those days, we maintained a withdrawal from antipsychotic drugs and provided nutrition supplement and anti-infection treatment. By the 18th day after her condition had changed, the director made the rounds of the ward and judged that the patient was having a withdrawal reaction. So we treated her with clozapine from 50 mg/d to 125 mg/d over 8 days. The patient’s bodily symptoms improved, she stopped sweating, myocardial enzyme spectrum gradually declined, and white blood cell count was below 10*10 ^9/L. Because the patient’s silent status did not resolve we provided MECT treatment combined with aripiprazole on the 26th day after her condition changed. The dosage of aripiprazole was increased from 10 mg/d to 15 mg/d within 2 days. Twenty nine days after the condition changed, the patient had slight improvement in her silent state and could speak very simply but lacked the ability to express anything complex. Thirty nine days after her condition changed, the patient’s silent condition went into remission, and she admitted the existence of some verbal hallucination. Since she was in a stable mood, the patient was reclassified as ‘level II’ within the ward (i.e. treatment of clozapine 150 mg/d and aripiprazole 15 mg/d). When we asked the patient if she had verbal hallucinations when she was in the state of silence she said she could not remember, though this may be slight memory loss resulting from the modified electroconvulsive therapy. The patient’s body temperature was in the normal range (36.6 °C-37 °C) during the process of her condition changing.

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 happens where there is a large increase in dosage over a short period of time, especially with the more potent antipsychotic medications. Patients present with high fever, muscle rigidity, swallowing difficulties, and prominent symptoms of the autonomic nervous system. Severe patients will present with disturbance of consciousness, sweating, exhaustion, breathing difficulties and even death. Laboratory results have also found increased leukocyte and muscle creatine kinase. [

Reaction due to drug withdrawal presents with a series of psychiatric symptoms and somatic symptoms, which appear during the sudden stop in usage of antipsychotic medication. Clozapine has an especially complex mechanism and its anti cholinergic action is strong, so the probability of withdrawal effects from clozapine is quite high. Withdrawal effects include many serious symptoms of mental disorder, including cognitive, mood, and behavior disorder. In addition there may be changes in consciousness and autonomic nervous system dysfunction, as well as insomnia, restlessness, behavioral disorder, gastrointestinal tract symptoms, abnormal muscle tone and hallucinations.[ Withdrawal reactions mostly occur during the first to second day (no more than after the fifth day) after stopping medication. Peak time is usually in the first week, and then the effects gradually reduce. There is a limit in the withdrawal reaction.[ It usually disappears within 2 weeks, and a few cases may take longer than 3 weeks to resolve.

This patient with refractory schizophrenia was treated with clozapine combined with risperidone and MECT. Since the treatment obtained poor curative effect, we changed to treatment with double chlorine. The patient’s condition changed during the double chlorine treatment. The director concluded that the process of the patient’s symptom change occurred in two stages. In the first stage she had low energy, was silent, had no fever or sweating and normal level of white blood cells and creatine kinase according to laboratory results. We considered this stage to be the side effects of high blood concentration. The next stage saw the patient still in a state of silence, and was sweating, had urinary retention, increased white blood cells and creatine kinase in the laboratory examination results. Therefore we considered it to be a withdrawal reaction from the discontinuation of clozapine (250 mg/d). However this deterioration is easily confused with malignant syndrome. The patient presented with low energy, sweating, urinary retention and difficulty swallowing. In addition, laboratory examination showed that white blood cells and myocardial enzyme spectrum had increased. Therefore, we could not exclude malignant syndrome. Although the patient did not have significantly increased body temperature and myotonia, there were several studies that mentioned early symptoms of malignant syndrome which were atypical.[ In some cases, malignant syndrome does not even appear with myotonia or fever, and the level of muscle enzymes does not increase greatly either. In our case, after we stopped using clozapine, 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 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 300-450mg, and an acute dose of chlorpromazine is 200-600mg. The highest dose of clozapine used on the patient was 450 mg, and the highest dose of chlorpromazine was 250 mg. Why did those doses cause such 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 indicates that the patient with CYP2D6 intermediate metabolizes (IM) with decreased activity enzyme. Since chlorpromazine is also one of the metabolic substrates of CYP2D6D, double chlorine treatment lead to a high drug concentration which resulted in the serious adverse reactions. This suggests 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 when using them and increase monitoring. Whether it is malignant syndrome or a clozapine withdrawal reaction, the consequences can be extremely dangerous. Clinicians should clearly understand and be able to distinguish the two kinds of syndromes. From the viewpoint of treatment, malignant syndrome and a withdrawal reaction caused by clozapine are completely different. Once malignant syndrome occurs, all antipsychotic medications need to stop immediately, while with withdrawal reactions from clozapine, a low dose of clozapine need to be applied, especially to relieve delirium which can be quickly relieved after using a small dose of clozapine. [ Therefore, in order to avoid misdiagnosing malignant syndrome, we should pay attention to the dosage and speed at which antipsychotic medications were added, especially when using powerful first generation antipsychotics. On the other hand, in order to avoid adrug withdrawal reaction, the withdrawal process of clozapine has to be slow and can be completely withdrawn after the decreased to around 12.5 to 25mg/d.

In addition, there is another point that deserves discussion. Common disorders in which a mute state is seen include organic diseases, schizophrenia, and depression. Why was this case not considered as having depression? Normally a mute state in depression will not present with noncompliance in treatment and the patient also had normal muscle tension. As well, depressed patients can normally give a short answer whereas this patient was in a completely mute state. In addition she had increased muscle tension, urine retention, sat motionless and was not eating or drinking. Therefore we did not consider her as being in a depressed state.

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