Abstract
To the Editor:
The incidence of NMS in persons treated with antipsychotics is estimated to be between 0.01% and 3% per year (Guerrero and Shifrar 1988; Caroff and Mann 1993; Strawn et al. 2007). Atypical antipsychotics have a decreased propensity to cause extrapyramidal side effects (EPS) relative to typical agents, and some have postulated that their use is associated with lower rates of NMS (Caroff et al. 2000). However, there have been numerous documented NMS cases in adults treated with atypical antipsychotics (Troller et al. 2009). Well-designed population studies to investigate this relationship are not available. There is evidence that clozapine, a dibenzodiazepine derivative that binds loosely to the D2 dopamine receptors, is effective for treatment-resistant psychosis (McEvoy et al. 2006). The most recent review of published adult cases showed that clozapine was implicated in at least 21 cases of NMS (Ananth et al. 2004).
There is an even greater paucity of data regarding the association of antipsychotics and NMS in the pediatric and adolescent population. A review of 77 cases of NMS in children treated with typical antipsychotics by Silva et al. (1999) found that the clinical presentation and course of NMS was similar to that in the adult population. However, since that time, the use of atypical antipsychotics in the pediatric population has increased dramatically (DelBello and Grcevich 2004; Findling et al. 2005; Patel et al. 2005; McClellan et al. 2007). There have been three suspected cases of clozapine-induced NMS reported in patients <18 years of age (Sachdev et al. 1995; Neuhut et al. 2009). However, two of these cases did not meet any of the four published diagnostic criteria for NMS (Croarkin et al. 2008) and the third case involved co-administration of an additional atypical antipsychotic (Skarpathiotakis and Westreich 2005). After reviewing MEDLINE, Embase, and PsycINFO®, it appears that there has never been a reported case of clozapine monotherapy-induced NMS. Here, we present the case of a 16-year-old boy who developed NMS more than 3 months after stabilization on 200 mg per day of clozapine.
Case Report
A 16-year-old white male presented with new onset psychosis in September 2010 and was admitted to our institution. He was the oldest male in a sibship of five, living mostly with his mother after his parents divorced when he was 11 years old. The family was supported by social assistance and lived in a rural area. His development was reportedly unremarkable and he had no medical illnesses. He had experienced some significant stressors, including discovering his mother after she had unsuccessfully attempted suicide when he was 10 years old, and accidentally setting fire to the family home at age 13. He was described as “parentified,” frequently taking on the primary caregiver role for his younger siblings. Although his mother was adopted, she was able to find out that there was a family history of schizophrenia, and disclosed that she had previously been diagnosed with benzodiazepine dependence and depression. The patient's father believed that there was substance misuse, depression, and anxiety on his side of the family. The patient was reportedly popular in school with many friends, and did well academically up until grade 9. He had no prior psychiatric history but family and friends noted a decline in his functioning ∼1 year prior to his presentation, as he began to withdraw socially and started skipping school. He began to smoke marijuana during this time period and progressed from one joint two to three times per week to three to four joints per day by the time of his admission. He also used alcohol intermittently when he could access it. In August 2010, he began to voice bizarre somatic preoccupations, for example believing that his nose was misaligned and that he had an extra rib, and became aggressive in the home. By the time he started school in September 2010 the teachers noted that his assignments were often disorganized and nonsensical. Prior to admission, he had ingested an unknown quantity of his mother's lorazepam and acetaminophen for the purpose of “expanding my brain,” and when he was assessed in the Emergency Department his mental status examination demonstrated persecutory delusions, grandiosity, disorganization, neologisms, thought insertion, and thought withdrawal.
Initial treatment consisted of 4 weeks of risperidone monotherapy. However, at doses of 2 mg/day the patient experienced marked rigidity and hypertonia, requiring benztropine administration. A maximum risperidone dose of 4 mg/day was reached with minimal symptomatic improvement before it was discontinued. A 6 week trial of olanzapine, titrated up to 30 mg daily, also resulted in no clinical improvement and was associated with significant sedation. It was therefore discontinued. During the course of olanzapine treatment, the patient showed signs of comorbid depression, for which fluoxetine was initiated and titrated up to 40 mg daily.
After two failed antipsychotic trials, our patient's parents elected for a trial of clozapine. Clozapine was initiated and slowly uptitrated with weekly laboratory monitoring. At a clozapine dose of 200 mg/day the patient's psychotic symptoms improved significantly, as did his mood symptoms, resulting in subsequent fluoxetine discontinuation. He was discharged home and followed by the community outpatient team. The only medication at the time of discharge was clozapine 200 mg daily, and this was unchanged during his 3 months at home.
Three months post-discharge the patient was found by his mother one morning with an acutely decreased level of consciousness. He was extremely rigid, and had slurred speech and difficulty breathing. He was transported by ambulance to a community hospital where he was intubated and transferred to our center's pediatric intensive care unit (PICU). The patient's mother reported that he had smoked marijuana the previous night, but otherwise appeared normal when he was last seen ∼8 hours prior to symptom onset. The patient later reported taking nine 100 mg clozapine pills the evening prior to his presentation, although medical reports state that all of the tablets were accounted for.
On admission to the PICU, the patient was febrile with a temperature of 39.0°C, hypertensive (systolic blood pressure ranging between 70 and 200 mm Hg), diaphoretic, tachycardic (120/min), and tachypneic (22/min). His Glasgow Coma Scale rating was 3T, and he demonstrated severe muscle rigidity. The presence or absence of incontinence or tremor was not documented. Laboratory investigations revealed a metabolic acidosis (pH 7.27), creatinine 303 μmol/L (H), international normalized ratio (INR) 16.2 (H), partial thromboplastin time (PTT) 38.8 (H), unconjugated bilirubin 62 μmol/L (H), aspartate aminotransferase (AST) 576 U/L (H), alanine aminotransferase (ALT) 92 U/L (H), amylase 434 U/L (H), K 6.6 mmol/L (H), Na 156 mmol/L (H), uric acid 1003 μmol/L (H), and lactate dehydrogenase 1072 U/L (H). Initial white blood cell count was 10.2×10e9/L (N), blood cultures were negative, toxicology was positive for trace THC, lumbar puncture was normal, and there was no evidence of myoglobinuria. A head CT was unremarkable and an ECG showed premature ventricular contractions. The patient's height was 179.5 cm and he weighed 85.8 kg. By post-admission day 3, he had an elevated WBC count (12.1×10e9/L) and a chest radiograph showed changes consistent with aspiration pneumonia. At the time of admission to the PICU, it was evident that the patient was experiencing multi-organ failure, and numerous consultations to specialist services including rheumatology, infectious diseases, nephrology, neurology, and hematology were obtained.
Approximately 48 hours post-admission, psychiatry was consulted and ordered a creatine kinase (CK) level, which was significantly elevated at 21,918 U/L. The patient was diagnosed with NMS and bromocriptine 10 mg t.i.d. was initiated. The patient underwent aggressive cooling in an attempt to control his fever, received empiric clindamycin and cefotaxime for presumed aspiration pneumonia, a dantrolene infusion for rigidity, and a labetolol infusion to combat hypertension. Labetalol was discontinued once adequate blood pressure control was achieved with clonidine. He gradually improved, and 12 days post-admission, with a CK of 579 U/L, he was extubated and transferred to an intermediate care unit. Bromocriptine and clonidine were tapered and discontinued.
While in the hospital the patient's mental status examination revealed ongoing somatic preoccupations (such as thoughts that he had an extra rib), but was otherwise unremarkable. After lengthy consultation with the family they elected to avoid re-challenging with antipsychotic medication and the patient was discharged home 21 days after admission, with no medications.
Three months after discharge from the hospital, the patient required readmission for psychotic symptoms. Over the course of those 3 months, he presented with significant depressive symptoms and was tentatively diagnosed with schizoaffective disorder. A trial of electroconvulsive therapy (ECT) was initiated in an attempt to treat the affective component of his illness. After ten sessions of ECT the patient exhibited increased disorganization and new hypomanic symptoms. ECT was therefore discontinued. After consultation with the patient's family, quetiapine therapy was initiated at a dose of 800 mg daily. After a 2 week trial of treatment, as there was no improvement in any of the patient's psychotic symptoms, his family requested that the medication be discontinued. Loxapine was initiated at that time, as its molecular structure is similar to that of clozapine (Stahl 2008), which was the only medication that had previously achieved remission of symptoms. The patient partially responded to loxapine (80 mg daily), but after 4 weeks, continued to have significant residual psychotic symptoms. As he also demonstrated mild rigidity, his treatment team decided against uptitration of the loxapine dosage. Lithium was then added in an attempt to control the patient's affective symptoms and augment the antipsychotic effects of loxapine (Leucht et al. 2007). Remission was achieved on combination loxapine 50 mg daily and lithium 900 mg daily.
Discussion
We believe this to be the first report of NMS induced by antipsychotic monotherapy with clozapine in an adolescent. Previous reports of this entity did not meet the accepted diagnostic criteria for NMS (Sachdev et al. 1995) or involved a concomitant atypical antipsychotic (Skarpathiotakis and Westreich 2005). In Croarkin et al.'s review (2008) of pediatric patients developing NMS on atypical antipsychotics, more than half the patients (55%, n=11) had concomitant use of least one other psychotropic medication.
This case is also interesting because the patient developed NMS on relatively low-dose clozapine remote 3 months after initiation of therapy. In the literature, the mean dose of clozapine of the adult patients who had NMS was 318 mg daily (Ananth et al. 2004). In the pediatric population, the two suspected cases of clozapine-induced NMS that did not meet the full diagnostic criteria reached doses of 300 mg and 375 mg in <8 weeks (Croarkin et al. 2008). The other documented case presented acutely within 8 hours of administration of the initial dose of clozapine (12.5 mg) with co-administration of intramuscular olanzapine. The period of highest risk for development of NMS is the first 2 weeks following initiation of a new antipsychotic (Rosebush et al. 1989). Our patient's prescribed dose of 200 mg daily was unchanged for 3 months prior to symptom onset. This patient may have ingested a higher dose the night before presentation. If so, this corresponds with a speculated risk factor. Sixteen (80%) of the patients reviewed by Croarkin et al. (2008) had a dose change of their atypical antipsychotic within 1 week of the NMS episode. In the adult population, the dose of atypical antipsychotic was noted to be increasing at the time of development of NMS in 31 of 68 cases (46%) and in clozapine cases in 11 of 21 (52%) presentations (Ananth et al. 2004).
A previous history of EPS is also a suspected risk factor for NMS. In a review by Croarkin et al. (2008) 50%, (n=11) of the pediatric patients on atypical antipsychotics who developed NMS had previously documented EPS. Our patient had previously experienced significant rigidity on risperidone. The patient's gender also may have been a risk factor. The majority of published cases of clozapine-associated NMS in the pediatric and adult literature involve male subjects (Ananth et al. 2004; Croarkin et al. 2008; Neuhut et al. 2009).
It is unclear what impact the patient's cannabis use had on the development of NMS. In the literature, only one case series has noted cannabis or other substance use prior to NMS onset in adolescents. Henderson (2011) presented four probable cases of NMS in adolescents in South Africa, and two of them had a history of both cannabis and crystal methamphetamine use, although the timing of their last use in relation to NMS presentation was not documented.
Others have reported that clozapine-induced NMS may present with atypical features, such as lack of rigidity and delayed elevation of CK levels (Neuhut et al. 2009; Trollor et al. 2009). However, the patient in our case presented with all the cardinal features of NMS including rigidity, fever, mental status change, autonomic instability, and CK elevation.
Of the 16 pediatric patients who developed NMS in the study by Croarkin et al. (2008), 9 (45%) were re-challenged successfully with antipsychotics and 5 (25%) underwent successful ECT for underlying psychiatric illness. In the adult literature, seven of the documented cases of clozapine-induced NMS were successfully re-challenged with clozapine, and none developed a recurrence of NMS (Ananth et al. 2004). Clozapine re-challenge may be considered in the future if our patient relapses.
Conclusion
We have described a case of acute-onset severe clozapine-induced NMS. Despite the rare occurrence of this entity, psychiatrists treating children with antipsychotics, including clozapine, should remain vigilant for its symptoms. Caregivers should also be educated to recognize the symptoms of NMS, as early identification may reduce morbidity and mortality.
Clinical Significance
There are no previous reports of clozapine monotherapy-induced NMS in an adolescent. Here, we present the case of a 16-year-old boy who developed NMS more than 3 months' after stabilization on 200 mg per day of clozapine. Practitioners should be cognizant of the potential for NMS in the setting of clozapine therapy.
Footnotes
Disclosures
The authors have no financial relationships to disclose.