Abstract
Objectives:
In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population.
Methods:
Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale (CGI-I).
Results:
One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 ± 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 ± 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or “much improved.”
Conclusion:
These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.
Introduction
A
Clozapine is a mild dopamine D2 receptor antagonist with distinct selectivity for mesolimbic neurons and action at serotonin, histamine, and noradrenergic receptors. The first approved SGA, clozapine, is a proven therapy for individuals with treatment-resistant bipolar disorder and schizophrenia (Lally and MacCabe 2015; Li et al. 2015). Clozapine also has demonstrated effectiveness in reducing aggression in psychiatrically ill adults and adolescents (Chalasani et al. 2001; Chengappa et al. 2002). In the ASD literature, which is often referenced as a prescribing guide in idiopathic developmental disability, clozapine has been shown to be well tolerated and effective in reducing irritability in several case reports (Chen et al. 2001; Gobbi and Pulvirenti 2001; Lambrey et al. 2010). More recently, rapid titration of clozapine for treatment of severe psychiatric symptoms and agitation in individuals with psychotic and affective disorders has been demonstrated safe and effective (Ifteni et al. 2014a, 2014b; Poyraz et al. 2015). Despite compelling evidence that clozapine may be rapidly effective for controlling aggression symptoms, it has yet to be studied in a controlled way for any treatment indication in individuals with developmental disability (Ayub et al. 2015). Furthermore, clozapine is typically used only as a “last resort” in individuals with developmental disability due to the potential of severe adverse effects, including lowered seizure threshold, cardiomyopathy, weight gain, metabolic adverse effects, and agranulocytosis (Maayan and Correll 2011).
In the following case series, we describe the clinical impact and tolerability of rapid titration of clozapine targeting irritability in five youth with developmental disability hospitalized for severe irritability that was refractory to first-line antipsychotic medication treatment. We offer this descriptive report in an effort to expand the evidence base guiding treatment of irritability symptoms refractory to first-line treatments in this population.
Methods
The five individuals described in this case series were each admitted to a 10-bed psychiatric crisis stabilization unit designed for children and adolescents with moderate to severe developmental disability. All patients received a thorough psychiatric and medical evaluation at the time of admission, including review of psychiatric symptoms, detailed review of past and current pharmacotherapy, and evaluation of comorbid medical illness. Psychiatric diagnoses were made by a clinician with expertise in developmental disability (C.A.E.), based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (American Psychiatric Association 2013). Medical illnesses believed to potentially contribute to behavioral symptoms (i.e., constipation, viral illness, neurologic concerns) were evaluated and treated in all cases. Patients were selected for potential clozapine treatment due to highly dangerous levels of irritability that previously had been nonresponsive to first-line medication trials. In these cases, the irritability symptoms were deemed to be the most pressing symptoms to be addressed during hospitalization. Other psychiatric illnesses that may have impacted behaviors (i.e., attention-deficit/hyperactivity disorder [ADHD]) were not directly addressed beyond continuation of previously initiated treatment.
Following discussion of the risks and potential benefits of clozapine treatment with the patients' legal guardians, informed consent was obtained in each case. Each patient then underwent rapid titration onto clozapine targeting refractory irritability symptoms (method described in each case below). Vital signs, including temperature, heart rate, and blood pressure, were recorded daily. Complete blood counts (CBCs) with differentials, including absolute neutrophil count (ANC), were obtained before initiating treatment and repeated twice a week during titration. Daily assessment for adverse effects was completed by discussion with the patient (when possible), daily nursing evaluation, direct care staff report, physician examination, and guardian report throughout the inpatient stay. For patients followed posthospitalization, adverse effects were monitored at all office visits and phone calls, and vital signs were assessed at all office visits. Clozapine monitoring guidelines were followed for all patients throughout treatment (HLS Therapeutics 2015).
Each patient's severity of illness at baseline was measured using the Clinical Global Impressions-Severity scale (CGI-S) by the treating physician (C.A.E.) (Guy 1976). The CGI-S is a clinician-rated global assessment of symptom severity scale ranging from 1 to 7 (1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients). As a qualitative measure of treatment response, Clinical Global Impressions-Improvement scale (CGI-I) scores were determined following clozapine treatment (also by C.A.E.) (Guy 1976). The CGI-I is a clinician-rated global assessment of symptom change rated on a scale from 1 to 7 (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse).
Results
One female and four males were included in this series. All five were diagnosed with developmental disability (ASD and/or cognitive impairment) and at least one other psychiatric diagnosis. All five patients suffered from severe irritability, which negatively impacted their quality of life, and had not responded to first-line pharmacotherapy (all participants had previous failed trials of risperidone and aripiprazole). All were medically stable at baseline. Ages ranged from 11 to 17 years, with mean age of 13.1 ± 2.1 years. The patients were taking an average of 4.0 ± 0.7 psychotropic medications at admission, including SGAs, mood-stabilizers, stimulants, α-agonists, and benzodiazepines. Mean CGI-S at baseline was 5.8. Mean therapeutic total daily dose (TDD) of clozapine was 380 ± 200 mg. Mean final CGI-I anchored to symptoms targeted with clozapine treatment was 2.0 (“much improved”). All patients tolerated rapid titration onto clozapine without an acute adverse effect, vital signs remained stable in all patients, and no cases of agranulocytosis occurred. Each case is described in detail below.
Patient 1
Patient 1 was an 11-year-old female with a history of ASD, intermittent explosive disorder (IED), ADHD, and mixed receptive-expressive language disorder. She also suffered from a stable spinal cord syrinx resulting in chronic urinary retention. She was admitted to the inpatient psychiatric unit for worsening impulsivity and aggressive behaviors. CGI-S at admission was 5. Medication changes before admission included increasing doses of methylphenidate and oxcarbazepine without benefit. At the time of admission, psychiatric medications included clonidine, guanfacine, amitriptyline, methylphenidate, oxcarbazepine, and olanzapine. Previous antipsychotic medication trials included risperidone, aripiprazole, quetiapine, and haloperidol. The patient was titrated off olanzapine. Clozapine treatment was initiated at 25 mg and increased by 25 mg per day until a minimum effective dose of 100 mg twice daily was reached. Following discharge from the hospital, the patient had a reemergence of aggressive behaviors and was readmitted 3 weeks later to continue upward titration of clozapine. She was subsequently discharged a second time on 250 mg twice daily with the dose ultimately increased to 300 mg twice daily (600 mg TDD) in outpatient follow-up. Her aggressive behaviors remitted with clozapine therapy, and she experienced no reported adverse effects beyond mildly increased appetite. This patient had a notable 2.7-kg weight loss over the first 12 weeks of treatment with clozapine. Weekly CBCs remained stable throughout treatment. CGI-I anchored to symptoms targeted with clozapine treatment was 2.
Patient 2
Patient 2 was a 12-year-old male with a history of IED, ADHD, chronic motor tic disorder, mild cognitive impairment, and mixed receptive-expressive language disorder. He was admitted to the inpatient psychiatric unit for worsening physical aggression at home and school. CGI-S at admission was 6. He had been admitted to inpatient psychiatry 1 month previously for similar aggressive behaviors, and discharged on both haloperidol and ziprasidone, which proved to be ineffective in managing his impulsivity and violence. At the time of admission, his medications included haloperidol, ziprasidone, lisdexamfetamine, and olanzapine. Previous antipsychotic medication trials included risperidone, aripiprazole, and chlorpromazine. During hospitalization, ziprasidone and haloperidol were tapered and discontinued. Clozapine treatment was subsequently initiated at 25 mg daily. Clozapine was increased by 25–50 mg daily until a minimum effective dose of 250 mg twice daily was reached 2 weeks later. After discharge, the patient continued to be aggressive, requiring readmission 4 weeks after starting treatment. Clozapine was further increased to 300 mg twice daily (600 mg TDD). Following the second discharge, the patient experienced more frequent violence-free days and was more responsive to verbal de-escalation when agitated. He suffered no significant adverse effects related to clozapine, with only minor reported sedation. Weight increased 4.1 kg over the first 12 weeks of treatment. The patient's CBC remained stable with the exception of an ANC <2.0 on two occasions, both resolved with repeat CBC. CGI-I anchored to symptoms targeted with clozapine treatment was 2.
Patient 3
Patient 3 was a 13-year-old male with a history of ASD, IED, moderate cognitive impairment, and complex partial epilepsy. He was admitted to the inpatient psychiatric unit for increasing aggressive behavior at home and school. CGI-S at admission was 6. He had previous admissions on the unit with brief periods of successful control of his problematic behavior, but was noted to be more aggressive since last discharge with significant psychomotor agitation. Previous antipsychotic medication trials included risperidone and aripiprazole. At the time of this admission, his seizures were well controlled on topiramate and oxcarbazepine. His psychotropic medications included risperidone, trazodone, zolpidem, and melatonin. Risperidone was weaned and discontinued, and trials of olanzapine and then haloperidol were initiated. Both trials proved largely ineffective and were discontinued. Subsequently rapid titration of clozapine was initiated. The patient received an initial dose of clozapine 25 mg, with dosage increased by 25–50 mg daily until minimum effective dose of 100 mg twice daily was reached. Due to increased aggression at home following discharge, clozapine was further increased to 125 mg twice daily (250 mg TDD) without adverse effects. Guardian reported great reduction in aggressive behaviors at home. The patient's CBC was stable, and no adverse effects were reported. This patient's weight initially increased by 2.8 kg over the first 6 weeks of treatment, but subsequently decreased to 0.4 kg below baseline weight after 6 months of treatment. CGI-I anchored to symptoms targeted with clozapine treatment was 1.
Patient 4
Patient 4 was a 16-year-old male with a history of ASD, IED, and mild cognitive impairment. He was admitted to the inpatient psychiatric unit with increased physical aggression, including episodes of hitting, kicking, and raising fists in a threatening manner. Family members were most concerned with his inability to remain safe during car drives, and the father reportedly had to restrain the patient for safety several times in the days before admission. The patient suffered intermittent cycles of aggression, which were interspersed with periods of low energy and dulled senses, as he seemed to be “doped up” on risperidone per parent report. CGI-S at admission was 6. Previous antipsychotic medication trials included risperidone, aripiprazole, ziprasidone, and quetiapine. At admission, risperidone was weaned and discontinued. Clozapine was initiated at 25 mg, with a 25 mg increase each day until a minimum effective dose of 100 mg twice daily was reached (200 mg TDD). After discharge, the patient had occasional, but less frequent periods of mild aggression toward his mother. The reduction in his overall irritability allowed therapeutic interventions to be more impactful. This patient did not follow up in our clinic postdischarge, due to lack of proximity to our medical center. However, adequate outpatient follow-up with weekly CBC at a community clinic was ensured. He tolerated clozapine without complaints of serious adverse effects. Weight remained stable through the first 8 weeks of treatment. CBC was stable throughout treatment. CGI-I anchored to symptoms targeted with clozapine treatment was 3.
Patient 5
Patient 5 was a 12-year-old male with a history of ASD, IED, ADHD, and moderate cognitive impairment. He had a history of repeated hospitalizations for SIB, physical aggression, and property destruction. Previous trials of antipsychotic and mood-stabilizing medications included risperidone, aripiprazole, olanzapine, quetiapine, chlorpromazine, divalproex, and lithium. Due to increasingly aggressive behaviors, he was admitted to the inpatient psychiatric unit to begin treatment with clozapine. CGI-S at admission was 6. Psychotropic medications at admission included chlorpromazine, divalproex, and methylphenidate extended release. Chlorpromazine was weaned and discontinued and clozapine was started at 25 mg, with a 25 mg daily increase until a minimum effective dose of 125 mg twice daily (250 mg TDD) was reached on day 10 of treatment. The patient was subsequently discharged from the hospital with improved behavior. He experienced a drop in white blood cell count (WBC) and ANC during week 9 of treatment, however repeat CBC demonstrated normalization of the WBC and ANC. Depakote was believed to have played a role in the low WBC count and was discontinued without an ill effect. The patient continued to demonstrate improvement in aggressive behavior both at home and school. Weight climbed by 3.3 kg over the first 16 weeks of treatment. CGI-I anchored to symptoms targeted with clozapine treatment was 2.
Discussion
In this case series, we present the successful rapid titration of clozapine in five youth with developmental disability admitted to our inpatient psychiatric unit with severe refractory irritability symptoms. In all five consecutively treated patients, rapid titration of clozapine was well tolerated and free of significant treatment limiting significant adverse effects. There were no notable changes in vital signs (heart rate and blood pressure), no increase in seizure frequency, no cardiac-related events, and no cases of agranulocytosis. Weight gain was reported in only two out of five patients in the time period reviewed (range 8 weeks to 6 months). These refractory patients were quickly stabilized on clozapine and tolerated the burden of weekly blood draws. All patients demonstrated significant clinical improvement with mean CGI-I score anchored to symptoms targeted with clozapine treatment of 2.0, or “much improved.”
These initial results support the potential utility of clozapine for treatment of severe refractory irritability in youth with developmental disability. However, this report is limited by the small sample size, lack of a blinded independent CGI-I rater, short time course, and lack of a control group for comparison. Furthermore, all five patients in this report received intensive behavior, speech, and occupational therapy while hospitalize, and the impact of these treatments in stabilizing the patients' behavior was not quantified in this report. In addition, we do not have available data on potential metabolic adverse effects of clozapine treatment in these patients, although overall weight gain was limited. Future controlled studies using parallel-groups design, which compare clozapine to standard approaches, including polypharmacy and behavioral interventions, may provide further evidence for the effectiveness of this often overlooked medication. In addition, detailed review of potential adverse effects, including impact on weight, metabolic profile, seizure activity, cardiac functioning, and CBC, must be included in future study. Such studies may shed light on questions of long-term safety and tolerability, as well as overall effectiveness in this difficult-to-treat population.
Footnotes
Disclosures
All contributing authors have read and approved the submission of this article to the journal. In addition, all authors report no direct conflicts with the content of this report. Dr. Wink's current research is supported by the Simons Research Foundation, Autism Speaks, Riovant Sciences Ltd, and Cures Within Reach. Dr. Wink has served as a past consultant for Otsuka. Dr. Pedapati receives research support from the Cincinnati Children's Hospital Research Foundation. Dr. Erickson is a consultant to and holds equity in Confluence Pharmaceuticals and is a consultant to Neurotrope. Dr. Erickson is a past consultant to Alcobra Pharmaceuticals, the Roche Group, and Novartis. Dr. Erickson holds nonrelated IP held by CCHMC and Indiana University. Dr. Erickson receives research grant support from the John Merck Fund, CCHMC, Autism Speaks, the National Fragile X Foundation, The Roche Group, Neuren Pharmaceuticals, and Riovant Sciences Ltd. Dr. Badran, Dr. Sorensen, Ms. Benton, Dr. Johnson, and Mr. Wissel have no disclosures to report.