Abstract
Chief Complaint and Presenting Problem
History of Present Illness
For approximately one year prior to admission, R. had experienced a period of progressively impaired functioning. During this time he was abusing marijuana on a daily basis and became increasingly socially withdrawn. He frequently spoke of his low self-esteem with family members, and he lost approximately 4.5 kg as a result of decreased appetite. His grades had declined significantly, and this culminated in a week-long inpatient psychiatric hospitalization for evaluation of depressive symptomatology. During this time he was trialed on fluoxetine (10–20 mg), and there were no reported adverse effects. Upon discharge, he was subsequently placed in a residential school near his mother's house in an attempt to refocus his academic studies. His trial on fluoxetine lasted less than one month when the medication was discontinued by the patient with his parents' knowledge “because it didn't help.” This occurred several months prior to his initial hospitalization.
The evening prior to his initial presentation, R. reportedly used marijuana and had taken 4 zolpidem pills (10 mg each) for inability to sleep. As a result of his jump from the sixth floor window, R. was initially admitted for surgery and medical stabilization after he was found unconscious by a neighbor, lying on the windshield of a parked car outside his father's residence.
R. sustained severe musculoskeletal injuries and required emergent surgical repair of his sacrum, pelvis, and left femur. He was evaluated by the consulting neurology service and was determined to have suffered no neurological damage, following examination and a workup that included multiple unremarkable brain imaging studies and normal electroencephalograms (EEG). While on the surgical service, R. was treated multiple times with low-dose intravenous haloperidol (1–2.5 mg) for delirium-related agitation and oral lorazepam (0.5 mg) for insomnia with good effect. Following his stabilization after 2 weeks on the surgical service, R. was transferred to an inpatient child and adolescent psychiatric unit.
Hospital Course
Upon admission to the unit, R. indicated in an interview that he had not been trying to kill himself when he jumped from his father's apartment building; rather he reported delusions of invincibility (“I am an Angel,” “I was touched by God,”) and expected that he could fly. Upon admission, R. reported passive suicidal ideation and an initial diagnosis of depressive disorder, not otherwise specified was made. R. was subsequently started on citalopram (10 mg by mouth daily) to target depressive symptoms. Within a few days of admission, R became notably confused and delirious. His delirium was determined to be secondary to infection of a sacral wound suffered during his trauma. He was transferred to a medical floor where he was treated with multiple antibiotics including daptomycin (266.4 mg intravenously (IV) four times a day) and piperacillin-tazobactam (3000 mg IV every 6 h). During this medical hospitalization, R. lost approximately 4.5 kg due to poor food intake. He was readmitted to the inpatient psychiatric unit approximately 10 days later.
The day following his readmission to the unit, R. had an abrupt change in mental status—he became largely unresponsive and began showing catatonic signs including waxy flexibility and echolalia. A neurology consultant saw the patient to rule out neurological origin of the patient's symptoms; additional neurological work up, including an EEG, was within normal limits. In his catatonic state, R. stopped all voluntary oral intake. Due to his poor nutritional status, he was transferred to the pediatric intensive care unit where he received intravenous fluids and nasogastric tube feeds. Clonazepam (0.5 mg by mouth twice a day) and lorazepam (1 mg IV as needed every 4 h) were started to target his catatonic symptoms.
Olanzapine was started the following day at 2.5 mg orally in the morning and 5 mg orally at bedtime for management of the patient's psychotic symptoms, including paranoid and bizarre delusions and auditory hallucinations. At this time his treatment regimen included the following other medications: citalopram (10 mg by mouth daily), clonazepam (1 mg by mouth twice a day), daptomycin (266.4 mg IV 4 times a day), diphenhydramine (12.5 mg IV every 6 h), lactobacillus rhamnosus (1 capsule orally twice a day), multivitamin (1 tablet by mouth twice a day), piperacillin-tazobactam (3000 mg IV every 6 h), zinc sulfate (220 mg orally twice a day), acetaminophen (650 mg orally as needed every 6 hours), and lorazepam (1mg IV as needed every 4 h).
Exactly 7 days prior to this time, R.'s baseline complete blood count (CBC) values were normal including a white blood cell (WBC) count of 6.24 x109/L (reference range 5.24 x109/L to 9.74 x109/L) and an absolute neutrophil count (ANC) of 4.39 x109/L (reference range 2.73 x109/L to 6.68 x109/L). Olanzapine was titrated up over six days to 5 mg orally three times a day with noted clinical improvement. Ten days after initiation of olanzapine, R.'s temperature was measured at 38.5° Celsius. He was asymptomatic and without notable findings on physical examination. A CBC revealed a WBC of 0.89 x109/L and ANC of 0.17 x109/L. Due to the critical nature of this laboratory value, the hematology smear was reviewed by the house staff and attending physician multiple times to assure its validity, which was subsequently confirmed.
Olanzapine was immediately discontinued, given the temporal relationship between its initiation and the subsequent onset of agranulocytosis. The identification of olanzapine as a causal agent was further confirmed by a consulting hematologist who confirmed the blood smear was consistent with a picture of marrow damage secondary to an adverse drug reaction. The infectious disease service was consulted, and their recommendations were to continue R.'s other medications, and to proceed with careful clinical monitoring. Serial CBC monitoring showed improvement of R.'s blood counts over the next two days, and at 48 hours the patient's WBC count was 4.04 x109/L with ANC of 1.85 x109/L.
Twenty days after discontinuation of olanzapine, R.'s laboratory values had completely normalized with a WBC count of 6.39 x109/L and ANC of 3.63 x109/L. After a two-week hiatus from antipsychotic medications at the patient's parents' request, R.'s clinical picture deteriorated with an increase of severe delusional and catatonic symptoms. At this point he was started on quetiapine, which was titrated slowly up to 300 mg orally 4 times a day over five weeks. During this time, R.'s CBC was monitored on a regular basis and no abnormalities were found. R.'s response to treatment with quetiapine was modest, and notable for a 35% decrease in Positive and Negative Syndrome Scale ratings after eight weeks of treatment.
Past Psychiatric History
There is no previous history of psychiatric evaluation or treatment other than those mentioned in the history of previous illness.
Substance Abuse History
R. reports having first used marijuana at age 14. At age 15 he was a daily marijuana user. He denies abuse of other hallucinogens, street drugs, or prescription medications and has no significant history of alcohol or tobacco abuse.
Developmental History
R. is the product of an uncomplicated pregnancy and delivery. He reached all childhood developmental milestones at the expected times.
Educational History
R. was an above-average student throughout elementary school and middle school. His grades began to slowly decline in 9th grade, which likely coincides with his regular abuse of marijuana. In 10th grade, he was placed in a therapeutic boarding school.
Social History
R. grew up in a suburban town in New England. His parents were married and had two older sons (approximately 2 and 6 years older than the patient). His father's work as a businessman provided the primary source of income in the family, although his mother worked intermittently as a grade school special needs assistant.
R.'s home life was initially complicated between ages 2 and 3 years when the younger of his two brothers was diagnosed with an autism spectrum disorder. This brother's functioning is severely impaired, and he requires 24-hour support for his activities of daily living. Another significant stressor for R. emerged when he was approximately 11 years old, when his eldest brother became quite disruptive as a teenager due to a significant substance abuse problem.
R.'s parents divorced approximately 3 years ago when he was 13 years old. He subsequently lived primarily with his mother, although he visited his father on weekends. His parents remain on speaking terms. The patient is described by his family as a “loner who always preferred to be by himself,” although he did have a small group of friends. His hobbies include skateboarding and playing video games.
Family History
R.'s father has been diagnosed with major depressive disorder and he has received psychopharmacological treatment in the past.
Paternal grandfather had depression, a history of electroconvulsive therapy treatments and succumbed to suicide under unclear circumstances. R.'s first cousin has two children with major mental illness: one with schizophrenia and the other with bipolar disorder.
R.'s maternal aunt has substance abuse problems.
R.'s oldest brother has a history of substance abuse, and the younger of his two older brothers is diagnosed with an autism spectrum disorder.
Medical History
R. had no history of serious medical problems, hospitalizations, or surgeries prior to his traumatic injury, which resulted in multiple orthopedic injuries. He received all his vaccinations in the proper time.
Medication History
R. had been treated with fluoxetine (10—20 mg) for less than a month several months prior to admission. The medication was discontinued by the patient “because it didn't help.” There were no reported adverse effects.
Mental Status Exam
Mental status examination, conducted shortly after initial presentation to the psychiatry unit, revealed a gaunt Caucasian adolescent wearing an oversized shirt with the image of Bob Marley on it. R. was unshaven for at least 3 weeks and his hair hung down across his forehead to his eyes. He made poor eye contact and had notable psychomotor slowing and intermittent catatonic posturing that lasted for up to 30 minutes. He had no spontaneous speech, although he responded slowly and monotonously when engaged in the interview. His thought process was at times very tangential; at other times he appeared to experience poverty of thought.
Thought content was notable for bizarre delusions that were both paranoid (“If I urinate then something bad will happen to my brother”) and somatic in nature (“My penis is shrinking any time they talk to me”). He experienced prominent auditory hallucinations in the form of “The Devil telling me I'm going to Hell.” Religious themes were prominent in the patient's thought content, including delusions that he was an Angel and that “God has touched me.” However R. did not display many common hyper-religious behaviors such as praying or reading religious texts.
The cognitive exam was difficult to perform due to his psychosis, but his orientation was intact, and he was attentive (completes Serial 7s), with intact registration, recall, calculations, and long-term memory. Insight and judgment were severely impaired secondary to his psychosis.
Diagnostic Impression and Case Formulation
In summary, R. is a 16-year-old male with psychotic symptoms, including delusions, hallucinations, and catatonia, who was initially transferred to an inpatient child and adolescent psychiatric unit following medical and surgical treatment for injuries sustained after his jump from a sixth floor apartment building in the context of delusions of invincibility. Upon admission, his profound psychiatric illness was characterized by a wide variety of symptoms including paranoid and delusional thinking, intermittent catatonia, and auditory hallucinations. Prior to hospitalization, R. had experienced a year-long prodromal period classified by social withdrawal, depressed mood, poor appetite with associated weight loss, and daily marijuana abuse. From a biological perspective, the patient had a diathesis for both mood and psychotic illness, given the family history of schizophrenia, autistic spectrum disorder, major depression, bipolar disorder, and completed suicide. Medical factors of note were orthopedic injuries sustained in the fall and cannabis abuse. From a psychosocial perspective, R. was a mid-adolescent who appeared to be somewhat socially isolated and had low self esteem. His parents' divorce and his brothers' illness and substance abuse were significant stressors at a crucial developmental time.
Multi-Axial Diagnoses
Discussion
This case report of agranulocytosis secondary to olanzapine in an adolescent with psychosis illustrates an uncommon but very serious example of an adverse medication reaction. To our knowledge, R.'s ANC of 0.17 x109/L represents the most severe agranulocytosis in association with olanzapine (Stip et al., 2007) reported in the literature to date.
While initially developed to be an agent structurally similar to clozapine without the risk of hematotoxicity, olanzapine has been associated with the third-highest incidence of neutropenia among all antipsychotics (Duggal et al., 2005). Reports published as recently as 1996 suggested that olanzapine-induced agranulocytosis was non-existent (Meltzer et al., 1996). However, by 1999 there were multiple published case reports describing olanzapine-induced neutropenia and agranulocytosis (Wray et al., 1998; Naumann et al., 1999), and as of August 2007, there were 37 case reports of olanzapine-induced agranulocytosis recorded in the FDA Adverse Event Reporting System Database.
This adverse-reaction has been thought to be dose-dependent (Kodesh et al., 2001), largely occurring within one month of treatment initiation with olanzapine (Stergiou et al., 2005), and usually self-resolving in context of drug discontinuation (Tolosa-Vilella et al., 2002), which fortunately was the case for R.
Generally children and adolescents are thought to be more susceptible than adults to adverse effects of second generation antipsychotics due to their relatively rapid metabolism, and the increased bioavailability of these medications in the younger population (DuBois 2005). Despite this, only 10% of drug-induced neutropenias occur in children and young adults (Duggal et al., 2005). A review of the literature, including searches using PubMed, Ovid, Medline, Psycinfo, and Embase, yielded approximately 45 published articles describing cases of olanzapine-induced neutropenia and agranulocytosis. Of the case reports describing olanzapine-induced hematotoxicity, the vast majority of patients were adults, with the notable exception of a case describing olanzapine-induced neutropenia in a 17-year-old female (Duggal et al., 2004). Thus, this case of a 16-year-old represents what we believe to be the youngest individual to experience this adverse reaction reported in the published literature.
The risk of all neutropenic reactions secondary to drugs in the phenothiazine class (e.g. olanzapine, chlorpromazine, etc.) is approximately 1 in 10,000 (Flanagan et al., 2007), with a significantly lower incidence of severe neutropenia and agranulocytosis secondary to olanzapine. A large percentage of case reports describing olanzapine-induced agranulocytosis are notable for prior history of neuroleptic-induced neutropenia, most commonly secondary to clozapine (Duggal et al., 2004; Tolosa-Vilella et al., 2002). Notably, a number of these cases describe patients with systemic diseases that could have contributed to hematopoetic failure, including systemic lupus erythematosus (Su et al., 2007) and chronic renal failure (Stip et al., 2007).
In addition, to further complicate R.'s clinical picture, nearly all of the concomitant medications he was prescribed have been associated with hematologic adverse effects—ascorbic acid (hemolysis), citalopram (anemia, thrombocytopenia, leukocytosis), clonazepam (thrombocytopenia), daptomycin (anemia, thrombocytopenia), heparin (thrombocytopenia), zinc sulfate (anemia, thrombocytopenia), acetaminophen (hemolysis), lidocaine (methemoglobinemia). Although lorazepam-induced leukopenia and agranulocytosis have been anecdotally reported, a Pubmed search for case reports detailing these toxicities yielded no results.
Interestingly, piperacillin-tazobactam is the only medication the patient was taking to have been regularly associated with neutropenia and agranulocytosis. A 2007 review article reports 58 cases of pipercillin-induced agranulocytosis through the FDA Adverse Events Reporting System Database, and 183 cases of pipercillin-induced neutropenia (Scheetz et al., 2007). This adverse effect is largely characterized as reversible with recovery of WBC following the discontinuation of the drug (Kumar et al., 2003).
Taken together, the immediate return of the patient's ANC to previously normal levels following discontinuation of olanzapine while he remained on the same other medications, including identical piperacillin-tazobactam and lorazepam, suggests a causal relationship between olanzapine and the patient's agranulocytosis.
The exact mechanisms underlying neutropenia in association with olanzapine are still under investigation. Current biochemical models include olanzapine metabolites that may be toxic to neutrophils and their stem-cell predecessors, as well as findings that olanzapine has been shown to alter endogenous levels of granulocyte colony-stimulating factor (G-CSF) and other hematopoietic modulators. (Duggal et al., 2004) Genetic predisposition to olanzapine-induced neutropenia based on increased prevalence of this adverse reaction in patients with specific haplotypes has also been hypothesized (Dettling et al., 1999).
The decision to immediately discontinue R.'s olanzapine was based on his clinical picture, expert recommendations from consulting physicians, and the parents' request. The general consensus for managing an abrupt drop in ANC or clinical neutropenia (ANC < 1.00 x109/L) during treatment with olanzapine is immediate discontinuation of the medication (Zyprexa™ package insert revised January 5, 2010). Aggressive treatment of drug-induced agranulocytosis is recommended, as the mortality rate is up to 5–10% in western countries (Flanagan et al., 2007). Treatment can include nursing and patient care precautions, broad-spectrum antibiotics, consultations with hematology and infectious disease specialists, and in some cases treatment with G-CSF, although the efficacy of this last intervention remains questionable (Duggal et al., 2005; Flanagan et al., 2007). Other case reports describe patients who were maintained on olanzapine but with lower doses, with the eventual resolution of abnormal WBC counts (Kodesh et al., 2001).
Screening for olanzapine-induced neutropenia should begin with measurement of WBC prior to treatment initiation to establish a baseline (Flanagan et al., 2007). Specific attention should be paid to the initial months of treatment, since most cases occur within this time frame (Stergiou et al., 2005). Given that this adverse effect has been thought to be dose-related, regular monitoring of CBC may be warranted when treating patients with higher doses (Duggal et al., 2004; Tolosa-Vilella et al., 2002). As fever may be the only sign of infection in a neutropenic patient, an aggressive investigation is warranted for elevated temperature (Flanagan et al., 2007).
Current guidelines regarding screening for olanzapine-induced neutropenia in adolescents, a population which the FDA (
Consideration of the following for screening for olanzapine-induced neutropenia and agranulocytosis is suggested: 1) prior to treatment initiation, screening for risk factors for olanzapine-induced neutropenia including personal history of leukopenia and prior drug-induced neutropenia, as well as family history of antipsychotic drug-induced neutropenia; 2) prior to treatment initiation, establishing a baseline CBC in all patients determined to be at risk for olanzapine-induced neutropenia; 3) frequent monitoring of CBC in all patients at risk for olanzapine-induced neutropenia, especially in patients undergoing rapid titration or on higher doses of this drug. In high-risk patients, monitoring of WBC/ANC at least once per month for the initial 3 months of treatment and as often as the schedule suggested to monitor for clozapine-induced agranulocytosis—weekly WBC/ANC for first six months of treatment (see Clozaril™ package insert revised January 2010); 4) consideration of evaluation of WBC/ANC in any patient determined to be at risk for olanzapine-induced neutropenia who presents with fever or other signs of infection.
In summary, olanzapine-induced agranulocytosis is a rare complication that has largely been unreported in the adolescent population. This case of a 16-year-old adolescent with psychosis who experienced olanzapine-induced agranulocytosis illustrates the importance of considering this potential adverse effect in any febrile patient recently started on olanzapine.
Disclosures
Neither Dr. Freedman nor Dr. Ryan reports any financial or pharmaceutical relationships to disclose. Dr. Coffey has received research support from Boehringer Ingelheim, Bristol Myers Squibb, Lilly Pharmaceutical, NIMH, NINDS, Otsuka, Shire, and the Tourette Syndrome Association.
Footnotes
Acknowledgments
The authors would like to thank Gary Gosselin MD and Enrico Mezzacappa MD of Children's Hospital Boston, Boston MA; Michael Mufson MD of Brigham and Women's Hospital, Boston MA; Bonnie Frawley BCPS of Brigham and Women's Hospital Pharmacy Services, Boston MA; and Meaghan Muir MLIS of Brigham and Women's Hospital Medical Library, Boston MA. We would like to acknowledge and thank Amanda Zwilling BA and Stephanie Samar for their assistance in review and preparation of the manuscript.