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Complicated Delirium in a Cancer Patient Successfully Treated with Olanzapine

      Abstract

      Delirium is common among cancer patients, especially those with advanced disease. Typical treatment involves addressing the underlying cause if possible; eliminating nonessential and/or other drugs that can worsen confusion, manipulating the environment; and administering antipsychotic drugs to control symptoms and agitated behavior, and attempt to clear the patient’s sensorium. The newer atypical antipsychotics may have potential in the treatment of delirium and also have the added benefit of causing less akithisia and other extrapyramidal side effects. This is illustrated by the case of a 59-year-old woman with leukemia and pain of unclear etiology who developed a delirium and a moderate to severe extrapyramidal syndrome (EPS) in the setting of escalation of her pain medications and concomitant escalation of prochlorperazine. The patient presented with confusion and moderate to severe cogwheeling rigidity, masked facies, bradykinesia, and tremor. Additionally, the patient had a relatively recent history of subdural hematoma and one seizure. Conservative management including eliminating multiple nonessential medications (including the prochlorperazine); changing her opioid analgesic; providing a 24-hour companion; and administering low doses of haloperidol (0.5 mg–2.0 mg) were not effective in treating the patient’s delirium. The patient’s EPS was dramatically worse following haloperidol doses. After approximately 1 week without improvement, the patient was started on olanzapine 5 mg daily with initial improvement but with residual confusion in the evenings and overnight. The dose was titrated up to 10 mg nightly with 2.5 mg as needed during the day. After 3 days on this regimen, the patient’s mental status exam was normal and she was discharged home. We discuss the potential utility of this atypical antipsychotic in the palliative care setting.

      Keywords

      Introduction

      The prevalence of delirium in cancer patients is estimated to be between 20%
      • Breitbart W
      Psychiatric complications of cancer.
      in ambulatory patients to as high as 85% in patients in the last weeks of life.
      • Massie M.J
      • Holland J.C
      • Glass E
      Delirium in terminally ill cancer patients.
      As patients live longer with cancer, more patients present with central nervous system disease and other complications that render them prone to developing organic mental states and delirium.
      • Breitbart W
      • Passik S
      Psychiatric aspects of palliative care.
      Typical treatment involves treatment of the underlying cause (as possible given the clinical context in which delirium is encountered); eliminating nonessential and/or other drugs that can worsen confusion; environmental manipulations; and the use of antipsychotic drugs for the control of psychotomimetic symptoms and agitated behavior, and an attempt to clear the patient’s sensorium.
      • Passik S
      • Massie M.J
      Psychiatric and psychosocial issues.
      Benzodiazepines are often added to the treatment regimen if sedation is needed for the control of severe agitation or if the delirium is related to withdrawal from benzodiazepines or alcohol.
      The newer, atypical antipsychotics are a growing class of agents that have potential utility in the management of delirium. These drugs have the benefit of lower rates of akathisia and extrapyramidal side effects. The first entry in this class, clozapine (Clozaril®) has been available for some time, but concerns related to the need to monitor blood counts and the possibility of agranulocytosis have limited its use in cancer patients. More recently, risperidone (Risperdol®) and olanzapine (Zyprexa®) have become available. These agents offer the same potential utility in the management of delirium in cancer patients with less concern over their effects on bone marrow.
      Olanzapine is an atypical antipsychotic agent of the thienobenzodiazepine class. It has an affinity for multiple neurotransmitter receptors, including dopaminergic (D1, D2, D3, D4), serotonergic (5-HT2A, 5-HT2C, 5-HT6, and to a lesser extent 5-HT3), adrenergic (alpha1), histaminergic (H1), and muscarinic (m1, m2, m3, m4) receptors.
      • Seeman P
      • Van Tol H
      Dopamine receptor pharmacology.
      • Bymaster F
      • Calligaro D
      • Falcone J
      • et al.
      Radioreceptor binding profile of the atypical antipsychotic olanzapine.
      • Schotte A
      • Janssen P
      • Gommeren W
      • et al.
      Risperidone compared with new and reference antipsychotic drugs in vitro and in vivo receptor binding.
      • Gobert A
      • Rivet J.-M
      • Audinot V
      • et al.
      Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist (+) -S 14297 II. Both D2 and “sient” D3 autoreceptors control synthesis and release in mesolimbic, mesocortical, and nigrostriatal pathways.
      • Meltzer H
      • Matsubara S
      • Lee J.-C
      Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin 2 pK, values.
      • Van Tol H
      • Bunzow J
      • Guan H
      • et al.
      Cloning of the gene for a human dopamine D4 receptor with a high affinity for the antipsychotic clozapine.
      • Roth B
      • Tandra S
      • Burgess L
      • et al.
      D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs.
      • Roth B
      • Craigo S
      • Choudhary M
      • et al.
      Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.
      While olanzapine is most chemically similar to clozapine, there are some significant differences in the two drugs. Olanzapine is much less likely to decrease white blood cell counts. The most common side effects reported with olanzapine include orthostatic hypotension, dry mouth, drowsiness, restlessness, and peripheral edema. In clinical trials in schizophrenics, rates of akithisia and extrapyramidal side effects were significantly lower than those seen with haloperiodol.
      • Beasley C
      • Sanger T
      • Satterlee W
      • et al.
      Olanzapine versus placebo results of a double-blind, fixed-dose olanzapine trial.
      • Beasley C
      • Tollefson G
      • Tran P
      • et al.
      Olanzapine versus placebo and haloperidol acute phase results of the North American double-blind olanzapine trial.
      We present a case of a complicated delirium in which olanzapine was highly effective after treatment with low-dose haloperidol failed.

      Case Report

      A 59-year-old female was successfully treated in 1982 with 6 cycles of CHOP (cytoxan, adriamycin, vincristine, prednisone) chemotherapy for non-Hodgkin’s lymphoma. Although she responded well in terms of her malignancy, she complained of various problems during chemotherapy, all of which were poorly characterized: weakness, nausea, nervousness, and sleeplessness. She relapsed in 1990 with axillary and retroperitoneal nodes and subsequently achieved a second remission with DHAP (high dose ara-c, cisplatin, and decadron) chemotherapy. She tolerated this rather poorly, again with an array of nonspecific complaints.
      After a period of relative health, the patient developed fever, sweats, and pancytopenia, and examination of the bone marrow demonstrated acute lymphocytic leukemia. She was treated with induction chemotherapy (daunorubicin, vincristine, and prednisone) and again had considerable problems. She required high doses of hydromorphone for pain that was never well characterized and was described as a diffuse bone pain. Despite the fact she went into remission, her bone pain continued.
      The patient had a Hickman catheter placed and developed thromboses in the brachiocephalic veins. The catheter was pulled, and she was placed on heparin. While anticoagulated, she fell out of bed and suffered a subdural hematoma. She underwent emergency surgery with evacuation of the hematoma. She had a witnessed seizure and was started on carbamazepine.
      In addition to the chronic diffuse pain of unclear etiology, which was subsequently treated with fentanyl, her history was noteworthy for depression and anxiety. She received amitriptyline, sertraline, and lorazepam for these symptoms. She was assisted by her family members at home, including her two grown daughters. Her daughters were very attentive to her symptom management and also tended to be highly reactive to the patient’s complaints, often requesting and obtaining additional medications for these problems. In addition, they would commonly increase the medicines on their own at home.
      Approximately 1 week prior to admission, she was seen as an outpatient and complained of increasing pain again of diffuse nature. Her physical and neurologic exams were unremarkable at that time. A bone marrow aspirate indicated her leukemia was stable, with 5% blasts noted in the marrow. She had been receiving transdermal fentanyl 50 μg/hr with frequent (every 2 hours) oxycodone “rescue” doses. Her pain medication was doubled during the clinic visit. Without checking with the medical team, the family added another 50 μg/hr patch 12 hours later, raising her total dose to 150 μg/hr. The patient had worsening nausea with this dose escalation, and the family increased her prochlorperazine to 10 mg every 4 to 6 hours.
      The patient was brought to the hospital emergency room the next morning with agitation, incoherent speech, hallucinations, and disorientation. She was admitted, and a psychiatric consultation was called. The mental status changes were noted and the patient was found to have moderate to severe cogwheeling rigidity, masked fasces, bradykinesia, and tremor. She did not have a fever on admission, but she was still on a prednisone taper from her previous chemotherapy. The team believed that this was the result of rapid escalation of pain medicine, and that the extrapyramidal syndrome (EPS) was due to increased use of prochlorperazine (possibly in combination with the sertraline). There was some concern that the patient, in addition to being highly sensitive to neuroleptics, might have been suffering neuroleptic malignant syndrome (NMS) or some variant of it. However, serum creatine phosphokinase level was only slightly elevated.
      Admission medicines include amitriptyline, sertraline, lorazepam, fentanyl, oxycodone, acetaminophen, carbamazepine, prochlorperazine, and a low dose of prednisone (5 mg per day). She also had been taking hydromorphone that she had been using on an “as needed” basis.
      Laboratory evaluation included a normal complete blood count, normal electrolytes, and slightly increased liver function tests. The thyroid stimulating hormone was low and thyroxine was started with an IV dose. A computerized tomogram of the brain showed no new structural lesions; there was a minimal amount of residual subdural blood identified in the left temporal parietal region adjacent to the bone flap. There was no significant mass effect. An EEG demonstrated slow waves consistent with a metabolic encephalopathy. No seizure activity was seen. The patient’s serum level of carbamazepine was subtherapeutic.

      Hospital Course

      Given the patient’s fragile state and the complex presenting problems, a relatively conservative management plan regarding the use of neuroleptics was initiated. The patient was begun on very low doses of haloperidol 0.5 mg IV twice daily, with as needed doses of haloperidol 2 mg IV and lorezapam 1.0 mg IV reserved for episodes of severe agitation. Several medications were discontinued, including amitriptyline, sertraline, and carbamezapine. Lorezapam was tapered and then switched to an as needed schedule. The fentanyl, oxycodone, and acetaminophen were discontinued and the patient was begun on an infusion of hydromorphone. Because there was some concern that the patient’s pain flare might have been precipitated by a too rapid taper of her steroids, the dose was initially raised and then slowly tapered. Thyroxine was continued for hypothyroidism. The patient was also given a 24-hour companion who helped to reorient her; restraint was required on occasion.
      After several days, the patient was less agitated but nonetheless very confused and essentially nonresponsive to interview. Her presentation was marked by continued but not worsening EPS and long periods of hypoactivity punctuated occasionally by agitation, especially at night. For these episodes, she periodically required the as needed doses of haloperidol and lorezapam; these would calm her but her mental status was unimproved. Importantly, her EPS was dramatically worse following these doses and the confusion may have been worsened slightly as well. This slight worsening of the patient’s mental state was difficult to interpret. The team was uncertain as to whether it was the effect of underdosing of the haloperidol (i.e., less than optimally treated delirium) or possibly the result of haloperidol worsening her mental status (i.e., a problem that might be related to NMS). The team grew uncomfortable with the lack of progress after several days and additionally was concerned about NMS enough to be uneasy with being more aggressive with the doses of haloperidol. A neurologic consultation was requested. A lumbar puncture was normal, as was magnetic resonance imaging of the head. When questioned about pain, the patient stated she was comfortable (though her self-report was of questionable accuracy).
      When the patient’s agitation at night worsened, coupled with a now nearly completely reversed sleep–wake cycle, the suggestion was made to discontinue the haloperidol/lorezapam and to substitute olanzapine 5 mg daily. Initially, the medication was ordered for mid-day. Within 24 hours of this starting dose, the patient was dramatically improved during the day but some “sundowning” was still noted in the early evening. The dose was then increased to 10 mg daily and moved to the early evening with 2.5 mg doses as needed during the day. She began to sleep during the night and her mental status returned to normal over approximately 72 hours, with no reemergence of EPS. She was discharged home.

      Discussion

      Delirium is a common problem in the palliative care setting. The presentation is often complicated and it is generally multifactorial in nature. Patients are often prescribed multiple medications, and additionally can be confused from a variety of other factors (sepsis, metabolic changes, central nervous system effects of disease and treatments, malnutrition and dehydration, and paraneoplastic phenomena). A very large clinical experience suggests the efficacy of typical management, including the use of haloperidol.
      • Breitbart W
      • Passik S
      Psychiatric aspects of palliative care.
      However, extremely few comparison studies have been carried out to date, and there is little known about the efficacy of low versus high potency drugs or the efficacy of neuroleptics versus benzodiazepines. Not surprisingly, given how recently the atypical antipsychotics have been introduced, they have not been studied. The sole comparison study in the literature is in delirium related to acquired immunodeficiency syndrome (AIDS), which demonstrated the efficacy of both haloperidol and chlorpromazine, and their superiority to lorezapam alone.
      • Breitbart W
      • Morotta R
      • Platt M
      • et al.
      Double blind trial of haloperidol, chlorpromazine, and lorezapam in the treatment of delirium in hospitalized AIDS patients.
      Such studies are needed to examine the safety and efficacy of the atypical antipsychotics in cancer patients and to possibly specify situations in which their use is clinically indicated and can justify the increased expense associated with using them.
      This case was complicated by the sensitivity the patient to the parkinsonian side effects of neuroleptics, the history of head trauma and seizures, and the multiple medications prescribed to her for symptom control. Her sensitivity to neuroleptics and the profound EPS she developed from a relatively low potency drug (prochlorperazine) made the treatment of her delirium difficult. Given that the team was never entirely sure of the cause of her delirium, it is difficult to know for certain what led to her improvement. While temporally, the escalation in pain medications seemed to be a precipitant, simple changes to her pain regimen did not lead to improvement in a typical time frame. Additionally, multiple changes were made in her management, some of which might have had their impact around the time that the olanzapine was added. Her pain medications were changed, and it might have taken longer than usual for the fentanyl to be cleared and eliminated given her debilitated state. Hypothyroidism was diagnosed and the thyroxine may have begun to have some impact on mental status at this time as well. Multiple other medications were stopped or tapered (amitriptyline, sertraline, lorezapam, steroids, carbamezapine), the effects of which might have become clinically evident at this juncture. Nevertheless, the initiation of olanzapine corresponded temporally to the patient’s major improvement in behavior and the clearing of her sensorium. Olanzapine therapy was well tolerated.
      Olanzapine may be a useful agent for the oncology population. Conceivably, its activity at multiple types of receptors may translate into utility in a number of psychiatric and other syndromes (including organic anxiety syndromes, insomnia induced by medications, and perhaps as an adjuvant analgesic). The weight gain associated with olanzapine in physically healthy schizophrenics might have positive implications for cancer patients as well. This case suggests its potential utility in the treatment of delirium and further suggests that it can be given to patients with advanced disease and be tolerated well. The role of atypical antipsychotics in the treatment of delirium in the medically compromised patient needs to be further pursued in formal clinical trials.

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