Managing schizophrenia in a patient with cancer: A fine balance
Ms. B, age 60, has schizophrenia, which has been stable on clozapine for 2 decades when she is diagnosed with cancer. How do you manage her psychiatric illness during chemotherapy?
When Ms. B is admitted to the psychiatric service, she is paranoid, disorganized, and guarded. She remains in her room for most of the day and either refuses to talk to providers or curses at them. She often is seen wearing soiled clothing with her hair mussed. She denies having rectal carcinoma, although she expressed understanding of her medical condition <2 months earlier.
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The authors’ observations
Clozapine is considered the most efficacious agent for treatment-resistant schizophrenia.6 Although non-compliance is the most common reason for discontinuing clozapine, >20% of patients stop clozapine because of adverse effects.7 Clozapine often is a drug of last resort because of the need for frequent monitoring and significant side effects; therefore deciding on a next step when clozapine fails or cannot be continued because of other factors can pose a challenge.
Ms. B’s treatment team gave serious consideration to restarting clozapine. However, because it was likely that Ms. B would undergo another round of chemotherapy and possibly radiation, the risk of neutropenia recurring was considered too high. Lithium has been used successfully to manage neutropenia in patients taking clozapine and, for some, adding lithium could help boost white cell count and allow a successful rechallenge with clozapine.3,8 However, because of Ms. B’s medical comorbidities, including cancer and chronic kidney disease, adding lithium was not thought to be clinically prudent at that time and the treatment team considered other options.
Olanzapine. Although research is limited, studies suggest olanzapine is the most commonly prescribed medication when a patient has to discontinue clozapine,7 with comparable response rates in those with refractory schizophrenia.9 Therefore, Ms. B was initially maintained on olanzapine, and the dosage increased to 30 mg over the course of 16 days in the hospital. However, she did not respond to the medication, remaining disorganized and paranoid without any notable improvement in her symptoms therefore other treatment options were explored.
Loxapine. Previous limited case reports have shown loxapine to be effective in treating individuals with refractory schizophrenia, either alone or in combination with other antipsychotics.10,11 FDA-approved in 1975, loxapine was among the last of the typical antipsychotics brought to the U.S. market before the introduction of clozapine, the first atypical.12 Loxapine is a dibenzoxazepine that has a molecular structure similar to clozapine.13 Unlike clozapine, however, loxapine is not known to cause agranulocytosis.14 Research suggests that although clozapine is oxidized to metabolites that are cytotoxic, loxapine is not, potentially accounting for their different effects on neutrophils.15
The efficacy of loxapine has shown to be similar to other typical and atypical antipsychotics, with approximately 70% of patients showing improvement.14 However, loxapine may be overlooked as an option, possibly because it was not included in the CATIE trial and was the last typical antipsychotic to be approved before atypicals were introduced.12 First available in oral and IM formulations, there has been increased interest in loxapine recently because of the approval of an inhaled formulation in 2012.16
Although classified as a typical antipsychotic, studies have suggested that loxapine acts as an atypical at low dosages.17,18 Previous work suggests, however, that the side effect profile of loxapine is similar to typical antipsychotics.14 At dosages <50 mg, it results in fewer cases of extrapyramidal side effects than expected with a typical antipsychotic.18
Loxapine’s binding profile seems to exist along this spectrum of typical to atypical. Tissue-based binding studies have shown a higher 5-HT2 affinity relative to D2, consistent with atypical antipsychotics.19 Positron emission tomography studies in humans show 5-HT2 saturation of loxapine to be close to equal to D2 binding in loxapine, thus a slightly lower ratio of 5-HT2 to D2 relative to atypicals, but more than that seen with typical antipsychotics.20 These differences between in vitro and in vivo studies may be secondary to the binding of loxapine’s active metabolites, particularly 7- and 8-hydroxyloxapine, which have more dopaminergic activity. In addition to increased 5-HT2A binding compared with typical antipsychotics, loxapine also has a high affinity for the D4 receptors, as well as interacting with other serotonin receptors 5-HT3, 5-HT6, and 5-HT7. Of note this is a similar pattern of binding affinity as seen in clozapine.19
